|
2 |
|
|
|
5 |
|
|
|
6 |
|
|
|
6 |
|
|
|
6 |
|
|
|
6 |
|
|
A. |
[Reserved.] |
6 |
|
|
|
B. |
Capitalization and Indebtedness |
6 |
|
|
|
C. |
Reasons for the Offer and Use of Proceeds |
6 |
|
|
|
D. |
Risk Factors |
6 |
|
|
|
|
34 |
|
|
A. |
History and Development of the Company |
34 |
|
|
|
B. |
Business Overview |
35 |
|
|
|
C. |
Organizational Structure |
|
|
|
|
D. |
Property, Plants and Equipment |
|
|
|
|
|
83 |
|
|
|
83 |
|
|
A. |
Operating Results |
84 |
|
|
|
B. |
Liquidity and Capital Resources |
91 |
|
|
|
C. |
Research and Development, Patents and Licenses, Etc. |
91 |
|
|
|
D. |
Trend Information |
91 |
|
|
|
E. |
Critical Accounting Estimates |
91 |
|
92 |
|
|
A. |
Directors and Senior Management |
92 |
|
|
|
B. |
Compensation |
94 |
|
|
|
C. |
Board Practices |
99 |
|
|
|
D. |
Employees |
109 |
|
|
|
E. |
Share Ownership |
109 |
|
|
|
F. |
Disclosure of a Registrant’s Action to Recover Erroneously Awarded Compensation
|
109 |
|
|
|
|
109 |
|
|
A. |
Major Shareholders |
109 |
|
|
|
B. |
Related Party Transactions |
112 |
|
|
|
C. |
Interests of Experts and Counsel |
112 |
|
|
|
|
112 |
|
|
A. |
Consolidated Statements and Other Financial Information |
112 |
|
|
|
B. |
Significant Changes |
113 |
|
|
|
|
113 |
|
|
A. |
Offer and Listing Details |
113 |
|
|
|
B. |
Plan of Distribution |
113 |
|
|
|
C. |
Markets |
113 |
|
|
|
D. |
Selling Shareholders |
113 |
|
|
|
E. |
Dilution |
113 |
|
|
|
F. |
Expenses of the Issue |
113 |
|
|
|
|
114 |
|
|
A. |
Share Capital |
114 |
|
|
|
B. |
Memorandum and Articles of Association |
114 |
|
|
|
C. |
Material Contracts |
114 |
|
|
|
D. |
Exchange Controls |
115 |
|
|
|
E. |
Taxation |
115 |
|
|
|
F. |
Dividends and Paying Agents |
124 |
|
|
|
G. |
Statement by Experts |
124 |
|
|
|
H. |
Documents on Display |
124 |
|
|
|
I. |
Subsidiary Information |
125 |
|
|
|
J. |
Annual Report to Security Holders |
125 |
|
125 |
|
|
|
126 |
|
|
|
133 |
|
|
|
133 |
|
|
|
134 |
|
|
|
134 |
|
|
|
135 |
|
|
|
135 |
|
|
|
135 |
|
|
|
135 |
|
|
|
136 |
|
|
|
136 |
|
|
|
136 |
|
|
|
136 |
|
|
|
137 |
|
|
|
137 |
|
|
|
138 |
|
|
|
138 |
|
|
|
139 |
|
|
|
139 |
|
|
|
139 |
|
|
|
139 |
|
|
|
141 |
|
|
INDEX |
F-1 |
INTRODUCTION
In this
Annual Report on Form 20-F (the “Annual Report”), unless context otherwise requires:
• |
references to “Chemomab Therapeutics Ltd.”, “Chemomab,” the
“Company,” “us,” “we” and “our” refer to Chemomab Therapeutics Ltd., an Israeli company
and its consolidated subsidiaries; however, with respect to the presentation of financial results for historical periods that preceded
the Merger (as defined below), these terms refer to the financial results of the Company’s wholly owned subsidiary, Chemomab Ltd.,
which was the accounting acquirer in the Merger; |
• |
references to “ordinary shares,” “our shares” and similar
expressions refer to the Company’s ordinary shares, no nominal (par) value; |
• |
references to “ADS” refer to the American Depositary Shares listed on
the Nasdaq Capital Market (“Nasdaq”) under the symbol “CMMB,” each representing twenty (20) ordinary shares;
|
• |
references to “dollars,” “U.S. dollars” and “$”
are to United States Dollars; |
• |
references to “NIS” are to New Israeli Shekels; |
• |
references to the “Companies Law” are to Israel’s Companies Law,
5759-1999, as amended; |
• |
references to the “SEC” are to the U.S. Securities and Exchange Commission;
and |
• |
references to the “Merger” refer to the merger involving Anchiano Therapeutics
Ltd., or Anchiano, and Chemomab Ltd., whereby a wholly owned subsidiary of Anchiano merged with and into Chemomab Ltd., with Chemomab
Ltd. surviving as a wholly owned subsidiary of Anchiano. Upon consummation of the Merger on March 16, 2021, Anchiano changed its name
to “Chemomab Therapeutics Ltd.” and the business conducted by Chemomab Ltd. became primarily the business conducted by the
Company. |
This Annual Report contains
estimates, projections and other information concerning our industry and our business, as well as data regarding market research, estimates
and forecasts prepared by our management. Information that is based on estimates, forecasts, projections, market research or similar methodologies
is inherently subject to uncertainties, and actual events or circumstances may differ materially from events and circumstances that are
assumed in this information. The industry in which we operate is subject to a high degree of uncertainty and risk due to a variety of
factors, including those discussed under the headings “Special Note Regarding Forward-Looking Statements” and Item 3.D. “Risk
Factors” in this Annual Report.
CAUTIONARY
STATEMENT REGARDING FORWARD-LOOKING STATEMENTS AND A
SUMMARY OF RISK FACTORS
This Annual Report contains
forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. We intend such forward-looking
statements to be covered by the safe harbor provisions for forward-looking statements as contained in Section 27A of the Securities Act
of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”). All statements
contained in this Annual Report other than statements of historical fact, including, without limitation, statements regarding our future
operating results and financial position, including our revenue and operating expenses profitability; our business strategies and plans;
our expectations regarding the development of our industry and the competitive environment in which we operate; our expectations regarding
partnerships and collaborations; our objectives for future operations; our ability to raise additional capital to fund our operations;
and the sufficiency of our cash, cash equivalents and short-term investments, are forward-looking statements. The words “may,”
“might,” “will,” “could,” “would,” “should,” “expect,” “plan,”
“anticipate,” “intend,” “target,” “seek,” “believe,” “estimate,”
“predict,” “potential,” “continue,” “contemplate,” “possible,” “forecasts,”
“aims” or the negative of these terms and similar expressions are intended to identify forward-looking statements, though
not all forward-looking statements use these words or expressions. These forward-looking statements are contained principally in the sections
titled Item 3.D. “Key Information-Risk Factors,” Item 4. “Information on the Company,” and Item 5. “Operating
and Financial Review and Prospects.” These statements are neither promises nor guarantees, but involve known and unknown risks,
uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from
any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to,
the following:
•
|
we have incurred significant losses since inception and anticipate that we will continue
to incur increasing levels of operating losses over the next several years and for the foreseeable future. We are unable to predict the
extent of any future losses or when we will become profitable, if at all. Even if we become profitable, we may not be able to sustain
or increase our profitability on a quarterly or annual basis; |
|
|
• |
we have a limited operating history and funding, which may make it difficult to evaluate
our prospects and likelihood of success; |
|
|
• |
our business is highly dependent on the success of our lead product candidate, nebokitug,
and any other product candidates that we advance into clinical studies. All of our programs will require significant additional clinical
development; |
|
|
•
|
our central objective is to design and develop targeted treatments for inflammation
and fibrosis with an initial focus on the antagonism of CCL24 signaling, which is known to regulate fibrotic and inflammatory processes.
While several studies are currently underway, our approach in the area of fibrotic diseases is novel and unproven and may not result in
marketable products; |
|
|
• |
the successful completion of clinical studies is a prerequisite to submitting a marketing
application to the FDA and similar marketing applications to comparable foreign regulatory authorities, for each product candidate and,
consequently, the ultimate approval and commercial marketing of any product candidates. We may experience negative or inconclusive results,
which may result in us deciding, or regulators requiring us, to conduct additional clinical studies or trials or abandon some or all of
our product development programs, which could have a material adverse effect on our business; |
|
|
• |
we may encounter difficulties enrolling patients in our clinical studies, including
any public health emergencies and related clinical development activities could be delayed or otherwise adversely affected; |
|
|
• |
our ongoing and future clinical studies may reveal significant adverse events or immunogenicity-related
responses and may result in a safety profile that could delay or prevent regulatory approval or market acceptance of our product candidate;
|
|
|
• |
the regulatory approval processes of the FDA and comparable foreign authorities are
lengthy, time consuming and inherently unpredictable, and if we are ultimately unable to obtain regulatory approval for nebokitug or any
other product candidates, our business will be substantially harmed; |
• |
if we do not achieve our projected development and commercialization goals in the
timeframes we announce and expect, the commercialization of our product candidates may be delayed and our business will be harmed;
|
|
|
• |
we face substantial competition, which may result in others discovering, developing
or commercializing products before or more successfully than us; |
|
|
•
|
we have been granted Orphan Drug Designation for nebokitug in connection with three
indications and may seek Orphan Drug Designation for other indications or product candidates, and we may be unable to maintain the benefits
associated with Orphan Drug Designation, including the potential for market exclusivity, and may not receive Orphan Drug Designation for
other indications or for our other product candidates; |
|
|
•
|
we expect to experience significant growth in the number of our employees over time
and the scope of our operations, particularly in the areas of product candidate development, regulatory affairs and sales and marketing.
We will therefore need to expand our organization, and we may experience difficulties in managing this growth, which could disrupt our
operations; |
|
|
• |
if we are unable to protect our patents or other proprietary rights, or if we infringe
the patents or other proprietary rights of others, our competitiveness and business prospects may be materially damaged. In addition,
changes in patent laws or patent jurisprudence could diminish the value of patents in general, thereby impairing our ability to protect
our product candidates; |
|
|
• |
risks related to our operations in Israel could materially adversely impact our business,
financial condition and results of operations; |
|
|
•
|
our principal executive offices are located in Israel and US and certain of our product
candidates may be manufactured at third-party facilities located in Europe. In addition, our business strategy includes potentially expanding
internationally if any of our product candidates receives regulatory approval. A variety of risks associated with operating internationally
could materially adversely affect our business; |
|
|
• |
holders of ADSs are not treated as holders of our Ordinary Shares; |
• |
holders of ADSs may not have the same voting rights as the holders of our Ordinary
Shares and may not receive voting materials in time to be able to exercise their right to vote; |
|
|
• |
holders of ADSs may be subject to limitations on the transfer of their ADSs and the
withdrawal of the underlying Ordinary Shares; |
|
|
• |
we are entitled to amend the deposit agreement and to change the rights of ADS holders
under the terms of such agreement, or to terminate the deposit agreement, without the prior consent of the ADS holders; |
|
|
• |
ADSs holders may not be entitled to a jury trial with respect to claims arising under
the deposit agreement, which could result in less favorable outcomes to the plaintiff(s) in any such action; |
|
|
• |
obtaining and maintaining our patent protection depends on compliance with various
procedural, document submission, fee payment and other requirements imposed by governmental patent agencies, and our patent protection
could be reduced or eliminated for non-compliance with these requirements; |
|
|
• |
the regulatory approval processes of the FDA and comparable foreign authorities are
lengthy, time consuming and inherently unpredictable, and if we are ultimately unable to obtain regulatory approval for nebokitug or any
other product candidates, our business will be substantially harmed; |
|
|
• |
obtaining and maintaining regulatory approval of our product candidates in one jurisdiction
does not mean that we will be successful in obtaining regulatory approval of our product candidates in other jurisdictions; |
|
|
• |
even if we obtain regulatory approval for nebokitug or any product candidate, we will
still face extensive and ongoing regulatory requirements and obligations and any product candidates, if approved, may face future development
and regulatory difficulties; |
|
|
•
|
disruptions at the FDA and other government agencies caused by funding shortages or
global health concerns could hinder our ability to hire, retain or deploy key leadership and other personnel, or otherwise prevent new
or modified products from being developed, approved or commercialized in a timely manner or at all, which could negatively impact our
business; |
|
|
• |
if we do not achieve our projected development and commercialization goals in the
timeframes we announce and expect, the commercialization of our product candidates may be delayed and our business will be harmed;
|
|
|
• |
we face substantial competition, which may result in others discovering, developing
or commercializing products before or more successfully than us; |
|
|
• |
even if nebokitug or any other product candidate we develop receives marketing approval,
it may fail to achieve market acceptance by physicians, patients, third-party payors or others in the medical community necessary for
commercial success; |
|
|
• |
we rely completely on third-party suppliers to manufacture our clinical drug supplies
for our product candidates, and we intend to rely on third parties to produce preclinical, clinical, and commercial supplies of any future
product candidates; |
|
|
• |
if we are unable to establish sales, marketing and distribution capabilities either
on our own or in collaboration with third parties, we may not be successful in commercializing nebokitug, if approved; |
|
|
• |
a variety of risks associated with operating internationally could materially adversely
affect our business; |
|
|
• |
conditions in Israel, including the ongoing hostilities by Hamas and other terrorist
organizations from the Gaza Strip and Israel’s war against them, may affect our operations; |
|
|
• |
because a certain portion of our expenses are incurred in currencies other than the
U.S. Dollar, our results of operations may be harmed by currency fluctuations and inflation; |
• |
we received Israeli government grants for certain of their research and development
activities as detailed below. The terms of those grants require us to satisfy specified conditions in order to transfer outside of Israel
the manufacture of products based on know-how funded by the Israel Innovation Authority or to transfer outside of Israel the know-how
itself. If we fail to comply with the requirements of Israeli law in this regard, we may be required to pay penalties, and it may impair
our ability to sell our technology outside of Israel; |
|
|
• |
we will need to raise additional capital to fund our operations, which may be unavailable
to us on acceptable terms or at all, or may cause dilution or place significant restrictions on our ability to operate our business;
|
|
|
• |
the trading price of the ADSs has been highly volatile, and is expected to continue
to be volatile; |
|
|
• |
we have not paid dividends in the past and do not expect to pay dividends in the future,
and, as a result, any return on investment may be limited to the value of the ADSs; and |
|
|
• |
if we fail to continue to meet all applicable Nasdaq requirements, Nasdaq may delist
the ADSs, which could have an adverse impact on the liquidity and market price of the ADSs. |
You should not rely on forward-looking
statements as predictions of future events. We have based the forward-looking statements contained in this Annual Report primarily on
our current expectations and projections about future events and trends that we believe may affect our business, financial condition and
operating results. The outcome of the events described in these forward-looking statements is subject to risks, uncertainties and other
factors described in the section titled “Risk factors” and elsewhere in this Annual Report. Moreover, we operate in a very
competitive and rapidly changing environment. New risks and uncertainties emerge from time to time, and it is not possible for us to predict
all risks and uncertainties that could have an impact on the forward-looking statements contained in this Annual Report. The results,
events and circumstances reflected in the forward-looking statements may not be achieved or occur, and actual results, events or circumstances
could differ materially from those described in the forward-looking statements.
The forward-looking statements
made in this Annual Report relate only to events as of the date on which the statements are made. We undertake no obligation to update
any forward-looking statements made in this Annual Report to reflect events or circumstances after the date of this Annual Report or to
reflect new information or the occurrence of unanticipated events, except as required by law. We may not actually achieve the plans, intentions
or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements.
Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or
investments.
PRESENTATION
OF FINANCIAL INFORMATION
Our consolidated financial
statements have been prepared in accordance with generally accepted accounting principles in the United States, or U.S. GAAP. We present
our consolidated financial statements in U.S. dollars.
Our fiscal year ends on December
31 of each year.
Certain monetary amounts,
percentages and other figures included elsewhere in this Annual Report have been subject to rounding adjustments. Accordingly, figures
shown as totals in certain tables or charts may not be the arithmetic aggregation of the figures that precede them, and figures expressed
as percentages in the text may not total 100% or, as applicable, when aggregated may not be the arithmetic aggregation of the percentages
that precede them.
PART
I
Item 1. Identity
of Directors, Senior Management and Advisers
Item 2. Offer Statistics
and Expected Timetable
Item 3.
Key Information
B. |
Capitalization and Indebtedness
Not applicable. |
C. |
Reasons for the Offer and Use of Proceeds
Not applicable. |
|
|
D. |
Risk Factors |
You should carefully
consider the risks and uncertainties described below and the other information contained in this Annual Report before making an investment
decision. Additional risks and uncertainties not presently known to us or that we currently deem immaterial may also impair our business
operations. Our business, financial condition, results of operations, or strategic objectives could be materially and adversely affected
by any of these risks and uncertainties. The trading price and value of our ordinary shares could decline due to any of these risks and
uncertainties, and you may lose all or part of your investment. This Annual Report also contains forward- looking statements that involve
risks and uncertainties. Our actual results could differ materially from those anticipated in these forward-looking statements as a result
of certain factors, including the risks and uncertainties faced by us described below and elsewhere in this Annual Report.
Risks Relating to Our Business and
Industry
Our limited operating
history and funding may make it difficult to evaluate our prospects and likelihood of success.
We are a clinical-stage biopharmaceutical
company with a limited operating history. We were incorporated in 2011, have no products approved for commercial sale and have not
generated any revenue. Our operations to date have been limited to organizing and staffing the company, business planning, raising capital,
establishing our intellectual property portfolio and conducting research and development of our product candidates, technology related
to CCL24 and novel therapies for the treatment of inflammation and fibrosis. Our approach to the discovery and development of product
candidates is unproven, and we do not know whether we will be able to develop any products of commercial value. In addition, our lead
product candidate, nebokitug (CM-101), is in relatively early clinical development for the treatment of primary sclerosing cholangitis
(PSC) (as defined below) and systemic sclerosis (SSc) (as defined below). The clinical programs will require substantial additional development
and clinical research, both in time and resources, before we are in a position to apply for or receive regulatory approvals and begin
generating revenue in connection with the sale of such product candidates. We have not yet demonstrated the ability to successfully complete
a large-scale, pivotal clinical trial, obtain marketing approval, manufacture a commercial scale product, or arrange for a third party
to do so on our behalf, or conduct sales and marketing activities necessary for successful product commercialization. Consequently, predictions
about our future success or viability may not be as accurate as they could be if we had a longer operating history or a history of successfully
developing and commercializing pharmaceutical products.
Our business is highly
dependent on the success of our lead product candidate, nebokitug, and any other product candidates that we advance into clinical studies.
All of our programs will require significant additional clinical development.
We currently have no products that
are approved for commercial sale and may never be able to develop marketable products. We are relatively early in our development efforts
and have only one product candidate, nebokitug, in clinical development. Because nebokitug is our lead product candidate, if nebokitug
encounters safety or efficacy problems, development delays, regulatory issues or other problems, our development plans and business would
be significantly harmed. We have completed a Phase 1a single ascending dose (SAD) safety study in healthy volunteers, a Phase 1b multiple
ascending dose (MAD) study of nebokitug in metabolic-associated fatty liver disease, or MAFLD, a Phase 2a safety, Pk and liver fibrosis
biomarker study in metabolic dysfunction-associated steatohepatitis, or MASH patients, an open-label exploratory study in severe lung
injury in hospitalized COVID-19 patients and a Phase 2 trial in PSC patients.
We expect that a substantial portion
of our efforts and expenditures over the next few years will be devoted to nebokitug, which will require additional clinical development,
management of clinical and manufacturing activities, regulatory approval in multiple jurisdictions, obtaining manufacturing supply, building
of a commercial organization, substantial investment and significant marketing efforts before we can generate any revenues from any commercial
sales. We cannot be certain that we will be able to successfully complete any of these activities. In addition, if one or more of our
product candidates are approved, we may need to ensure access to sufficient commercial manufacturing capacity and conduct significant
marketing efforts in connection with any commercial launch. These efforts will require substantial investment, and we may not have the
financial resources to continue the development of our product candidates.
We
will need to raise substantial additional funds through public or private equity or debt transactions and/or complete one or more strategic
transactions or partnerships, to complete development of nebokitug or any other product candidates. If we are unable to raise such financing
or complete such a transaction, we may not be able to fund the clinical trials of our product candidates and potentially commercialize
those product candidates.
As a result of the expected development
timeline to potentially obtain FDA approval for nebokitug, the substantial additional costs associated with the development of our product
candidates, including the costs associated with clinical trials related thereto, and the substantial cost of commercializing nebokitug,
we will need to raise substantial additional funding through public or private equity or debt transactions or a strategic combination
or partnership. If we are delayed in obtaining funding or are unable to complete a strategic transaction, we may have to delay or discontinue
development activities on nebokitug and our other product candidates. Even if we are able to fund continued development of nebokitug
or any of our other product candidates is approved, we expect that we will need to raise substantial additional funding through public
or private equity or debt securities or complete a strategic transaction or partnership to successfully commercialize nebokitug or any
other product candidate.
We believe our cash and cash equivalents
and bank deposits as of December 31, 2024, will be sufficient to fund our operations through the first quarter of 2026. Sales of
our ADSs dilute the ownership interest of our shareholders and may cause the price per ADS to decrease. Changing circumstances may cause
us to consume capital significantly faster or slower than we currently anticipate. We have based these estimates on assumptions that may
prove to be wrong, and we could exhaust our available financial resources sooner than currently anticipated.
Our liquidity, and ability to raise additional capital
or complete any strategic transaction, depends on a number of factors, including, but not limited to, the following:
• |
the costs and timing for potential additional clinical trials in order to gain possible
regulatory approval for nebokitug and our other product candidates; |
|
|
• |
the market price of our ADSs and the availability and cost of additional equity capital
from existing and potential new investors; |
|
|
• |
our ability to retain the listing of our ADSs on the Nasdaq Capital Market;
|
|
|
• |
general economic and industry conditions affecting the availability and cost of capital,
including as a result of deteriorating market conditions due to investor concerns regarding inflation, the imposition of tariffs and other
measures affecting trade and the economy in the U.S. and continued hostilities between Israel and Hamas, and Russia and Ukraine;
|
|
|
• |
our ability to control costs associated with our operations; |
|
|
• |
the costs of filing, prosecuting, defending and enforcing any patent claims and other
intellectual property rights; and |
|
|
• |
the terms and conditions of our existing collaborative and licensing agreements.
|
The sale of additional equity or
convertible debt securities would likely result in substantial dilution to our shareholders. If we raise additional funds through the
incurrence of indebtedness, the obligations related to such indebtedness would be senior to rights of holders of our capital stock and
could contain covenants that would restrict our operations. We also cannot predict what consideration might be available, if any, to us
or our shareholders, in connection with any strategic transaction. Should strategic alternatives or additional capital not be available
to us, or not be available on acceptable terms, we may be unable to realize value from our assets and discharge our liabilities in the
normal course of business which may, among other alternatives, cause us to further delay, substantially reduce or discontinue operational
activities to conserve our cash resources.
Our
approach in the area of fibrotic diseases is novel and unproven and may not result in marketable products.
Our central objective is to design
and develop targeted treatments for inflammation and fibrosis with an initial focus on the neutralization of CCL24 signaling, which is
shown to regulate fibrotic and inflammatory processes. While several studies are currently underway, this mechanism has not yet been proven
to successfully treat inflammation and fibrosis in patients. Targeting CCL24 to treat inflammation and fibrosis is a novel approach in
a rapidly developing field, and there can be no assurance that we can avoid unforeseen problems or delays in the development of our product
candidates, that such problems or delays will not result in unanticipated costs, or that any such development problems can or will be
solved. We have completed clinical studies of our lead product candidate, nebokitug, in relatively early trials in healthy volunteers,
MAFLD, MASH, PSC and COVID-19 lung injury patients. Therefore, we may ultimately discover that our approach does not possess properties
required for therapeutic effectiveness. As a result, we may elect to abandon the program or never succeed in developing a marketable product,
which would have a significant effect on the success and profitability of our business.
Clinical development
involves a lengthy, complex and expensive process, with an uncertain outcome.
Before obtaining the requisite
regulatory approvals from the FDA or other comparable foreign regulatory authorities for the sale of any of our product candidates, we
must support our application with clinical studies that prove that such product candidate is safe and effective in humans. Clinical testing
is expensive and can take many years to complete, and its outcome is inherently uncertain. In particular, the general approach for FDA
approval of a new drug requires positive data from two well-controlled Phase 3 clinical studies of the relevant drug in the relevant patient
population. Failure can occur at any time during the clinical study process. We may experience delays in initiating and completing any
clinical studies that we are conducting or intend to conduct, including as a result of public health emergencies, and we do not know whether
our ongoing or planned clinical studies will begin or progress on schedule, need to be redesigned, enroll patients on time or be completed
on schedule, or at all.
Phase 3 clinical studies typically
involve hundreds of patients, have significant costs and take years to complete. A product candidate can fail at any stage of testing,
even after observing promising signals of activity in earlier preclinical studies or clinical trials. The results of preclinical studies
and early clinical trials of our product candidates may not be predictive of the results of later-stage clinical studies. In addition,
initial or interim success in clinical studies may not be indicative of results obtained when such studies are completed. There is typically
an extremely high rate of attrition from the failure of product candidates proceeding through clinical studies. Product candidates in
later stages of clinical studies may fail to show the desired safety and efficacy profile despite having progressed through preclinical
studies and initial clinical trials. A number of companies in the biopharmaceutical industry have suffered significant setbacks in advanced
clinical studies due to lack of efficacy or unacceptable safety issues, notwithstanding promising results in earlier studies. Most product
candidates that commence clinical studies are never approved as products and there can be no assurance that any of our future clinical
studies will ultimately be successful or support further clinical development of nebokitug. Product candidates that appear promising in
the early phases of development may fail to reach the market for several reasons, including:
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the FDA or comparable foreign regulatory authorities disagreeing as to the design
or implementation of our clinical studies; |
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obtaining regulatory authorizations to commence a trial or consensus with regulatory
authorities on trial’s design; |
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reaching an agreement on acceptable terms with prospective clinical research organizations,
or CROs, and clinical trial sites, the terms of which can be subject to extensive negotiation and may vary significantly among different
CROs and trial sites; |
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obtaining IRB approval at each site, or Independent Ethics Committee, or IEC, approval
at sites outside the United States; |
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imposition of a clinical hold by regulatory authorities, including as a result of
unforeseen safety issues or side effects or failure of trial sites to adhere to regulatory requirements or follow trial protocols;
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clinical studies may show the product candidates to be less effective than expected
(e.g., a clinical study could fail to meet its primary endpoint(s)) or to have unacceptable side effects or toxicities; |
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failure to establish clinical endpoints that applicable regulatory authorities would
consider clinically meaningful; |
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the occurrence of serious adverse events in trials of the same class of agents conducted
by other companies; |
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adding a sufficient number of clinical study sites; |
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manufacturing sufficient quantities of product candidate with sufficient quality for
use in clinical studies; |
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having patients complete a trial or return for post-treatment follow-up; |
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recruiting suitable patients to participate in a trial in a timely manner and in sufficient
numbers; |
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a facility manufacturing our product candidates or any of their components being ordered
by the FDA or comparable foreign regulatory authorities to temporarily or permanently shut down due to violations of current good manufacturing
practice, or cGMP, regulations or other applicable requirements, or infections or cross-contaminations of product candidates in the manufacturing
process; |
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third-party clinical investigators losing the licenses or permits necessary to perform
our clinical studies, not performing our clinical studies on our anticipated schedule or consistent with the clinical study protocol,
GCP, or other regulatory requirements; |
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third-party contractors not performing data collection or analysis in a timely or
accurate manner; |
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manufacturing costs, formulation issues, pricing or reimbursement issues, or other
factors that make a product candidate uneconomical; or |
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the proprietary rights of others and their competing products and technologies that
may prevent our product candidates from being commercialized. |
In addition, differences
in trial design between early-stage clinical studies and later-stage clinical studies make it difficult to extrapolate the results of
earlier clinical studies to later clinical studies. Moreover, clinical data are often susceptible to varying interpretations and analyses,
and many companies that have believed their product candidates performed satisfactorily in clinical studies have nonetheless failed to
obtain marketing approval of their products.
In addition, the standards
used by the FDA and comparable foreign regulatory authorities when regulating us require judgment and can change, which makes it difficult
to predict with certainty how they will be applied. For more information, see “Risk Factors –
Risks Related to Our Regulatory Approvals.”
Successful completion of
clinical studies is a prerequisite to submitting a marketing application to the FDA and similar marketing applications to comparable foreign
regulatory authorities, for each product candidate and, consequently, the ultimate approval and commercial marketing of any product candidates.
We may experience negative or inconclusive results, which may result in us deciding, or us being required by regulators, to conduct additional
clinical studies or trials or abandon some or all of our product development programs, which could have a material adverse effect on our
business.
We may incur
additional costs or experience delays in completing the development and commercialization of nebokitug or any other product candidates.
We may experience delays in initiating
or completing clinical studies. We also may experience numerous unforeseen events during, or as a result of, any future clinical studies
that could delay or prevent our ability to receive marketing approval or commercialize nebokitug or any other product candidates, including:
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regulators, IRBs, or IECs may not authorize us or our investigators to commence a
clinical study or conduct a clinical study at a prospective trial site; |
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the FDA or other comparable regulatory authorities may disagree with our clinical
study design, including with respect to dosing levels administered in our planned clinical studies, which may delay or prevent us from
initiating our clinical studies with our originally intended trial design; |
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we may experience delays in reaching, or fail to reach, agreement on acceptable terms with prospective
trial sites and prospective CROs, which can be subject to extensive negotiation and may vary significantly among different CROs and trial
sites; |
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the number of subjects required for clinical studies of any product candidates may
be larger than we anticipate or subjects may drop out of these clinical studies or fail to return for post-treatment follow-up at a higher
rate than we anticipate; |
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our third-party contractors may fail to comply with regulatory requirements or meet
our contractual obligations to us in a timely manner, or at all, or may deviate from the clinical study protocol or drop out of the trial,
which may require that we add new clinical study sites or investigators; |
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due to the impact of emerging public health threats, we may experience delays and
interruptions to clinical studies, we may experience delays or interruptions to our manufacturing supply chain, or we could suffer delays
in reaching, or we may fail to reach, agreement on acceptable terms with third-party service providers on whom we rely; |
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additional delays and interruptions to our clinical studies could extend the duration
of the trials and increase the overall costs to finish the trials as our fixed costs are not substantially reduced during delays;
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we may elect to, or regulators, IRBs, Data Safety Monitoring Boards or ethics committees may require that
us or its investigators suspend or terminate clinical research or trials for various reasons, including noncompliance with regulatory
requirements or a finding that the participants are being exposed to unacceptable health risks; |
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we may not have the financial resources available to begin and complete the planned trials, or the cost
of clinical studies of any product candidates may be greater than we anticipate; and |
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the supply or quality of our product candidates or other materials necessary to conduct
clinical studies of our product candidates may be insufficient or inadequate to initiate or complete a given clinical study. |
Our product development costs will
increase if we experience additional delays in clinical testing or in obtaining marketing approvals. We do not know whether any of our
clinical studies will begin as planned, will need to be restructured or will be completed on schedule, or at all. If we do not achieve
our product development goals in the time frames we announce and expects, the approval and commercialization of our product candidates
may be delayed or prevented entirely. Significant clinical study delays also could shorten any periods during which we may have the exclusive
right to commercialize our product candidates and may allow our competitors to bring products to market before we do, potentially impairing
our ability to successfully commercialize our product candidates and harming our business and results of operations. Any delays in our
clinical development programs may harm our business, financial condition and results of operations significantly.
Our ongoing and
future clinical studies may reveal significant adverse events or immunogenicity related responses and may result in a safety profile that
could delay or prevent regulatory approval or market acceptance of our product candidate.
We completed our Phase 1a and Phase
1b and Phase 2 clinical studies of our product candidate, nebokitug, in healthy volunteers, MAFLD, MASH, PSC and COVID-19 lung injury
patients, and, with the exception of a number of reported minor adverse events (including mild headaches, changes in blood pressure and
mild-moderate increases in liver enzymes,) and one serious adverse event (a transient ischemic attack or seizure judged to be unrelated
to administration of nebokitug, nebokitug was observed to be generally well-tolerated across all doses in about 120 trial participants.
Some potential therapeutics developed in the biopharmaceutical industry that initially showed therapeutic promise in early-stage trials
have later been found to cause side effects that prevented their further development and ultimately commercialization. Even if side effects
do not preclude the product candidate from obtaining or maintaining marketing approval, undesirable side effects may inhibit market acceptance
of the approved product due to its tolerability versus other therapies.
Protein biopharmaceuticals, including
monoclonal antibodies, or mAbs, may be immunogenic and promote immune responses against themselves. In particular, anti-drug antibodies,
or ADAs, may be produced by patients following infusion of mAbs and may disturb the pharmacokinetics of mAbs, neutralize their therapeutic
activities or induce allergic or autoimmune symptoms. Clinical immunogenicity can range from mild, transient antibody responses with no
apparent clinical manifestations to loss of therapeutic efficacy and even life-threatening reactions. Several approved therapeutic antibodies
have been found to induce neutralizing antibodies, as illustrated by the approved anti-TNFa antibodies infliximab and adalimumab as well
as the approved anti-IL-17 mAb ixekizumab. Our product candidate, nebokitug, is a humanized antibody that, similar to other humanized
approved mAbs, was shown to include several non-germline sequences that may serve as a source for immunogenicity in therapeutic antibodies.
Clinical studies to date have not identified any anti-drug antibodies, or ADAs. Additional larger clinical studies will be needed to address
the risk of immunogenicity and, if discovered, our business will be materially and adversely affected.
Additionally, if unacceptable side
effects, including materialized risks of immunogenicity, do arise in the development of our product candidates, we, the FDA or the IRBs
at the institutions in which our studies are conducted, or the Data Safety Monitoring Board, if constituted for our clinical studies,
could recommend a suspension or termination of our clinical studies, or the FDA or comparable foreign regulatory authorities could order
us to cease further development of or deny approval of a product candidate for any or all targeted indications. In addition, drug-related
side effects could affect patient recruitment or the ability of enrolled patients to complete a trial or result in potential product liability
claims. In addition, these side effects may not be appropriately recognized or managed by the treating medical staff. We expect to have
to train medical personnel using our product candidates to understand the side effect profiles for our clinical studies and upon any commercialization
of any of our product candidates. Inadequate training in recognizing or managing the potential side effects of our product candidates
could result in patient injury or death. Any of these occurrences may harm our business, financial condition and prospects significantly.
Additionally, if one or more of our
product candidates receives marketing approval, and we or others later identify undesirable side effects caused by such products, a number
of potentially significant negative consequences could result, including:
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regulatory authorities may withdraw approvals of such product; |
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regulatory authorities may require additional warnings on the label, such as a “black
box” warning or contraindication; |
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additional restrictions may be imposed on the marketing of the particular product
or the manufacturing processes for the product or any component thereof; |
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we may be required to implement a Risk Evaluation and Mitigation Strategy, or REMS,
or create a medication guide outlining the risks of such side effects for distribution to patients; |
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we could be sued and held liable for harm caused to patients; |
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the product may become less competitive; and |
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our reputation may suffer. |
Any of these events could prevent
us from achieving or maintaining market acceptance of a product candidate, if approved, and could significantly harm our business, results
of operations and prospects.
Interim,
topline and preliminary data from our clinical trials that we announce or publish from time to time may change as more patient data become
available or as additional analyses are conducted and are subject to audit and verification procedures that could result in material changes
in the final data.
From time to time, we may publicly
disclose preliminary, interim or topline data from our clinical trials. The preliminary data is based on a preliminary analysis of then
available data, and the results and related findings and conclusions are subject to change following a more comprehensive review of the
data related to the particular study or trial. For example, we may report responses in certain patients that are unconfirmed at the time
and which do not ultimately result in confirmed responses to treatment after follow-up evaluations. We also make assumptions, estimations,
calculations and conclusions as part of our analyses of data, and we may not have received or had the opportunity to fully and carefully
evaluate all data. As a result, the topline results that we report may differ from future results of the same studies, or different conclusions
or considerations may qualify such results, once additional data have been received and fully evaluated. Topline data also remain subject
to audit and verification procedures that may result in the final data being materially different from the preliminary data we previously
published. As a result, topline data should be viewed with caution until the final data are available. In addition, we may report interim
analyses of only certain endpoints rather than all endpoints. Interim data from clinical trials that we may complete are subject to the
risk that one or more of the clinical outcomes may materially change as patient enrollment continues and more patient data become available.
Adverse changes between interim data and final data could significantly harm our business and prospects. Further, additional disclosure
of interim data by us or by our competitors in the future could result in volatility in the price of our common stock.
In addition, the information we choose
to publicly disclose regarding a particular clinical trial is typically selected from a more extensive amount of available information.
You or others may not agree with what we determine is the material or otherwise appropriate information to include in our disclosure,
and any information we determine not to disclose may ultimately be deemed significant with respect to future decisions, conclusions, views,
activities or otherwise regarding a particular product candidate or our business. If the preliminary or topline data that we report differ
from late, final or actual results, or if others, including regulatory authorities, disagree with the conclusions reached, our ability
to obtain approval for any product candidates that we may develop in the future may be harmed, which could harm our business, financial
condition, results of operations and prospects.
Changes
in methods of product candidate manufacturing or formulation may result in additional costs or delay.
As product candidates progress through
preclinical studies and clinical trials to regulatory approval and commercialization, it is common that various aspects of the development
program, such as manufacturing methods and formulation, are altered along the way in an effort to optimize yield and manufacturing batch
size, minimize costs and achieve consistent quality and results. Any material manufacturing changes made to any product candidate that
we may develop could perform differently and affect the results of planned clinical trials or other clinical trials conducted with the
altered materials. This could delay completion of clinical trials, require the conduct of bridging clinical trials or the repetition of
one or more clinical trials, increase clinical trial costs, delay approval of our product candidates and jeopardize our ability to commercialize
any product candidates that we may develop in the future, if approved, and generate revenue.
If
we encounter difficulties enrolling patients in our clinical studies, our clinical development activities could be delayed or otherwise
adversely affected.
We may experience difficulties in
patient enrollment in our clinical studies for a variety of reasons. The timely completion of clinical studies in accordance with our
protocols depends, among other things, on our ability to enroll a sufficient number of patients who remain in the trial until its conclusion.
The enrollment of patients depends on many factors, including:
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the patient eligibility and exclusion criteria defined in the protocol; |
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the need to receive study drug via an IV infusion; |
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the size of the patient population required for analysis of the trial’s primary
endpoints and the process for identifying patients; |
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the willingness or availability of patients to participate in our trials; |
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the proximity of patients to trial sites; |
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the design of the trial; |
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our ability to recruit clinical study investigators with the appropriate competencies
and experience; |
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clinicians’ and patients’ perceptions as to the potential advantages and
risks of the product candidate being studied with respect to other available therapies, including any new products that may be approved
for the indications we are investigating; |
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the availability of competing commercially available therapies and other competing
product candidates’ clinical studies; |
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our ability to obtain and maintain patient informed consents; and |
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the risk that patients enrolled in clinical studies will drop out of the trials before
completion. |
Further, timely enrollment in clinical
studies is reliant on clinical study sites which may be adversely affected by global health matters, including, among other things, pandemics
or armed conflicts.
The market opportunities for nebokitug, if approved,
may be smaller than we anticipate.
We expect to initially seek approval
of nebokitug for the treatment of PSC and SSc. Our projections of the number of PSC and SSc patients is based on our beliefs and estimates.
These estimates have been derived from a variety of sources, including scientific literature, patient foundations and publicly available
databases, and may prove to be incorrect. Further, new sources may reveal a change in the estimated number of patients, and the number
of patients may turn out to be lower than we expected. The potential addressable patient population for our current programs or future
product candidates may be limited. The ultimate market opportunity for our product candidates will depend on, among other things, the
final labeling for such product candidates as agreed with the FDA or comparable foreign regulatory authorities, acceptance by the medical
community and patient access, potential competition and drug pricing and reimbursement. Even if we obtain significant market share for
any product candidate, if approved, if the potential target populations are small, we may never achieve profitability without obtaining
marketing approval for additional indications.
Due
to our limited resources and access to capital, we must make decisions on the allocation of resources to certain programs and product
candidates; these decisions may prove to be wrong and may adversely affect our business.
We have limited financial and human
resources and intend to initially focus on research programs and product candidates for a limited set of indications. As a result, we
may forgo or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial
potential or a greater likelihood of success.
There can be no assurance that we
will ever be able to identify additional therapeutic opportunities for our product candidates or to develop suitable potential product
candidates through internal research programs, which could materially adversely affect our future growth and prospects. We may focus our
efforts and resources on potential product candidates or other potential programs that ultimately prove to be unsuccessful.
If product liability
lawsuits are brought against us, we may incur substantial financial or other liabilities and may be required to limit commercialization
of our product candidates.
We face an inherent risk of product
liability as a result of testing nebokitug, and will face an even greater risk if we commercialize any products. For example, we may be
sued if any of our product candidates cause or are perceived to cause injury or are found to be otherwise unsuitable during clinical studies,
manufacturing, marketing or sale. Any such product liability claims may include allegations of defects in manufacturing, defects in design,
a failure to warn of dangers inherent in the product, negligence, strict liability or a breach of warranties. Claims could also be asserted
under state consumer protection acts. If we cannot successfully defend itself against product liability claims, we may incur substantial
liabilities or be required to limit commercialization of our product candidates. Even successful defense would require significant financial
and management resources. Our inability to obtain sufficient product liability insurance at an acceptable cost to protect against potential
product liability claims could prevent or inhibit the commercialization of products we develop. We will need to obtain additional insurance
for clinical studies as we continue clinical development of nebokitug and as additional product candidates enter clinical studies.
However, we may be unable to obtain, or may obtain on unfavorable terms, clinical study insurance in amounts adequate to cover any liabilities
from any of our clinical studies. Our insurance policies may also have various exclusions, and we may be subject to a product liability
claim for which we have no coverage. We may have to pay any amount awarded by a court or negotiated in a settlement that exceeds our coverage
limitations or that are not covered by insurance, and we may not have, or be able to obtain, sufficient capital to pay such amounts. Even
if our agreements with any future corporate collaborators entitles us to indemnification against losses, such indemnification may not
be available or adequate should any claim arise.
We
have been granted Orphan Drug Designation for nebokitug in connection with three indications and may seek Orphan Drug Designation
for other indications or product candidates, and we may be unable to maintain the benefits associated with Orphan Drug Designation, including
the potential for market exclusivity, and may not receive Orphan Drug Designation for other indications or for our other product candidates.
Regulatory authorities in some jurisdictions,
including the United States and Europe, may designate drugs intended for relatively small patient populations as orphan drugs. Under the
Orphan Drug Act, the FDA may designate a drug as an orphan drug if it is a drug intended to treat a rare disease or condition, which is
generally defined as a patient population of fewer than 200,000 individuals in the United States, or a patient population greater than
200,000 in the United States where there is no reasonable expectation that the cost of developing the drug will be recovered from sales
in the United States. In the United States, Orphan Drug Designation has entitled a party to financial incentives such as opportunities
for grant funding toward clinical study costs, tax advantages and user-fee waivers. In addition, if a product that has Orphan Drug Designation
subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug
exclusivity, which means that the FDA may not approve any other applications, including a full NDA to market the same product for the
same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan
drug exclusivity or where the manufacturer is unable to assure sufficient product quantity. However, Orphan Drug Designation neither shortens
the development time or regulatory review time of a drug nor gives the drug any advantage in the regulatory review or approval process.
In 2022, the Eleventh Circuit’s decision in Catalyst Pharmaceuticals, Inc. v. FDA challenges FDA’s long-standing interpretation
and provides that the orphan drug exclusivity should be applied to block FDA approval of the same drug for the “same disease or
condition” instead of the approved indication during the exclusivity period. If the Catalyst decision is applied beyond the facts
of that case, FDA may revoke approvals or the grant of subsequent orphan exclusivity periods for the same drugs approved for different
indications within the same orphan-designated disease or condition. Catalyst has created some uncertainty with respect to the scope of
the orphan drug exclusivity and may increase legal challenges in the field. FDA may work with the Congress to amend the orphan drug provisions
in the law to provide more clarity to stakeholders. The extent of the impact of the Catalyst decision on the industry and on FDA’s
regulation and policies with respect to orphan exclusivity as well as the impact of any future legislation on orphan drug approval and
exclusivity is unclear.
In Catalyst Pharms., Inc. v. Becerra,
14 F.4th 1299 (11th Cir. 2021), the court disagreed with the FDA’s longstanding position that the orphan drug exclusivity only applies
to the approved use or indication within an eligible disease. This decision created uncertainty in the application of the orphan drug
exclusivity. On January 24, 2023, the FDA published a notice in the Federal Register to clarify that while the agency complies with the
court’s order in Catalyst, FDA intends to continue to apply its longstanding interpretation of the regulations to matters outside
of the scope of the Catalyst order – that is, the agency will continue tying the scope of orphan-drug exclusivity to the uses or
indications for which a drug is approved, which permits other sponsors to obtain approval of a drug for new uses or indications within
the same orphan designated disease or condition that have not yet been approved. It is unclear how future litigation, legislation, agency
decisions, and administrative actions will impact the scope of the orphan drug exclusivity.
The FDA and EMA granted Orphan Drug
Designation to nebokitug in its primary indications of PSC, SSc and idiopathic pulmonary fibrosis, or IPF. We may seek Orphan Drug Designations
for nebokitug in other indications or for other product candidates. There can be no assurance that we will be able to obtain such designations.
Even if we obtain Orphan Drug Designation
for any product candidate in specific indications, we may not be the first to obtain marketing approval of such product candidate for
the orphan-designated indication due to the uncertainties associated with developing pharmaceutical products. In addition, exclusive marketing
rights in the United States may be limited if we seek approval for an indication broader than the orphan-designated indication or may
be lost if the FDA later determines that the request for designation was materially defective or if the manufacturer is unable to assure
sufficient quantities of the product to meet the needs of patients with the rare disease or condition.
Further, even if we obtain orphan
drug exclusivity in the United States for a product, that exclusivity may not effectively protect the product from competition because
different drugs with different active moieties can be approved for the same condition. Even after an orphan product is approved, the FDA
can subsequently approve the same drug with the same active moiety for the same condition if the FDA concludes that the later drug is
safer, more effective or makes a major contribution to patient care.
We
will need to expand our organization, and we may experience difficulties in managing this growth, which could disrupt our operations.
As of December 31, 2024,
we had 16 employees / consultants. In the future, we expect to experience significant growth in the number of our employees and
the scope of our operations, particularly in the areas of product candidate development, regulatory affairs and sales and marketing. We
may have difficulty identifying, hiring and integrating new personnel. Future growth would impose significant additional responsibilities
on our management, including the need to identify, recruit, maintain, motivate and integrate additional employees, consultants and contractors.
Also, our management may need to divert a disproportionate amount of its attention away from our day-to-day activities and devote a substantial
amount of time to managing these growth activities. We may not be able to effectively manage the expansion of our operations, which may
result in weaknesses in our infrastructure, give rise to operational mistakes, loss of business opportunities, loss of employees and reduced
productivity among remaining employees. Our expected growth could require significant capital expenditures and may divert financial resources
from other projects, such as the development of product candidates. If our management is unable to effectively manage our growth, our
expenses may increase more than expected, our ability to generate and/or grow revenues could be reduced, and we may not be able to implement
our business strategy. Our future financial performance and our ability to commercialize our product candidates and compete effectively
will depend, in part, on our ability to effectively manage any future growth.
Many of the biopharmaceutical
companies that we compete against for qualified personnel and consultants have greater financial and other resources, different risk profiles
and a longer history in the industry than we do. If we are unable to continue to attract and retain high-quality personnel and consultants,
the rate and success at which we can discover and develop product candidates and operate our business will be limited.
We
have incurred significant operating losses since our inception and anticipate we will incur continued losses for the foreseeable future.
We have funded our operations to date through
proceeds from sales of our equity and grants from the Israel Innovation Authority, or the IIA, which as of December 31, 2024, resulted
in gross proceeds of approximately $1.2 million. As of December 31, 2024, our cash, cash equivalents and deposits were approximately $14.3
million. We have incurred net losses in each year since our inception, and we have an accumulated deficit of $102.6 million as of December
31, 2024. We expect our existing cash, cash equivalents and bank deposits will allow us to fund our operating expenses and capital expenditure
requirements through the end of first quarter of 2026.These indicators raising substantial doubt about our ability to continue as a going
concern. The Company will be required to raise additional funds to support its operations and continue as a going concern. While we believe
that the Company can raise additional funds, there can be no assurance that these efforts will be successful or sufficient.
Substantially all of our
operating losses have resulted from general and administrative costs associated with our operations, and costs associated with our research
and development programs, including for our preclinical and clinical product candidates. We expect to incur increasing levels of operating
losses over the next several years and for the foreseeable future. Our prior losses, combined with expected future losses, have had and
will continue to have an adverse effect on our shareholders’ deficit and working capital. In any particular quarter or quarters,
our operating results could be below the expectations of securities analysts or investors, which could cause the price of our ADSs to
decline.
We expect our research and
development expenses to significantly increase in connection with our clinical studies of our product candidates. In addition, if we obtain
marketing approval for our product candidates, we will incur significant sales and marketing, legal, and outsourced-manufacturing expenses.
As a public company, we expect to continue to incur significant and increasing operating losses for the foreseeable future. Because of
the numerous risks and uncertainties associated with developing pharmaceutical products, we are also unable to predict the extent of any
future losses or when we will become profitable, if at all. Even if we do become profitable, we may not be able to sustain or increase
our profitability on a quarterly or annual basis.
We
may be subject to cyber-attacks or other disruptions to or breaches of our information technology, systems or networks that could irreparably
damage our reputation and our business, expose us to liability and materially and adversely affect our results of operations.
In conducting our business,
we routinely collect, store and otherwise process proprietary, confidential or sensitive data, including personal information and proprietary
technology and information about our business and patients, suppliers and business partners, including proprietary technology. The secure
maintenance, transmission and other processing of this data and information is critical to our operations and business strategy. Our employees
occasionally work remotely, based on a hybrid work model, which creates a heightened risk of cyber-attacks or other disruptions to or
breaches of our information technology, systems or networks.
We may be subject to cyber-attacks
or other disruptions to or breaches of our information technology, systems or networks caused by computer viruses, software bugs, server
malfunctions, software or hardware failure, illegal hacking, criminal fraud or impersonation, ransomware attacks, denial-of-service attacks,
malware, social engineering or phishing attacks, acts of vandalism or terrorism, unauthorized access, theft or employee malfeasance or
error.
Cyber-attacks are increasing
in number and sophistication, are well-financed, in some cases supported by state actors, and are designed to not only attack, but also
to evade detection. Since the techniques used to obtain unauthorized access to information technology, systems, and networks, or to otherwise
sabotage them, change frequently, have become increasingly complex and sophisticated, including through the use of artificial intelligence,
and are often not recognized until launched against a target, we and third parties associated with us may be unable to anticipate these
techniques or to implement adequate preventative measures. Cyber-attacks can originate from a wide variety of sources, including organized
crime, hackers, activists, terrorists, nation-states, nation-state supported actors and others, any of which may see their effectiveness
enhanced by the use of artificial intelligence.
In addition, certain global
geopolitical events can increase our cybersecurity risk. For example, due to the ongoing Russia-Ukraine conflict, there have been publicized
threats to increase cyber-attack activity against the critical infrastructure of any nation or organization that retaliates against Russia
for its invasion of Ukraine. There have also been similar publicized threats in connection with the geopolitical tension with the Iranian
regime and more specifically in connection with the terror attacks by Hamas on Israel, since October 7, 2023. These threats include
threats to harm Western countries’ infrastructure and assets. The costs to us to reduce the risk of or alleviate cybersecurity breaches
and vulnerabilities could be significant.
Any type of security breach, attack or misuse of data, whether actual or perceived,
and whether experienced by us or an associated third party, could harm our reputation or deter existing or prospective patients from enrolling
or continuing in clinical trials, increase our operating expenses in order to contain and remediate the incident, expose us to unbudgeted
or uninsured liability, disrupt our operations, divert management focus away from other priorities, increase our risk of regulatory scrutiny,
result in litigation from patients, employees or other third parties, lead to the imposition of penalties, reporting obligations and fines
under state, federal and foreign laws or by payment networks or adversely affect our continued payment network registration and financial
institution sponsorship. Moreover, any such compromise of our information security could result in the loss, misappropriation, corruption
or unauthorized publication of our confidential business or proprietary information or personal or sensitive information, or that of other
parties with which we do business, an interruption or other failure of our information technology, systems, networks or operations, the
unauthorized transfer of cash or other of our assets, the unauthorized release of patient or employee data or a violation of laws, regulations,
industry standards or other legal or contractual obligations related to privacy, data protection and information security. Computer programmers
and hackers also may be able to develop and deploy viruses, worms and other malicious software programs that attack our products, or that
otherwise exploit any security vulnerabilities, and any such attack, if successful, could expose us to liability to patient claims. In
addition, our ability to monitor our third-party service providers’ data security is limited. Some of our third-party service providers
may store or have access to our data and may not have effective controls, processes, or practices to protect our information from loss,
unauthorized disclosure, unauthorized use or misappropriation or other cyber-attacks or other disruptions to or breaches of information
security. A vulnerability in our third-party service providers’ software or information technology, systems or networks, a failure
of our third-party service providers’ safeguards, policies or procedures, or a cyber-attack or other disruption to or breach of
information security affecting any of these third parties could irreparably damage our reputation and business. The costs related to significant
cyber-attacks or other disruptions to or breaches of our information technology, systems or networks could be material and cause us to
incur significant expenses. If the information technology, systems or networks of third parties associated with us become subject to cyber-attacks
or other disruptions or security breaches, we may have insufficient recourse against such third parties and we may have to expend significant
resources to mitigate the impact of such an event, and to develop and implement protections to prevent future events of this nature from
occurring. Any of the foregoing could irreparably damage our reputation and business, which could have a material adverse effect on our
results of operations.
We cannot ensure that any
limitation of liability provisions in our agreements with patients, service providers, business partners and other third parties with
which we do business would be enforceable or adequate or would otherwise protect us from any liabilities or damages with respect to any
particular claim in connection with a cyber-attack or other disruption to or breach of information security. Additionally, we cannot be
certain that our insurance coverage will be adequate for cybersecurity liabilities actually incurred, that insurance will continue to
be available to us on economically reasonable terms, or at all, or that our insurer will not deny coverage as to any future claim.
Risks Related to Our Intellectual Property Rights
If
we are unable to protect our patents or other proprietary rights, or if we infringe the patents or other proprietary rights of others,
our competitiveness and business prospects may be materially damaged.
Patent and other proprietary
rights are essential to our business. Our success depends to a significant degree on our ability to obtain and enforce patents and licenses
to patent rights, both in the United States and in other countries. We cannot guarantee that pending patent applications will result in
issued patents, that patents issued or licensed will not be challenged or circumvented by competitors, that the patents and other intellectual
property rights of us and our business partners will not be found to be invalid or that the intellectual property rights of others will
not prevent us from selling our products or from executing on our strategies.
The patent position of a
biopharmaceutical company is often uncertain and involves complex legal and factual questions. Significant litigation concerning patents
and products is pervasive in our industry. Patent claims include challenges to the coverage and validity of our patents on products or
processes as well as allegations that our products infringe patents held by competitors or other third parties. A loss in any of these
types of cases could result in a loss of patent protection or the ability to market products, which could lead to a significant loss of
sales, or otherwise materially affect future results of operations. We also rely on trademarks, copyrights, trade secrets and know-how
to develop, maintain and strengthen our competitive positions. Third parties may know, discover or independently develop equivalent proprietary
information or techniques, or they may gain access to our trade secrets or disclose such trade secrets to the public.
Although our employees, consultants,
parties to collaboration agreements and other business partners are generally subject to confidentiality or similar agreements to protect
our confidential and proprietary information, these agreements may be breached, and we may not have adequate remedies for any breach.
In addition, our trade secrets may otherwise become known or be independently discovered by competitors. To the extent that our employees,
consultants, parties to collaboration agreements and other business partners use intellectual property owned by others in their work for
the company, disputes may arise as to the rights in related or resulting know-how and inventions.
Furthermore, our intellectual
property, other proprietary technology and other sensitive company data is potentially vulnerable to loss, damage or misappropriation
from system malfunction, computer viruses, unauthorized access to data or misappropriation or misuse thereof by those with permitted access
and other events. While we have invested to protect our intellectual property and other data, and continue to work diligently in this
area, there can be no assurance that our precautionary measures will prevent breakdowns, breaches, cyber incidents or other events. Such
events could have a material adverse effect on our reputation, business, financial condition or results of operations. Misappropriation
or other loss of our intellectual property from any of the foregoing could have a material adverse effect on our competitive position
and may cause us to incur substantial litigation costs.
We
may not identify relevant third-party patents or may incorrectly interpret the relevance, scope or expiration of a third-party patent,
which might adversely affect our ability to develop, manufacture and market our product candidates.
From time to time, we may identify
patents or applications in the same general area as our products and product candidates. We may determine these third-party patents are
irrelevant to our business based on various factors, including our interpretation of the scope of the patent claims and our interpretation
of when the patent expires. If the patents are asserted against us, however, a court may disagree with our determinations. Further, while
we may determine that the scope of claims that will issue from a patent application does not present a risk, it is difficult to accurately
predict the scope of claims that will issue from a patent application, our determination may be incorrect, and the issuing patent may
be asserted against us. We cannot guarantee that we will be able to successfully settle or otherwise resolve such infringement claims.
If we fail in any such dispute, in addition to being forced to pay monetary damages, we may be temporarily or permanently prohibited from
commercializing our product candidates or be required to obtain a license under such patent, which may not be available on reasonable
terms or at all. We might, if possible, also be forced to redesign our product candidates so that it no longer infringes, misappropriates
or otherwise violates the third-party intellectual property rights. Any of these events, even if we were ultimately to prevail, could
require us to divert substantial financial and management resources that we would otherwise be able to devote to our business. Any of
the foregoing could have a material adverse effect on our business, financial condition, results of operations, and prospects.
Changes
in patent laws or patent jurisprudence could diminish the value of patents in general, thereby impairing our ability to protect our product
candidates.
As is the case with other biopharmaceutical
and pharmaceutical companies, our success is heavily dependent on intellectual property, particularly patents. Obtaining and enforcing
patents in the biopharmaceutical and pharmaceutical industries involves both technological and legal complexity. Therefore, obtaining
and enforcing biopharmaceutical and pharmaceutical patents is costly, time-consuming and inherently uncertain. In addition, the Leahy-Smith
America Invents Act, or the AIA, which was passed in September 2011, resulted in significant changes to the United States patent system.
An important change introduced by
the AIA is that, as of March 16, 2013, the United States transitioned from a “first-to-invent” to a “first-to-file”
system for deciding which party should be granted a patent when two or more patent applications are filed by different parties claiming
the same invention. Under a “first-to-file” system, assuming the other requirements for patentability are met, the first inventor
to file a patent application generally will be entitled to a patent on the invention regardless of whether another inventor had made the
invention earlier. A third party that files a patent application in the USPTO after that date but before we could therefore be awarded
a patent covering an invention of ours even if we made the invention before it was made by the third party. This will require us to be
cognizant of the time from invention to filing of a patent application and be diligent in filing patent applications, but circumstances
could prevent us from promptly filing patent applications on our inventions.
Among some of the other changes introduced
by the AIA are changes that limit where a patentee may file a patent infringement suit and providing opportunities for third parties to
challenge any issued patent with the USPTO. This applies to all of our United States patents, even those issued before March 16, 2013.
Because of a lower evidentiary standard in USPTO proceedings compared to the evidentiary standard in United States federal courts necessary
to invalidate a patent claim, a third party could potentially provide evidence in a USPTO proceeding sufficient for the USPTO to hold
a claim invalid even though the same evidence would be insufficient to invalidate the claim if first presented in a district court action.
Accordingly, a third party may attempt
to use the USPTO procedures to invalidate our patent claims that would not have been invalidated if first challenged by the third party
as a defendant in a district court action. It is not clear what, if any, impact the AIA will have on the operation of our business. However,
the AIA and its implementation could increase the uncertainties and costs surrounding the prosecution of our or our licensors’ patent
applications and the enforcement or defense of our or our licensors’ issued patents.
We may become involved in opposition,
interference, derivation, inter partes review, post-grant review, reexamination or other proceedings challenging our or our licensors’
patent rights, and the outcome of any proceedings are highly uncertain. An adverse determination in any such proceeding could reduce the
scope of, or invalidate, our owned or in-licensed patent rights, in whole or in part, allow third parties to commercialize our technology
or products and compete directly with us, without payment to it, or result in our inability to manufacture or commercialize products without
infringing third-party patent rights.
Additionally, the United States Supreme
Court has ruled on several patent cases in recent years either narrowing the scope of patent protection available in certain circumstances
or weakening the rights of patent owners in certain situations. In addition to increasing uncertainty with regard to our ability to obtain
patents in the future, this combination of events has created uncertainty with respect to the validity, enforceability and value of patents,
once obtained. Depending on decisions by Congress, the federal courts and the USPTO, as well as similar bodies in other jurisdictions,
the laws and regulations governing patents could change in unpredictable ways that could weaken our ability to obtain new patents or to
enforce our existing patents and patents that we might obtain in the future. Similarly, the complexity and uncertainty of European patent
laws have also increased in recent years. In addition, the European patent system is relatively stringent in the type of amendments that
are allowed during prosecution. Complying with these laws and regulations could limit our ability to obtain new patents in the future
that may be important for our business, and these laws and regulations patents could continue to change in unpredictable ways that could
have a material adverse effect on our existing patent rights and our ability to protect and enforce our intellectual property in the future.
Obtaining
and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other requirements
imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.
The USPTO and European and other
patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent
application process. In addition, periodic maintenance, renewal and annuity fees on any issued patent are due to be paid to the USPTO
and European and other patent agencies over the lifetime of a patent. While an inadvertent failure to make payment of such fees or to
comply with such provisions can in many cases be cured by additional payment of a late fee or by other means in accordance with the applicable
rules, there are situations in which such noncompliance will result in the abandonment or lapse of the patent or patent application, and
the partial or complete loss of patent rights in the relevant jurisdiction. Non-compliance events that could result in abandonment or
lapse of a patent or patent application include failure to respond to official actions within prescribed time limits, non-payment of fees
and failure to properly legalize and submit formal documents within prescribed time limits. If we or our licensors fails to maintain the
patents and patent applications covering our product candidates or if we or our licensors otherwise allow our patents or patent applications
to be abandoned or lapse, our competitors might be able to enter the market, which would hurt our competitive position and could
impair our ability to successfully commercialize our product candidates in any indication for which they are approved, which could have
a material adverse effect on our business, financial condition, results of operations, and prospects.
Risks Related to Our Regulatory Approvals
The regulatory
approval processes of the FDA and comparable foreign authorities are lengthy, time consuming and inherently unpredictable, and if we are
ultimately unable to obtain regulatory approval for nebokitug or any other product candidates, our business will be substantially harmed.
The time required to obtain approval
by the FDA and comparable foreign authorities is unpredictable but typically takes many years following the commencement of clinical studies
and depends upon numerous factors, including the substantial discretion of the regulatory authorities. In addition, approval policies,
regulations or the type and amount of clinical data necessary to gain approval may change during the course of a product candidate’s
clinical development and may vary among jurisdictions, which may cause delays in the approval or the decision not to approve an application.
Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application or may decide that
our data is insufficient for approval and require additional preclinical, clinical or other data. Even if we eventually complete clinical
testing and receives approval of any regulatory filing for our product candidates, the FDA and other comparable foreign regulatory authorities
may approve our product candidates for a more limited indication or a narrower patient population than we originally requested. We have
not obtained regulatory approval for any product candidate and it is possible that we will never obtain regulatory approval for nebokitug
or any other product candidate. We are not permitted to market any of our product candidates in the United States until we receive regulatory
approval of an NDA from the FDA.
Prior to obtaining approval to commercialize
a product candidate in the United States or abroad, we must demonstrate with substantial evidence from well-controlled clinical studies,
and to the satisfaction of the FDA or foreign regulatory agencies, that such product candidate is safe and effective for its intended
use. Results from preclinical studies and clinical trials can be interpreted in different ways. Even if we believe the preclinical or
clinical data for our product candidates are promising, such data may not be sufficient to support approval by the FDA and other regulatory
authorities.
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the FDA or any foreign regulatory bodies can delay, limit or deny approval of our
product candidates or require us to conduct additional preclinical or clinical testing or abandon a program for many reasons, including:
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the FDA or comparable foreign regulatory authorities may disagree with the design
or implementation of our clinical studies; |
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we may be unable to demonstrate to the satisfaction of the FDA or comparable foreign
regulatory authorities that a product candidate is safe and effective for its proposed indication; |
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serious and unexpected drug-related side effects experienced by participants in our
clinical studies or by individuals using drugs similar to our product candidates, or other products containing the active ingredient in
our product candidates; |
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negative or ambiguous results from our clinical studies or results that may not meet
the level of statistical significance required by the FDA or comparable foreign regulatory authorities for approval; |
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the population studied in the clinical study may not be sufficiently broad or representative
to assure efficacy and safety in the full population for which we seek approval; |
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we may be unable to demonstrate that a product candidate’s clinical and other
benefits outweigh its safety risks; |
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the FDA or comparable foreign regulatory authorities may disagree with our interpretation
of data from preclinical studies or clinical trials; |
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the data collected from clinical studies of our product candidates may not be acceptable
or sufficient to support the submission of an NDA or other submission or to obtain regulatory approval in the United States or elsewhere,
and we may be required to conduct additional clinical studies; |
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the FDA’s or the applicable foreign regulatory agency’s disagreement regarding
the formulation, labeling and/or the specifications of our product candidates; |
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the FDA or comparable foreign regulatory authorities may fail to approve or find deficiencies
with the manufacturing processes or facilities of third-party manufacturers with which our contracts for clinical and commercial supplies;
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the approval policies or regulations of the FDA or comparable
foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient for approval. |
Moreover, preclinical and
clinical data are often susceptible to varying interpretations and analyses and many companies that believed their product candidates
performed satisfactorily in preclinical studies and clinical trials nonetheless failed to obtain FDA or comparable foreign regulatory
authority approval. We cannot guarantee that the FDA or foreign regulatory authorities will interpret trial results as we do, and more
trials could be required before we are able to submit applications seeking approval of our product candidates. To the extent that the
results of the trials are not satisfactory to the FDA or foreign regulatory authorities for support of a marketing application, we may
be required to expend significant resources, which may not be available to us, to conduct additional trials in support of potential approval
of our product candidates. Furthermore, the approval policies or regulations of the FDA or comparable foreign regulatory authorities may
significantly change in a manner rendering our clinical data insufficient for approval, which may lead to the FDA or comparable foreign
regulatory authorities delaying, limiting or denying approval of our product candidates.
Of the large number of drugs
in development, only a small percentage successfully complete the regulatory approval processes and are commercialized. This lengthy approval
process, as well as the unpredictability of future clinical trial results, may result in us failing to obtain regulatory approval to market
nebokitug or any other product candidate, which would significantly harm our business, results of operations and prospects.
In addition, the FDA or the
applicable foreign regulatory agency also may approve a product candidate for a more limited indication or patient population than we
originally requested, and the FDA or applicable foreign regulatory agency may approve a product candidate with a REMS or a label that
does not include the labeling claims necessary or desirable for the successful commercialization of that product candidate. Regulatory
authorities may also grant approval contingent on the performance of costly post-marketing clinical trials. Any of the foregoing scenarios
could materially harm the commercial prospects for our product candidates.
Obtaining
and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining
regulatory approval of our product candidates in other jurisdictions.
In order to market any product
outside of the United States, we must establish and comply with the numerous and varying safety, efficacy, and other regulatory requirements
of other countries. Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not guarantee that
we will be able to obtain or maintain regulatory approval in any other jurisdiction, but a failure or delay in obtaining regulatory approval
in one jurisdiction may have a negative effect on the regulatory approval process in others. Our product candidates may not receive marketing
approval even if they achieve their primary endpoints in future Phase 3 clinical studies or registrational trials. The FDA or comparable
foreign regulatory authorities may disagree with our trial designs and our interpretation of data from preclinical studies or clinical
trials. In addition, any of these regulatory authorities may change requirements for the approval of a product candidate even after reviewing
and providing comments or advice on a protocol for a pivotal Phase 3 or registrational clinical study. In addition, any of these regulatory
authorities may also approve a product candidate for fewer or more limited indications than our request or may grant approval contingent
on the performance of costly post-marketing clinical trials. The FDA or comparable foreign regulatory authorities may not approve the
labeling claims that we believe would be necessary or desirable for the successful commercialization of our product candidates, if approved.
Furthermore, even if the
FDA or other comparable foreign regulatory authority grants marketing approval of a product candidate, comparable regulatory authorities
in foreign jurisdictions must also approve the manufacturing, marketing, and promotion of the product candidate in those countries. Approval
procedures vary among jurisdictions and can involve requirements and administrative review periods different from those in the United
States, including additional preclinical studies or clinical trials as clinical studies conducted in one jurisdiction may not be accepted
by regulatory authorities in other jurisdictions. The marketing approval processes in other countries may implicate all of the risks detailed
above regarding FDA approval in the United States, as well as other risks. In many jurisdictions outside the United States, a product
candidate must be approved for reimbursement before it can be approved for sale in that jurisdiction. In some cases, the price that we
intend to charge for our products is also subject to approval.
Obtaining foreign regulatory
approvals and compliance with foreign regulatory requirements could result in significant delays, difficulties, and costs for us and could
delay or prevent the introduction of our products in certain countries. Failure to obtain marketing approval in other countries or any
delay or other setback in obtaining such approval would impair our ability to market our product candidates in such foreign markets. Any
such impairment would reduce the size of our potential market, which could have a material adverse impact on our business, results of
operations, and prospects.
Even
if we obtain regulatory approval for nebokitug or any product candidate, we will still face extensive and ongoing regulatory requirements
and obligations and any product candidate, if approved, may face future development and regulatory difficulties.
Any product candidate for which we
obtain marketing approval, along with the manufacturing processes, post-approval clinical data, labeling, packaging, distribution, adverse
event reporting, storage, recordkeeping, export, import, advertising and promotional activities for such product, among other things,
will be subject to extensive and ongoing requirements of and review by the FDA and other regulatory authorities. These requirements include
submissions of safety and other post-marketing information and reports, establishment registration and drug listing requirements, continued
compliance with cGMP requirements relating to manufacturing, quality control, quality assurance and corresponding maintenance of records
and documents, requirements regarding the distribution of samples to physicians and recordkeeping and GCP requirements for any clinical
studies that we conduct post-approval.
Even if marketing approval of a product
candidate is granted, the approval may be subject to limitations on the indicated uses for which the product candidate may be marketed
or to the conditions of approval, including a requirement to implement a REMS. If any of our product candidates receives marketing approval,
the accompanying label may limit the approved indicated use of the product candidate, which could limit sales of the product candidate.
The FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy
of a product. Violations of the Federal Food, Drug, and Cosmetic Act, or FDCA, relating to the promotion of prescription drugs may lead
to FDA enforcement actions and investigations alleging violations of federal and state healthcare fraud and abuse laws, as well as state
consumer protection laws.
In addition, later discovery of previously
unknown adverse events or other problems with our products, manufacturers or manufacturing processes or failure to comply with regulatory
requirements, may yield various results, including:
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restrictions on manufacturing such products; |
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restrictions on the labeling or marketing of products; |
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restrictions on product manufacturing, distribution or use; |
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requirements to conduct post-marketing studies or clinical trials; |
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warning letters or untitled letters; |
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withdrawal of the products from the market; |
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refusal to approve pending applications or supplements to approved applications that we submit; |
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recall of products; |
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fines, restitution or disgorgement of profits or revenues; |
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suspension or withdrawal of marketing approvals; |
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refusal to permit the import or export of our products; |
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product seizure; or |
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injunctions or the imposition of civil or criminal penalties. |
Further, the FDA’s
policies may change, and additional government regulations may be enacted that could impose extensive and ongoing regulatory requirements
and obligations on any product candidate for which we obtain marketing approval. If we are slow or unable to adapt to changes in
existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may
lose any marketing approval that we may have obtained, which would adversely affect our business, prospects and ability to achieve or
sustain profitability.
Disruptions
at the FDA and other government agencies caused by funding shortages or global health concerns could hinder our ability to hire, retain
or deploy key leadership and other personnel, or otherwise prevent new or modified products from being developed, approved or commercialized
in a timely manner or at all, which could negatively impact our business.
The ability of the FDA to
review and approve new products can be affected by a variety of factors, including government budget and funding levels, ability to hire
and retain key personnel and accept the payment of user fees, and statutory, regulatory, and policy changes. Average review times at the
agency have fluctuated in recent years as a result. In addition, government funding of other government agencies that fund research and
development activities is subject to the political process, which is inherently fluid and unpredictable.
Disruptions at the FDA and other
agencies may also slow the time necessary for new drugs to be reviewed and/or approved by necessary government agencies, which would harm
our business. For example, over the last several years, including for 35 days beginning on December 22, 2018, the United States government
has shut down several times and certain regulatory agencies, such as the FDA, have had to furlough critical FDA employees and stop critical
activities. If a prolonged government shutdown occurs, it could significantly impact the ability of the FDA to timely review and process
our regulatory submissions, which could harm our business.
During the COVID-19 pandemic, the
FDA imposed preventive measures, including postponements of non-United States manufacturing and product inspections. If global health
concerns re-occur, similar restrictions could be implemented that might prevent the FDA or other regulatory authorities from conducting
their regular inspections, reviews, or other regulatory activities. This could significantly impact the ability of the FDA or other regulatory
authorities to timely review and process our regulatory submissions, which could have a material adverse effect on our business.
Current and future
legislation may increase the difficulty and cost for us to obtain marketing approval of and commercialize our drug candidates and affect
the prices we may obtain.
The healthcare industry in the United
States is subject to extensive regulation by a number of governmental entities at the federal, state and local level. The healthcare regulatory
landscape is also subject to frequent change. In addition to the FDA’s restrictions on marketing of pharmaceutical products, the
U.S. healthcare laws and regulations that may apply to pharmaceutical companies include, without limitation: the federal fraud and abuse
laws, including the federal anti-kickback and false claims laws; federal health data privacy and security laws; and federal transparency
laws related to payments and/or other transfers of value made to physicians and other healthcare professionals and teaching hospitals.
Many states have similar laws and regulations that may differ from each other and federal law in significant ways, thus complicating compliance
efforts. These laws may impose administrative and compliance burdens on the sales, marketing and other activities of pharmaceutical manufacturers
with approved products for market in the United States.
Because of the breadth of these laws
and the narrowness of available statutory exceptions and regulatory safe harbors, it is possible that some of our business activities,
could be subject to legal challenge and enforcement actions. Violations of any of the federal and state laws described above or any other
governmental regulations, may result in significant civil, criminal, and administrative penalties, including, without limitation, damages,
fines, imprisonment, exclusion from participation in government healthcare programs, additional reporting obligations and oversight pursuant
to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, and the curtailment or
restructuring of operations.
Additionally, in the United States
and some foreign jurisdictions there have been, and continue to be, several legislative, executive and regulatory changes and proposed
reforms of the healthcare system in an effort to contain costs, improve quality, and expand access to care, particularly in light of the
recent U.S. Presidential and Congressional elections. These reform initiatives may, among other things, result in modifications to the
aforementioned laws and/or the implementation of new laws affecting the healthcare industry. The adoption of any future cost containment
or other health reform initiative may result in additional downward pressure on the price for any approved product.
Risks Related to Commercialization
of Our Product Candidates
If
we do not achieve our projected development and commercialization goals in the timeframes we announce and expect, the commercialization
of our product candidates may be delayed and our business will be harmed.
For planning purposes, we sometimes
estimate the timing of the accomplishment of various scientific, clinical, regulatory and other product development objectives. These
milestones may include our expectations regarding the commencement or completion of scientific studies and clinical trials, the regulatory
submissions or commercialization objectives. From time to time, we may publicly announce the expected timing of some of these milestones,
such as the completion of an ongoing clinical study, the initiation of other clinical studies, receipt of regulatory approval or the commercial
launch of a product. The achievement of many of these milestones may be outside of our control. All of these milestones are based on a
variety of assumptions which may cause the timing of achievement of the milestones to vary considerably from our estimates, including:
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our available capital resources or capital constraints we experience; |
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the rate of progress, costs and results of our clinical studies and research and development
activities, including the extent of scheduling conflicts with participating clinicians and collaborators; |
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our ability to identify and enroll patients who meet clinical study eligibility criteria;
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our receipt of authorizations by the FDA and comparable foreign regulatory authorities,
and the timing thereof; |
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other actions, decisions or rules issued by regulators; |
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our ability to access sufficient, reliable and affordable supplies of materials used
in the manufacture of our product candidates; |
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our ability to manufacture and supply clinical study materials to our clinical sites
on a timely basis; |
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the efforts of our collaborators with respect to the commercialization of our products,
if any; and |
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the securing of, costs related to, and timing issues associated with, commercial product
manufacturing as well as sales and marketing activities. |
If we fail to achieve announced
milestones in the timeframes we expect, the commercialization of any of our product candidates may be delayed, and our business, results
of operations, financial condition and prospects may be adversely affected.
We
face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully
than us.
The development and commercialization
of new drug products is highly competitive. We may face competition with respect to any product candidates that we seek to develop or
commercialize in the future from major biopharmaceutical companies, specialty biopharmaceutical companies, and biotechnology companies
worldwide. Potential competitors also include academic institutions, government agencies, and other public and private research organizations
that conduct research, seek patent protection, and establish collaborative arrangements for research, development, manufacturing, and
commercialization.
There are a number of large biopharmaceutical
and biotechnology companies that are currently pursuing the development of products for the treatment of inflammation and fibrosis. Companies
that we are aware of that are targeting the treatment of inflammation and fibrosis include large companies with significant financial
resources as well as a substantial number of small-mid size biotechnology companies. However, we do not know of any other companies currently
in clinical development with an anti CCL24 mAb. For additional information regarding our competition, see “Business Overview - Competition.”
Many of our current or potential
competitors, either alone or with their strategic partners, have significantly greater financial resources and expertise in research and
development, manufacturing, preclinical testing, conducting clinical studies, obtaining regulatory approvals, and marketing approved products
than we do.
Even if nebokitug
or any other product candidate we develop receives marketing approval, it may fail to achieve market acceptance by physicians, patients,
third-party payors or others in the medical community necessary for commercial success.
If nebokitug or any other product
candidate we develop receives marketing approval, it may nonetheless fail to gain sufficient market acceptance by physicians, patients,
third-party payors and others in the medical community. If it does not achieve an adequate level of acceptance, we may not generate significant
product revenues or become profitable. The degree of market acceptance of our product candidates, if approved, will depend on a number
of factors, including but not limited to:
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the efficacy and potential advantages compared to alternative treatments; |
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effectiveness of sales and marketing efforts; |
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the cost of treatment with respect to alternative treatments, including any similar
generic treatments; |
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our ability to offer our products for sale at competitive prices; |
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the convenience and ease of administration compared to alternative treatments;
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the willingness of the target patient population to try new therapies and of physicians
to prescribe these therapies; |
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the strength of marketing and distribution support; |
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the timing of market introduction of competitive products; |
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the availability of third-party coverage and adequate reimbursement; |
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product labeling or product insert requirements of the FDA, EMA or other regulatory
authorities, including any limitations on warnings contained in a product’s approved labeling; |
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the prevalence and severity of any side effects; and |
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any restrictions on the use of our product together with other medications.
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Because we expect sales of our product
candidates, if approved, to generate substantially all of our revenues for the foreseeable future, the failure of our product candidates
to find market acceptance would harm its business and could require us to seek additional financing.
We rely completely
on third-party suppliers to manufacture our clinical drug supplies for our product candidates, and we intend to rely on third parties
to produce preclinical, clinical, and commercial supplies of any future product candidates.
We do not currently have,
nor do we plan to acquire, the infrastructure or capability to internally manufacture our clinical drug supply of our product candidates,
or any future product candidates, for use in the conduct of our preclinical studies and clinical trials.
We lack the internal resources
and the capabilities to manufacture any product candidates on a clinical or commercial scale. The facilities used by our contract manufacturers
to manufacture the active pharmaceutical ingredient and final drug product must complete a pre-approval inspection by the FDA and other
comparable foreign regulatory agencies to assess compliance with applicable requirements, including cGMPs, after we submit our NDA or
relevant foreign regulatory market application to the applicable regulatory agency.
We are responsible for setting
the product specifications and approving master batch records, but do not oversee the manufacturing process itself, and are completely
dependent on our contract manufacturers to comply with cGMPs for manufacture of both active drug substances and finished drug products.
If our contract manufacturers cannot successfully manufacture material that conforms to our specifications and the strict regulatory requirements
of the FDA or applicable foreign regulatory agencies, they will not be able to pass a pre-approval inspection or secure and/or maintain
regulatory approval for their manufacturing facilities. In addition, we have no direct control over our contract manufacturers’
ability to maintain adequate quality control, quality assurance, and qualified personnel. Furthermore, all of our contract manufacturers
are engaged with other companies to supply and/or manufacture materials or products for such companies, which exposes our manufacturers
to regulatory risks for the production of such materials and products. As a result, failure to satisfy the regulatory requirements for
the production of those materials and products may affect the regulatory clearance of our contract manufacturers’ facilities generally.
If the FDA or an applicable foreign regulatory agency determines now or in the future that these facilities for the manufacture of our
product candidates are noncompliant, we may need to find alternative manufacturing facilities, which would adversely impact our ability
to develop, obtain regulatory approval for or market our product candidates. Our reliance on contract manufacturers also exposes us to
the possibility that they, or third parties with access to their facilities, will have access to and may compromise our trade secrets
or other proprietary information.
If
we are unable to establish sales, marketing and distribution capabilities either on our own or in collaboration with third parties, we
may not be successful in commercializing nebokitug, if approved.
We do not have any infrastructure
for the sales, marketing or distribution of nebokitug , and the cost of establishing and maintaining such an organization may exceed the
cost-effectiveness of doing so. In order to market and successfully commercialize nebokitug or any other product candidate we develop,
if approved, we must build our sales, distribution, marketing, managerial and other non-technical capabilities or make arrangements with
third parties to perform these services. We expect to build a focused sales, distribution and marketing infrastructure to market nebokitug,
if approved. There are significant expenses and risks involved with establishing our own sales, marketing and distribution capabilities,
including our ability to hire, retain and appropriately incentivize qualified individuals, generate sufficient sales leads, provide adequate
training to sales and marketing personnel and effectively manage a geographically dispersed sales and marketing team. Any failure or delay
in the development of our internal sales, marketing and distribution capabilities could delay any product launch, which would adversely
impact the commercialization of that product. Additionally, if the commercial launch of nebokitug for which we recruit a sales force and
establishes marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these
commercialization expenses. This may be costly, and our investment would be lost if we cannot retain or reposition our sales and marketing
personnel.
Factors that may inhibit our efforts
to commercialize our product candidates on our own include:
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our inability to recruit, train and retain adequate numbers of effective sales and marketing personnel;
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the inability of sales personnel to obtain access to physicians or attain adequate numbers of physicians
to prescribe our products; and |
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unforeseen costs and expenses associated with creating an independent sales and marketing organization.
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We do not anticipate having the resources
in the foreseeable future to allocate to the sales and marketing of our product candidates, if approved, in certain markets overseas.
Therefore, our future success will depend, in part, on our ability to enter into and maintain collaborative relationships for such capabilities,
the collaborator’s strategic interest in a product and such collaborator’s ability to successfully market and sell the product.
We intend to pursue collaborative arrangements regarding the sale and marketing of nebokitug, if approved, for certain markets overseas;
however, we cannot guarantee that we will be able to establish or maintain such collaborative arrangements, or if able to do so, that
we will have effective sales forces. To the extent that we depend on third parties for marketing and distribution, any revenues we receive
will depend upon the efforts of such third parties, and there can be no assurance that such efforts will be successful.
If we are unable to build our own
sales force or negotiate a collaborative relationship for the commercialization of nebokitug, we may be forced to delay the potential
commercialization of nebokitug or reduce the scope of our sales or marketing activities for nebokitug. If we need to increase our expenditures
to fund commercialization activities for nebokitug, we will need to obtain additional capital, which may not be available to us on acceptable
terms, or at all. We may also have to enter into collaborative arrangements for nebokitug at an earlier stage than otherwise would be
ideal and we may be required to relinquish rights to nebokitug or otherwise agree to terms unfavorable to us. Any of these occurrences
may have an adverse effect on our business, operating results and prospects.
If we are unable to establish adequate
sales, marketing and distribution capabilities, either on our own or in collaboration with third parties, we will not be successful in
commercializing our product candidates and may never become profitable. We will be competing with many companies that currently have extensive
and well-funded marketing and sales operations. Without an internal team or the support of a third party to perform marketing and sales
functions, we may be unable to compete successfully against these more established companies.
Even if we receive
marketing approvals our current or any future product candidates, we may not be able to successfully commercialize our product candidates
due to unfavorable pricing regulations or third-party coverage and reimbursement policies, which could make it difficult for us to sell
our product candidates profitably.
There may be significant delays in
obtaining such coverage and reimbursement for newly approved products, and coverage may be more limited than the purposes for which the
product is approved by the FDA or comparable non-U.S. regulatory agencies. Moreover, eligibility for coverage and reimbursement does not
imply that a product will be paid for in all cases or at a rate that covers costs, including research, development, intellectual property,
manufacture, sale and distribution expenses. Interim reimbursement levels for new products, if applicable, may also not be sufficient
to cover costs and may not be made permanent. Obtaining coverage and reimbursement approval for a product from a government or other third-party
payor is a time consuming and costly process that could require us to provide supporting scientific, clinical and cost effectiveness data
to the payor. Reimbursement rates may vary according to the use of the product and the clinical setting in which it is used, may be based
on reimbursement levels already set for lower cost products and may be incorporated into existing payments for other services. Net prices
for products may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors, by any future
laws limiting drug prices and by any future relaxation of laws that presently restrict imports of product from countries where they may
be sold at lower prices than in the United States.
There is significant uncertainty
related to the insurance coverage and reimbursement of newly approved products. Third-party payors in the United States often rely upon
Medicare coverage policy and payment limitations in setting reimbursement policies, but also have their own methods and approval process
apart from Medicare coverage and reimbursement determinations. Pricing and reimbursement outside of the United States vary widely and
are constantly evolving, with requirements and limitations becoming increasingly strict.
Our inability to promptly obtain
coverage and adequate reimbursement rates from both government-funded and private payors for any approved products that we develop could
have a material adverse effect on our operating results, our ability to raise capital needed to commercialize products and our overall
financial condition.
A
variety of risks associated with operating internationally could materially adversely affect our business.
Our research and development facilities
and certain of our executives are located in Israel and certain of our product candidates may be manufactured at third-party facilities
located in Europe. In addition, our business strategy includes potentially expanding internationally if any of our product candidates
receives regulatory approval. Doing business internationally involves a number of risks, including but not limited to:
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multiple, conflicting and changing laws and regulations, such as privacy regulations,
tax laws, export and import restrictions, employment laws, regulatory requirements and other governmental approvals, permits and licenses;
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failure by us to obtain and maintain regulatory approvals for the use of our products
in various countries; |
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additional potentially relevant third-party patent rights; |
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complexities and difficulties in obtaining protection and enforcing our intellectual
property; |
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difficulties in staffing and managing foreign operations; |
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complexities associated with managing multiple payor reimbursement regimes, government
payors or patient self-pay systems; |
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limits in our ability to penetrate international markets; |
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financial risks, such as longer payment cycles, difficulty collecting accounts receivable,
the impact of local and regional financial crises on demand and payment for our products and exposure to foreign currency exchange rate
fluctuations; |
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natural disasters, political and economic instability, including wars, terrorism and
political unrest, outbreak of disease, boycotts, curtailment of trade and other business restrictions; |
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certain expenses including, among others, expenses for travel, translation and insurance;
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regulatory and compliance risks that relate to maintaining accurate information and
control over sales and activities that may fall within the purview of the United States Foreign Corrupt Practices Act, its books and records
provisions, or its anti-bribery provisions. |
Any of these factors could significantly
harm our international expansion and operations and, consequently, our results of operations.
Risks Related to Our Incorporation
and Location in Israel
Conditions in Israel, including the
attack by Hamas and other terrorist organizations from the Gaza Strip and elsewhere in the region, and the threat of a wider regional
conflict and Israel’s actions to counter these threats, may affect our operations.
Our headquarters, ten of our employees,
including our Chief Executive Officer and Chief Financial Officer, and two members of our board of directors (not including our Chief
Executive Officer) are located in Israel and therefore our business and operations are at risk of being directly affected by economic,
political, geopolitical and military conditions in Israel.
Since the establishment of the State
of Israel in 1948, a number of armed conflicts have occurred between Israel and its neighboring countries and terrorist organizations
active in the region. These conflicts have involved missile strikes, hostile infiltrations and terrorism against civilian targets in various
parts of Israel, which have negatively affected business conditions in Israel.
Following the October 7th
attacks by Hamas terrorists in Israel's southern border, Israel declared war against Hamas and since then, Israel has been involved in
military conflicts with Hamas, Hezbollah, a terrorist organization based in Lebanon, and Iran, both directly and through proxies like
the Houthi movement in Yemen and armed groups in Iraq and other terrorist organizations. Additionally, following the fall of the Assad
regime in Syria, Israel has conducted limited military operations targeting the Syrian army, Iranian military assets and infrastructure
linked to Hezbollah and other Iran-supported groups. Although certain ceasefire agreements have been reached with Hamas and Lebanon (with
respect to Hezbollah), and some Iranian proxies have declared a halt to their attacks, there is no assurance that these agreements will
be upheld, military activity and hostilities continue to exist at varying levels of intensity, and the situation remains volatile, with
the potential for escalation into a broader regional conflict involving additional terrorist organizations and possibly other countries.
Also, the fall of the Assad regime in Syria may create geopolitical instability in the region.
The continuation of the war has also
led to a deterioration of certain indicators of Israel’s economic standing, for instance, a downgrade in Israel’s credit rating
by rating agencies (such as by Moody’s, S&P Global, and Fitch).
In connection with the war, several
hundred thousand Israeli military reservists were called up to service. All of our Israeli personnel (including employees, consultants
and directors) are exempt from military reserve duty, including our Chief Executive Officer and Chief Financial Officer.
Nebokitug clinical trial supplies
are manufactured by our supplier in Denmark and are not required to be manufactured in Israel under the regulations of the Israel Innovation
Authority of the Israeli Ministry of Economy and Industry.
Our commercial insurance does not
cover losses that may occur as a result of events associated with war and terrorism. Although the Israeli government currently covers
the reinstatement value of direct damages that are caused by terrorist attacks or acts of war, we cannot assure that such government coverage
will be maintained or that it will sufficiently cover our potential damages. Any losses or damages incurred by us could have a material
adverse effect on our business.
The global perception of Israel and
Israeli companies, influenced by actions by international judicial bodies, may lead to increased sanctions and other negative measures
against Israel, as well as Israeli companies and academic institutions. There is also a growing movement among countries, activists, and
organizations to boycott Israeli goods, services and academic research or restrict business with Israel, which could affect business operations.
If these efforts become widespread, along with any future rulings from international tribunals against Israel, they could significantly
and negatively impact business operations.
Prior to the October 2023 war, the
Israeli government pursued changes to Israel’s judicial system and has recently renewed its efforts to effect such changes. In response
to the foregoing developments, certain individuals, organizations, and institutions, both within and outside of Israel, voiced concerns
that such proposed changes, if adopted, may negatively impact the business environment in Israel. Such proposed changes may also lead
to political instability or civil unrest. If such changes to Israel’s judicial system are pursued by the government and approved
by the parliament, this may have an adverse effect on our business, results of operations, and ability to raise additional funds, if deemed
necessary by our management and board of directors.
Because
a certain portion of our expenses are incurred in currencies other than the U.S. Dollar, our results of operations may be harmed by currency
fluctuations and inflation.
Our reporting and functional currency
is the United States Dollar, but some portion of our clinical studies and operations expenses are in NIS. As a result, we are exposed
to some currency fluctuation risks. Fluctuation in the exchange rates of foreign currency has an influence on the cost of goods sold and
our financing revenues and expenses. We may, in the future, decide to enter into currency hedging transactions to decrease the risk of
financial exposure from fluctuations in the exchange rate of the currencies mentioned above with respect to the U.S. Dollar. These measures,
however, may not adequately protect us from adverse effects.
We
received Israeli government grants for certain of our research and development activities as detailed below. The terms of those grants
require us to satisfy specified conditions in order to transfer outside of Israel the manufacture of products based on know-how funded
by the Israel Innovation Authority or to transfer outside of Israel the know-how itself. If we fail to comply with the requirements of
Israeli law in this regard, we may be required to pay penalties, and it may impair our ability to sell our technology outside of Israel.
Some of our research and development
efforts were financed through grants that were received from the Israel Innovation Authority of the Israeli Ministry of Economy and Industry,
or the IIA (formerly known as the Office of the Chief Scientist). When know-how is developed using IIA grants, the Encouragement of Research,
Development and Technological Innovation in Industry Law 5744-1984, or the Innovation Law, and the regulations thereunder, restrict our
ability to transfer outside of Israel either the manufacture of products based on IIA-funded know-how or the know-how itself. Such restrictions
continue to apply even after financial obligations to the IIA are paid in full. The consideration available to our shareholders in a future
transaction involving the transfer outside of Israel of know-how developed with IIA funding (such as a merger or similar transaction)
may be reduced by any amounts that we are required to pay to the IIA.
Risks Related to our ADSs
We will need
to raise additional capital to fund our operations, which may be unavailable to us on acceptable terms or at all, or may cause dilution
or place significant restrictions on our ability to operate our business.
If our
available cash resources are insufficient to satisfy our liquidity requirements, we will be required to raise additional capital through
issuances of equity or convertible debt securities, or seek debt financing or other form of third-party funding.
If we
are unable to obtain adequate financing or financing on terms satisfactory to us when needed, our ability to continue to pursue our business
objectives and to respond to business opportunities, challenges, or unforeseen circumstances could be significantly limited, and could
have a material adverse effect on our business, financial condition, results of operations and prospects.
The various
ways we could raise additional capital carry potential risks. If we raise funds by issuing equity securities, dilution to our shareholders
would result. If we raise funds by issuing debt securities, those debt securities would have rights, preferences and privileges senior
to those of holders of our ADSs. The terms of debt securities issued or borrowings pursuant to a credit agreement could impose significant
restrictions on our operations. If we raise funds through collaborations or licensing arrangements, we might be required to relinquish
significant rights to our product candidates or grant licenses on terms that are not favorable to us.
The trading price
of the ADSs has been highly volatile and is expected to continue to be volatile.
The trading price of the ADSs has
been highly volatile, particularly over the last year. For example, on September 3, 2024, the closing price of the ADSs was $2.46 and
on January 22, 2024, the closing price of the ADSs was $0.51. This volatility may affect the price at which you are able to sell ADSs.
Our ADS price is likely to continue to be volatile and subject to significant price and volume fluctuations in response to market and
economic factors that are beyond our control. In addition, while the stock market in general has experienced high volatility, biotechnology
companies in particular have experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to operating
performance. Broad market and industry factors may negatively affect the market price of the ADSs, regardless of our actual operating
performance.
We have not paid
dividends in the past and do not expect to pay dividends in the future, and, as a result, any return on investment may be limited to the
value of the ADSs.
We have never paid dividends and
do not anticipate paying dividends in the foreseeable future. The payment of dividends will depend on our earnings, capital requirements,
financial condition, prospects and other factors our board of directors may deem relevant. If we do not pay dividends, the ADSs may be
less valuable because a return on your investment will only occur if our ADS price appreciates and you sell your ADS thereafter. In addition,
the Companies Law imposes restrictions on our ability to declare and pay dividends.
As a foreign
private issuer whose ADSs are listed on the Nasdaq, we intend to follow certain home country corporate governance practices instead of
certain Nasdaq requirements.
As a foreign private issuer whose
ADSs are listed on the Nasdaq, we are permitted to follow certain home country corporate governance practices instead of certain requirements
of the rules of the Nasdaq. For more information regarding our corporate governance practices and foreign private issuer status,
see Item 16G. “Corporate Governance.”
Accordingly, our shareholders and,
indirectly, our ADS holders may not be afforded the same protection as provided under the Nasdaq corporate governance rules. Following
our home country governance practices as opposed to the requirements that would otherwise apply to a U.S. company listed on the Nasdaq
may provide less protection than is accorded to investors of domestic issuers.
As a foreign
private issuer, we are not subject to U.S. proxy rules and are exempt from certain reports under the Exchange Act.
As of June 30, 2023, we became a
foreign private issuer and are not now subject to the requirements that are imposed upon U.S. domestic issuers by the SEC. As a foreign
private issuer, we are exempt from the rules and regulations under the Exchange Act related to the furnishing and content of proxy statements,
and our officers, directors, and principal shareholders are exempt from the reporting and short-swing profit recovery provisions contained
in Section 16 of the Exchange Act. Furthermore, although under regulations promulgated under the Companies Law, as an Israeli public company
listed on the Nasdaq, we are required to disclose the compensation of our five most highly compensated officers on an individual basis,
this disclosure is not as extensive as that required of U.S. domestic reporting companies. In addition, we are not required under the
Exchange Act to file annual, quarterly and current reports and financial statements with the SEC, as frequently or as promptly as U.S.
domestic reporting companies whose securities are registered under the Exchange Act. These exemptions and leniencies reduce the frequency
and scope of information and protections available to you in comparison to those applicable to a U.S. domestic reporting companies.
If we cease to
qualify as a foreign private issuer, we would be required to comply fully with the reporting requirements of the Exchange Act applicable
to U.S. domestic issuers, and we would incur significant legal, accounting and other expenses that we do not incur as a foreign private
issuer.
We would lose our foreign private
issuer status if a majority of our shares are owned by U.S. residents and a majority of our directors or executive officers are U.S. citizens
or residents or we fail to meet additional requirements necessary to avoid loss of foreign private issuer status. We cannot assure you
that at June 30, 2025, the next determination date of our foreign private issuer status, we will qualify as a foreign private issuer.
If we cease to qualify as a foreign private issuer at this determination date, we will be required to begin reporting as a domestic issuer
on January 1, 2026. The regulatory and compliance costs to us under U.S. securities laws as a U.S. domestic issuer may be significantly
higher. If we are not a foreign private issuer, we will be required to file periodic reports and registration statements on U.S. domestic
issuer forms with the SEC, which are more detailed and extensive than the forms available to a foreign private issuer. In addition,
we would lose our ability to rely upon exemptions from certain Nasdaq corporate governance requirements that are available to foreign
private issuers.
Holders of ADSs
are not treated as holders of our ordinary shares.
Holders of ADSs are not treated as
holders of our ordinary shares, unless they withdraw the ordinary shares underlying their ADSs in accordance with the deposit agreement
and applicable laws and regulations. The depositary is the holder of the ordinary shares underlying the ADSs. Holders of ADSs therefore
do not have any rights as holders of our ordinary shares, other than the rights that they have pursuant to the deposit agreement.
You may not have
the same voting rights as the holders of our ordinary shares and may not receive voting materials in time to be able to exercise your
right to vote.
Except as described in the deposit
agreement, holders of the ADSs will not be able to exercise voting rights attaching to the ordinary shares represented by the ADSs. If
we request the depositary to solicit your voting instructions (and we are not required to do so), the depositary will notify you of a
shareholders’ meeting and send or make voting materials available to you. Those materials will describe the matters to be voted
on and explain how ADS holders may instruct the depositary how to vote. We cannot guarantee that ADS holders will receive the voting materials
in time to ensure that they can instruct the depositary to vote the ordinary shares underlying their ADSs. For instructions to be valid,
they must reach the depositary by a date set by the depositary. The depositary will try, as far as practical, subject to the laws of Israel
and the provisions of our articles of association or similar documents, to vote or to have its agents vote the ordinary shares or other
deposited securities as instructed by ADS holders. If we do not request the depositary to solicit your voting instructions, you can still
send voting instructions, and, in that case, the depositary may try to vote as you instruct, but it is not required to do so.
Otherwise, ADS holders will not be
able to exercise their right to vote, unless they withdraw the ordinary shares underlying the ADSs they hold. However, ADS holders may
not know about the meeting far enough in advance to withdraw those ordinary shares. In any event, the depositary will not exercise any
discretion in voting deposited securities and it will only vote or attempt to vote as instructed. In addition, the depositary and its
agents are not responsible for failing to carry out voting instructions or for the manner of carrying out voting instructions. This means
that you may not be able to exercise your right to vote and there may be nothing you can do if your ordinary shares are not voted as you
requested.
Holders of ADSs
may be subject to limitations on the transfer of their ADSs and the withdrawal of the underlying ordinary shares.
ADSs are transferable on the books
of the depositary. However, the depositary may refuse to deliver ADSs or register transfers of ADSs when the transfer books of the depositary
or our transfer books are closed or at any time if the depositary or we think it advisable to do so. These limitations on transfer may
have a material adverse effect on the value of the ADSs.
We are entitled
to amend the deposit agreement and to change the rights of ADS holders under the terms of such agreement, or to terminate the deposit
agreement, without the prior consent of the ADS holders.
We are entitled to amend the deposit
agreement and to change the rights of the ADS holders under the terms of such agreement without the prior consent of the ADS holders.
We and the depositary may agree to amend the deposit agreement in any way we decide is necessary or advantageous to us or to the depositary.
Amendments may reflect, among other things, operational changes in the ADS program, legal developments affecting ADSs or changes in the
terms of our business relationship with the depositary. If an amendment adds or increases fees or charges, except for taxes and other
governmental charges or expenses of the depositary for registration fees, facsimile costs, delivery charges or similar items, or prejudices
a substantial right of ADS holders, it will not become effective for outstanding ADSs until 30 days after the depositary notifies ADS
holders of the amendment. At the time an amendment becomes effective, you are considered, by continuing to hold the ADSs, to agree to
the amendment and to be bound by the ADSs and the deposit agreement as amended. If we make an amendment to the deposit agreement that
is disadvantageous to ADS holders or terminate the deposit agreement, the ADS holders may choose to sell their ADSs or surrender their
ADSs and become direct holders of the underlying ordinary shares, but they will have no right to any compensation whatsoever.
ADS holders may
not be entitled to a jury trial with respect to claims arising under the deposit agreement, which could result in less favorable outcomes
to the plaintiff(s) in any such action.
The deposit agreement governing the
ADSs representing our ordinary shares provides that, to the fullest extent permitted by law, holders and beneficial owners of ADSs irrevocably
waive the right to a jury trial of any claim they may have against us or the depositary arising out of or relating to the ADSs or the
deposit agreement.
If this jury trial waiver provision
is not permitted by applicable law, an action could proceed under the terms of the deposit agreement with a jury trial. If we or the depositary
opposed a jury trial demand based on the waiver, the court would determine whether the waiver was enforceable based on the facts and circumstances
of that case in accordance with the applicable state and federal law. We believe that a contractual pre-dispute jury trial waiver provision
is generally enforceable, including under the laws of the State of New York, which governs the deposit agreement. In determining whether
to enforce a contractual pre-dispute jury trial waiver provision, courts will generally consider whether a party knowingly, intelligently
and voluntarily waived the right to a jury trial. We believe that this is the case with respect to the deposit agreement and the ADSs.
If any holders or beneficial owners
of ADSs bring a claim against us or the depositary in connection with matters arising under the deposit agreement or the ADSs, including
claims under federal securities laws, such holder or beneficial owner may not be entitled to a jury trial with respect to such claims,
which may have the effect of limiting and discouraging lawsuits against us or the depositary. If a lawsuit is brought against us or the
depositary under the deposit agreement, it may be heard only by a judge or justice of the applicable trial court, which would be conducted
according to different civil procedures and may result in different outcomes than a trial by jury would have had, including results that
could be less favorable to the plaintiff(s) in any such action, depending on, among other things, the nature of the claims, the judge
or justice hearing such claims, and the venue of the hearing.
No condition, stipulation or provision
of the deposit agreement or ADSs serves as a waiver by any holder or beneficial owner of ADSs or by us or the depositary of compliance
with any substantive provision of the U.S. federal securities laws and the rules and regulations promulgated thereunder.
If
we are unable to satisfy the requirements of Sections 404(a) and 404(b) of the Sarbanes-Oxley Act of 2002 or if our internal control
over financial reporting is not effective, investors may lose confidence in the accuracy and the completeness of our financial reports, and
the trading price of our ADSs may be negatively affected.
Pursuant to Section 404 of the
Sarbanes-Oxley Act of 2002 (the “Sarbanes-Oxley Act”), we are required to furnish a report by management on the effectiveness
of our internal control over financial reporting.
If we identify material weaknesses
in our internal control over financial reporting, if we are unable to comply with the requirements of Section 404in a timely manner
or to assert that our internal control over financial reporting is effective, or if our independent registered public accounting firm
is unable to express an opinion or issues an adverse opinion in its attestation as to the effectiveness of our internal control over financial
reporting required by Section 404, investors may lose confidence in the accuracy and completeness of our financial reports and the trading
price of our ordinary shares could be negatively affected. We could also become subject to investigations by Nasdaq, the SEC or other
regulatory authorities, which could require additional financial and management resources.
We have not yet determined whether we were classified as a PFIC
for our 2024 taxable year, and the determination of our status as a PFIC for our 2025 taxable year is made at the end of the 2025 taxable
year, accordingly, no assurances can be provided in this regard.
We would be classified as a passive foreign investment company,
or PFIC, for any taxable year if, after the application of certain look-through rules, either: (i) 75% or more of our gross income for
such year is “passive income” (as defined in the relevant provisions of the Internal Revenue Code of 1986, as amended, or
the Code), or (ii) 50% or more of the value of our assets (generally determined on the basis of a quarterly average) during such year
is attributable to assets that produce or are held for the production of passive income. Passive income generally includes, among other
things, rents, dividends, interest, royalties, gains from the disposition of passive assets, and gains from commodities and securities
transactions. For the purposes of this test, we will be treated as owning a proportionate share of the assets and earning a proportionate
share of the income of any other corporation of which we own, directly or indirectly, at least 25% (by value) of the stock. We have not
yet determined whether we were a PFIC for our 2024 taxable year, and the determination of our status as a PFIC for our 2025 taxable year
is made at the end of the 2025 taxable year, accordingly, no assurances can be made in this regard. If we were treated as a PFIC,
a U.S. holder of the ordinary shares may be subject to adverse U.S. federal income tax consequences, such as taxation at the highest marginal
ordinary income tax rates on capital gains and on certain actual or deemed distributions, interest charges on certain taxes treated as
deferred, and additional reporting requirements. U.S. Holders should consult their own tax advisors and should read the discussion below
under “Item 10. Additional Information - E. Taxation - Material U.S. Federal Income Tax Considerations for U.S. Holders.”
Item 4. Information
on the Company
A. |
History and Development of the Company |
We were incorporated on November
30, 2011, under the laws of the State of Israel. In March 2021, in connection with the Merger, we changed our name from Anchiano Therapeutics
Ltd. to Chemomab Therapeutics Ltd. Our principal executive offices are located at Kiryat Atidim, Building 7, Tel Aviv, Israel 6158002,
and our phone number is +972-77-331-0156. Our website is: www.chemomab.com.
We use our website as a means of
disclosing material non-public information. Such disclosures will be included on our website in the “Investor Relations” sections.
Accordingly, investors should monitor such sections of our website, in addition to following our press releases, SEC filings and public
conference calls and webcasts. Information contained on, or that can be accessed through, our website does not constitute a part of this
Annual Report and is not incorporated by reference herein. We have included our website address in this Annual Report solely for informational
purposes. Our SEC filings are available to you on the SEC’s website at http://www.sec.gov. This site contains reports and other
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Our agent for service of process
in the United States is Chemomab Therapeutics, Inc. which maintains its principal offices at One Kendall Square, Building 1400E, Suite
14-105, Cambridge, MA 02139. Its telephone number is (857) 259-4622.
For a description of our principal
capital expenditures and divestitures, see Item 5. “Operating and Financial Review and Prospects-Liquidity and Capital Resources”
and Note 2 to our audited consolidated financial statements included elsewhere in this Annual Report.
Overview
We are a clinical-stage biotechnology
company focused on the discovery and development of innovative therapeutics for fibrotic and inflammatory diseases with high unmet needs.
Based on the unique and pivotal role of the soluble protein CCL24 in promoting fibrosis and inflammation, we have developed nebokitug,
a monoclonal antibody designed to bind and block CCL24 activity. Nebokitug has demonstrated the potential to treat multiple severe
and life-threatening fibrotic and inflammatory diseases.
We have pioneered the therapeutic
targeting of CCL24, a chemokine also known as eotaxin-2, which promotes various types of cellular processes that regulate inflammatory
and fibrotic activities through the CCR3 receptor. CCL24 is expressed in various types of cells, including immune cells, endothelial cells
and epithelial cells. We have developed a novel CCL24 inhibiting product candidate with dual anti-fibrotic and anti-inflammatory activity
that modulates the complex interplay of these inflammatory and fibrotic mechanisms, which drive abnormal states of fibrosis and fibrotic
diseases. This innovative approach is currently being developed for difficult-to-treat rare diseases, also known as orphan indications
or diseases, such as primary sclerosing cholangitis (PSC) and systemic sclerosis (SSc) for which patients have no established disease-modifying
or standard-of-care treatment options. We estimate that there are approximately 77,000 patients suffering from PSC in the United States,
European Union and Japan, representing a more than $1 billion market opportunity, and approximately 170,000 patients suffering from SSc
in those same markets, representing a more than $1.5 billion market opportunity.
Nebokitug, our lead clinical product
candidate, is a first-in-class humanized monoclonal antibody that attenuates the basic function of CCL24 as a regulator of major inflammatory
and fibrotic pathways. We have demonstrated that nebokitug interferes with the underlying biology of inflammation and fibrosis through
a novel and differentiated mechanism of action. We have recently completed a Phase 2 clinical study in PSC, a rare obstructive and cholestatic
liver disease. Positive topline results from the double-blinded portion of this trial were reported in July, 2024 and results from the
open label part were reported in March 2025. The company had an End-of-Phase 2 meeting with the FDA in December, 2024. At this meeting,
the FDA and Chemomab agreed on the design for a single Phase 3 pivotal PSC trial that could result in full regulatory approval of nebokitug
for patients with PSC.
The randomized, placebo-controlled
Phase 2 study design included two doses of nebokitug (10 or 20mg/kg) vs placebo, administered once every three weeks for 15 weeks, as
well as an open label extension in which all nebokitug eligible patients could receive nebokitug for an additional 33 weeks. In the Phase
2 study, nebokitug achieved its primary endpoint of safety and tolerability and demonstrated anti-fibrotic, anti-inflammatory and anti-cholestatic
effects across a broad range of disease-related secondary efficacy endpoints, including statistically significant improvements in liver
stiffness, a key PSC disease marker, after just 15-weeks of treatment. Moreover, nebokitug showed a reduction in total bilirubin, an important
marker of cholestasis and liver health, as well as reductions in pruritus, a cholestatic indicator of great relevance to patients. Nebokitug
is the first investigational drug being developed for PSC to exhibit broad, clinically relevant effects on all three components of the
disease, establishing clinical proof-of-concept and providing further evidence of its multifactorial mechanism of action and disease-modifying
potential. The open label extension portion of the trial was reported recently and showed the nebokitug continued to demonstrate
good tolerability safety and anti-fibrotic, anti-inflammatory and anti-cholestatic activity of nebokitug up to 48 weeks of treatment.
Chemomab and the FDA aligned on a
clinical events-driven Phase 3 trial design, The trial is planned to be a randomized placebo-controlled clinical event-driven study. Patients
in the active treatment arm will receive 20 mg/kg of nebokitug administered intravenously every three weeks. The primary endpoint is the
time-to-first clinical event. The endpoint is a composite encompassing multiple, equally-weighted adverse clinical events associated with
PSC disease progression, which may include acute cholangitis, biliary strictures requiring intervention, portal hypertension, hepatic
decompensation, elevated MELD score (a measure associated with the need for liver transplant), liver transplantation, cholangiocarcinoma
and death. Enrolled patients remain in the trial until they experience an event, and the trial continues until the requisite number of
events has been collected. It is estimated that in the absence of intervention, participants would require on average about two years
to achieve a clinically meaningful event. Clinical events will be assessed in a blinded fashion by an independent clinical endpoint adjudication
committee. Approximately 350 PSC patients will be enrolled in the trial, and the study population will be enriched for patients with moderate
to advanced disease. Chemomab expects to leverage the strong relationships with global clinical investigators it developed during its
successful Phase 2 SPRING study to facilitate enrollment in the nebokitug pivotal trial.
The nebokitug SSc clinical program is Phase
2-ready and we have an open IND in the United States for a Phase 2 clinical trial. However, Chemomab has suspended initiation of this
study while we focus our resources on the Phase 2 PSC Program. We believe that nebokitug could have disease-modifying potential
in this poorly treated condition.
While our primary focus is on these
two rare indications, early in 2024 we reported results from a completed Phase 2a clinical study in patients with liver fibrosis due to
metabolic dysfunction-associated steatohepatitis (MASH). This trial provided safety and pharmacokinetic (“PK”) data
and information useful for assessing our current subcutaneous formulation of nebokitug. Additionally, the trial measured a number of biomarkers
that may be relevant to the activity of nebokitug in other fibro-inflammatory conditions. The results showed that the trial met its primary
endpoint of safety and tolerability, and that nebokitug demonstrated consistent data trends and positive activity across secondary endpoints
that included a range of liver fibrosis biomarkers and physiologic assessments. A secondary analysis, that further confirmed and extended
these initial results was reported at the 2023 EASL Congress in June 2023.
Fibrosis is the abnormal and excessive
accumulation of collagen and extracellular matrix, the non-cellular component in all tissues and organs, which provides structural and
biochemical support to surrounding cells. When present in excessive amounts, collagen and extracellular matrix lead to scarring and thickening
of connective tissues, affecting tissue properties and potentially leading to organ dysfunction and failure. Fibrosis can occur in many
different tissues, including lung, liver, kidney, muscle, skin, and the gastrointestinal tract, resulting in a wide array of progressive
fibrotic conditions. Fibrosis and inflammation are intrinsically linked. While a healthy inflammatory response is necessary for efficient
tissue repair; after disease or injury, an excessive, uncontrolled inflammatory response can lead to tissue fibrosis that in turn can
further stimulate inflammatory processes in a fibro-inflammatory vicious cycle.
Recent Developments
•
On March 27, 2025, Chemomab reported positive clinical data
from the open label (OLE) part of the PSC SPRING study. Treatment with nebokitug for up to 48 weeks was well-tolerated and the data reinforced
and expanded the positive results seen in the 15-week double-blinded portion of the Phase 2 SPRING trial. Treatment in PSC patients with
moderate/advanced disease for up to 48 weeks resulted in continued substantial improvements across key biomarkers of liver injury/inflammation
and fibrosis, including ELF score, fibrosis-related ELF score components and PRO-C. OLE patients treated with nebokitug showed stabilization
of liver stiffness and a significantly lower number of clinical events compared to historical controls.
On February 19, 2025, Chemomab reported that the International
Nonproprietary Names (INN) program of the World Health Organization had assigned the INN designation nebokitug to the company’s
lead product candidate CM-101.
•
On February 19, 2025, Chemomab announced the successful completion of its End-of-Phase
2 Meeting with the U.S. Food and Drug Administration (FDA) and alignment with the FDA on the design of a Phase 3 registration study for
nebokitug for the treatment of PSC. We believe the design provides clarity on a streamlined path to full regulatory approval based on
a single pivotal trial that does not require liver biopsies or confirmatory studies. The primary endpoint measures time-to-first clinical
event and encompasses multiple clinical events associated with disease progression. Key publications have shown that the reductions in
PSC biomarkers seen in the nebokitug Phase 2 SPRING trial are associated with reductions in clinical events, which we believe increases
confidence in the relevance of this approach for the nebokitug Phase 3 trial.
• On
November 19, 2024, Chemomab reported that data from its Phase 2 SPRING trial in patients with PSC was presented at the American Association
for the Study of Liver Disease (AASLD) The Liver Meeting® 2024. In an oral, late-breaking presentation, Professor Christopher Bowlus,
MD, a SPRING trial investigator and Professor and Chief of the Division of Gastroenterology and Hepatology at the University of
California Davis School of Medicine, discussed data from the double-blinded, placebo-controlled portion of the Phase 2 trial.
• On
July 30, 2024, Chemomab announced the closing of a private placement that resulted in gross proceeds of approximately $10 million to the
company. Existing investors such as OrbiMed and new investors including HBM Partners and Sphera Biotech Master Fund participated in the
financing. The financing extended the Chemomab’s runway through early 2026.
• On
July 25, 2024, Chemomab reported positive topline results from the nebokitug Phase 2 SPRING trial in patients with PSC. Nebokitug met
the primary study endpoint, demonstrating that it is well tolerated and nebokitug-treated patients with moderate/advanced disease showed
improvements on a wide range of disease-related secondary endpoints, including liver stiffness, liver fibrosis biomarkers, such as the
Enhanced Liver Fibrosis (ELF) score and PRO-C3 levels; total bilirubin and liver function tests; pruritus (itch) and markers of inflammation.
Dose-dependent responses were observed for multiple disease-related biomarkers. A consistent pattern of greater improvement on the secondary
endpoints was observed in the study arm receiving the 20mg/kg dose of nebokitug. This dose has been selected for the active treatment
arm of the Phase 3 trial.
• On
June 18, 2024, Chemomab announced new scientific publications had been published in the peer-reviewed journals International Journal of
Molecular Science and Drug Safety that reinforced the clinical potential of nebokitug in PSC.
• On
June 6, 2024, Chemomab presented new scientific and clinical data at EASL 2024 and at a Gordon Research Conference supporting the clinical
potential of nebokitug as a novel treatment for PSC. The findings helped elucidate nebokitug’s mode of action in liver fibrosis
and could help in characterizing its anti-fibrotic drug effects.
• On
April 18, 2024, Chemomab announced the publication of a new study in the journal Arthritis Care and Research that confirms the key role
of CCL24 in systemic sclerosis. The longitudinal study of more than 200 SSc patients showed that elevated levels of serum CCL24
are associated with increased mortality and disease severity across the fibrotic and vascular manifestations of the disease.
• On
April 10, 2024, Chemomab hosted an expert PSC webinar featuring Christopher Bowlus, MD, of UC Davis Health; Ricky Safer, founder and CEO
of PSC Partners Seeking a Cure and Massimo Pinzani, MD, PhD, of the UCL Institute for Liver and Digestive Health and UPMC ISMETT.
• In
March, 2024, Chemomab reported that the European Patent Office had granted a new patent for nebokitug, covering the use of nebokitug and
sequence-related anti-CCL24 antibodies for the treatment of liver diseases, such as PSC. In February, new patents were granted in Brazil
and Israel.
• In
January, 2024, Chemomab reported publication of new proteomics research in the peer-reviewed journal Cells. The proteomic analyses of
human samples highlighted the unique role of CCL24 in activating key PSC-related disease mechanisms and further confirmed the potential
of nebokitug as a promising treatment for PSC.
• In
January, 2024, Chemomab announced early completion of patient enrollment in the nebokitug Phase 2 PSC SPRING trial and moved up the expected
topline data readout to midyear 2024.
Private Placement
Securities Purchase Agreement
On July 25, 2024, the Company entered into a Securities Purchase Agreement (the “Securities
Purchase Agreement”) with certain investors (the “Purchasers”), pursuant to which the Company agreed to sell to the
Purchasers: (i) 4,148,867 ADSs, at a purchase price of $1.235 per ADS; and (ii), in lieu of ADSs, Pre-Funded Warrants to purchase up to
3,948,300 ADSs at a purchase price of $ 1.2349 per warrant. The Pre-Funded Warrants have an exercise price of $0.0001 per ADS, are
immediately exercisable and remain exercisable until exercised in full.
The July 2024 Private Placement closed
on July 30, 2024, and the Company received gross proceeds from the July 2024 Private Placement of approximately $10.0 million before deducting
any offering expenses payable by the Company.
The Company is using the net proceeds from
the July 2024 Private Placement, together with the Company’s existing cash and cash equivalents, to fund its development programs
for nebokitug and for general corporate purposes and working capital.
Registration Rights Agreement
In connection with the July 2024
Private Placement, the Company also entered into a registration rights agreement, dated July 25, 2024 (the “Registration Rights
Agreement”) with the Purchasers requiring the Company to file a registration statement with respect to the resale of the securities.
The Company filed a registration statement with the SEC on August 23, 2024, which was declared effective on September 6, 2024. The Company
granted the Purchasers customary indemnification rights in connection with the Registration Rights Agreement, and the Purchasers granted
the Company customary indemnification rights in connection with the Registration Rights Agreement.
Pipeline

Our lead product candidate, nebokitug,
is a first-in-class humanized monoclonal antibody targeting CCL24 that is being assessed in two orphan indications: PSC and SSc. CCL24
has been extensively studied in airway inflammation and, more recently, we have demonstrated in preclinical studies and early clinical
studies that it plays an important role in additional indications, including inflammation and fibrosis of the liver, skin and lung. While
CCL24 is found in low levels in blood and tissue samples from healthy volunteers, elevated levels of both CCL24 and its receptor CCR3
have been found in patients with PSC, SSc and MASH. CCL24 levels have also been correlated to different stages of disease. Based on extensive
preclinical, nonclinical and early clinical studies, we expect that neutralizing CCL24 will result in anti-fibrotic and anti-inflammatory
effects in patients. Nebokitug has been granted orphan drug designation by both the FDA and the EMA in its primary indications of PSC
and SSc. In addition, nebokitug was granted a Fast Track designation in PSC from the FDA. These designations provide multiple benefits
for these indications, including the potential for accelerated clinical and regulatory pathways as well as exclusive marketing and development
rights for a period of time.
PSC is a rare, chronic cholestatic
liver disease characterized by progressive inflammation, fibrosis, and destruction of the intrahepatic and extrahepatic bile ducts. The
cause of the disease is not known, although a high proportion of PSC patients also have inflammatory bowel disease. Fibrosis and inflammatory
responses induce a progressive spread of the fibrotic condition. Cholestasis is a symptom of liver injury and is characterized as the
interruption of bile flow from hepatocytes to the intestine, which leads to bile acid accumulation in the liver, resulting in oxidative
stress, inflammation, apoptosis and fibrosis. PSC affects approximately 30,000-45,000 patients in the United States. It leads to end-stage
liver disease and cancer, which causes about half of PSC deaths. About half of patients require liver transplantation, but PSC then re-occurs
in about 20% of transplant recipients, Median transplant-free survival is estimated at 10-20 years.
No treatment aside from a liver transplant
has been associated with change of the disease course or significant long-term improvement in the clinical outcome. PSC is a clear serious
unmet medical need with no FDA approved therapeutics and for which the current standard of care is inadequate.
SSc is a rare connective tissue disease
characterized by excessive fibrosis and extracellular matrix accumulation in the skin, lung and other visceral organs. The disease initiates
with an early inflammatory phase involving the immune cell network, as well as endothelial cells. As the disease progresses, the inflammation
increases and fibroblasts and myofibroblasts generate tissue fibrosis, while endothelial cells promote vascular injury, which can lead
to skin fibrosis, interstitial lung disease, myocardial insufficiency, vascular obliteration, distal ulcerations and gangrene. SSC affects
approximately 75,000-100,000 patients in the United States. SSc has the highest mortality rate among the systemic rheumatic diseases and
has high unmet need, as current treatments manage only disease manifestations and there is no disease modifying drug available.
We are primarily focused on the orphan
indications PSC and SSc but believe that nebokitug may have additional applications in other fibrotic-inflammatory disease areas such
as idiopathic pulmonary fibrosis, or IPF and MASH. Nebokitug has shown promising anti-fibrotic and anti-inflammatory effects in preclinical
studies of liver fibrosis and PSC, with significant reductions in fibrotic genes, liver enzymes, bile acid and cholangiocyte proliferation,
all reflecting a potential improvement in disease status. In preclinical studies of SSc, nebokitug reduced inflammatory and fibrotic injury
resulting in reductions in dermal thickness, collagen concentration in the skin and the lung, and immune cell infiltration in the lung.
We have completed two Phase 1a single
ascending dose studies with intravenous, or IV, and subcutaneous, or SC, administrations of nebokitug in healthy volunteers. The drug
was shown to be well-tolerated, with a PK profile supporting dosing once every 2-4 weeks. We also completed a Phase 1b multiple administration
ascending dose study in 16 MAFLD patients, expanding the safety, tolerability, and pharmacodynamics database with patients with early
liver disease. Early evidence of anti-fibrotic activity was also seen in this study.
In 2023 we reported topline and secondary
results from our Phase 2a randomized, double-blind, placebo-controlled study in patients with liver fibrosis associated with MASH. The
trial met its primary endpoint of safety and tolerability, and nebokitug demonstrated promising activity in secondary endpoints that included
pharmacokinetic and target engagement profiles of the SC formulation, as well as a range of liver fibrosis biomarkers and physiologic
assessments measured at baseline and at week 20.
The trial enrolled 23 MASH patients
with stage F1c, F2 and F3 disease who were randomized to receive either nebokitug or placebo. Patients received eight doses of 5 mg/kg
of study drug administered by SC injection once every two weeks, for a treatment period of 16 weeks. Key findings of the nebokitug
Phase 2a trial included the following.
• |
Nebokitug appeared to be well tolerated when administered
subcutaneously. Most reported adverse events observed were mild, with one unrelated serious adverse event reported. No significant injection
site reactions were reported and no anti-drug antibodies, or ADAs, were detected. Nebokitug administered subcutaneously demonstrated
favorable pharmacokinetics and target engagement profiles as expected, which were similar to what we have previously reported. A
higher proportion of patients in the nebokitug-treated group showed improvement than in the placebo group in a number of liver fibrosis-related
biomarkers, including ProC-3, ProC-4, ProC-18, TIMP-1, ELF and Liver stiffness. |
Data from this trial provided important
insights in support of the nebokitug development program, including the favorable safety and tolerability of nebokitug in patients with
serious liver disease, confirmation of early signs of biomarker activity that are relevant for a number of fibro-inflammatory disorders,
and additional tolerability and pharmacokinetic data needed to assess next steps in the development of our current subcutaneous formulation.
Earlier, we also reported positive
clinical data from an investigator-initiated clinical study assessing nebokitug activity and safety in hospitalized patients with severe
lung injury derived from COVID-19. The objective of the study was to evaluate the drug’s safety and activity in hospitalized COVID-19
patients with severe pneumonia, including its impact on biomarkers related to lung inflammation that are also relevant in systemic sclerosis.
The open label, single arm trial enrolled 16 hospitalized adult COVID-19 patients with severe respiratory involvement. All patients were
receiving standard of care therapy. All were treated with a single 10mg/kg intravenous dose of nebokitug on the first day of the study
and followed for 30 days. Administration of nebokitug to this acutely ill patient population appeared to be well tolerated. Nebokitug
exposures and target engagement profiles were similar to what our researchers have seen in previous clinical studies of nebokitug. Importantly,
rapid reductions in serum biomarkers of lung inflammation, fibrogenesis and neutrophil activity were observed post-treatment with nebokitug.
Overall, this study confirmed and extended the safety and tolerability profile of nebokitug and demonstrated clinically relevant changes
in biomarkers associated with lung inflammation and fibrogenesis, further supporting nebokitug’s anti-inflammatory and anti-fibrotic
effects.
The Phase 2 SPRING study enrolled
76 patients with PSC who were treated with nebokitug or placebo for 15 weeks. The double-blinded trial design included 2 dose cohorts
of nebokitug (10 or 20 mg/kg) vs placebo who received treatment for 15 weeks, as well as an open-label (OLE) extension of 33 weeks to
evaluate the safety, tolerability and durability of effect over longer treatment durations. The open label part of the study included
50 patients who elected to continue, out of 54 patients who were eligible to enter into the open label phase.
In July, 2024 we reported the results
of the Phase 2 SPRING trial, a randomized, double-blind, placebo-controlled study of nebokitug in PSC patients. Nebokitug met the primary
study endpoint, demonstrating that it is well tolerated and nebokitug-treated patients with moderate/advanced disease showed improvements
on a wide range of disease-related secondary endpoints, including liver stiffness, liver fibrosis biomarkers, such as the Enhanced Liver
Fibrosis (ELF) score and PRO-C3 levels; total bilirubin and liver function tests; pruritus (itch) and markers of inflammation. Dose-dependent
responses were observed for multiple disease-related biomarkers. A consistent pattern of greater improvement on the secondary endpoints
was observed in the study arm receiving the 20mg/kg dose of nebokitug. This dose has been selected for the active treatment arm of the
Phase 3 trial design.
In March 2025, we reported the results
of the open label part of the study. The OLE study confirmed that in PSC patients receiving 10 mg/kg or 20 mg/kg of nebokitug administered
once every three weeks for 48 weeks, the drug was safe and well-tolerated and resulted in positive effects, including continued improvements
in key liver biomarkers such as the ELF score, the fibrosis-related components of ELF and the fibrosis biomarker PRO-C3. Liver stiffness
scores (transient elastography), as measured by FibroScan® were substantially lower in the nebokitug-treated patients with moderate/advanced
disease compared to matching historical controls. Cholestasis-related markers stabilized over 48 weeks of treatment and total serum bile
acids were reduced.
We may also explore nebokitug in other indications, where
the dual activity of nebokitug acting on both inflammation and fibrosis could provide new avenues for treating inflammatory and fibrotic
conditions.
Chemomab was founded in 2011, based
on a novel discovery originating from the Sourasky Medical Center in Tel-Aviv, Israel, where Professor Jacob George first identified CCL24
as a key regulator of unstable plaque formation in atherosclerotic patients. In our early years, we focused on research directed at clarifying
the role and effectiveness of CCL24 blockade. In 2015, we selected our proprietary lead product candidate, nebokitug, and started product
development directed towards human testing.
We have assembled an executive team with highly relevant
experience in inflammation and fibrosis, and biologics drug discovery and clinical development. Adi Mor, Ph.D., our Chief Executive Officer,
Chief Scientific Officer and Co-founder, has 16 years of experience in immunology and has led the nebokitug program from discovery stage
into Phase 2 clinical studies. Matthew Frankel, M.D., our Chief Medical Officer, brings deep experience in clinical development. Dr. Frankel,
who is based in the U.S., has more than 25 years of experience in the discovery and clinical development of novel therapeutics and has
held senior executive roles at both global pharmaceutical and biotechnology companies. Jack Lawler, our Senior Vice President of Global
Development Operations, is highly experienced in managing clinical trials across a wide range of indications and geographies.
Company strategy
We aim to become a world-leading
company for the treatment of diseases involving inflammation and fibrosis, developing novel therapies across a wide range of indications.
To achieve this, we are focused on the following key strategies:
• |
Advance our lead product, nebokitug, for the
treatment of PSC and potentially SSc, through clinical development to approval |
The clinical development plan of
lead product candidate nebokitug was optimized to maximize the clinical information obtained, generating additional important data to
support future advancement to registration trials, and decreasing the overall risk of the nebokitug clinical development program in the
lead indication of PSC and potentially SSc, as well as potentially in additional indications where the scientific rationale is strong.
• |
Selectively evaluate partnership opportunities
|
We continuously explore partnership
opportunities to advance nebokitug development in PSC and SSc, and possibly additional indications, identifying companies with drugs (either
approved or in development) that could possibly be combined with nebokitug, extending the development of nebokitug to new indications
beyond PSC and SSc, and seeking additional significant commercial or drug development capabilities that may accelerate nebokitug’s
time to market.
• |
Explore opportunities for nebokitug in additional
inflammatory/fibrotic indications |
We continue to evaluate the potential
benefit of nebokitug outside of our current lead indications of PSC and SSc, in order to maximize the product’s potential. nebokitug
has shown anti-fibrotic activity in animal models and human tissue studies of IPF and MASH. We will continue to assess ways to leverage
the dual anti-inflammatory and anti-fibrotic activity of nebokitug in new disease areas and to form additional collaborations with global
medical researchers and drug developers.
• |
Strengthen our intellectual property portfolio
|
We believe that we have developed a strong intellectual
property portfolio and will continue to seek, maintain, and defend our patent rights, whether developed internally or licensed to protect
and enhance the proprietary technology, inventions, and improvements that are commercially important to the development of our business
proprietary position in the field of inflammation and fibrosis.
Fibrosis and inflammation
Tissue damage activates a repair
process that includes acute inflammation followed by either successful complete repair or tissue replacement by fibrosis. However, persistent
and repeated damage can result in continuous activation of the repair process leading to chronic inflammation, progressive tissue fibrosis
and sclerosis.
Fibrosis is an accumulation of non-functional
tissue and can occur in many different tissues, including lung, liver, kidney, muscle, skin and the gastrointestinal tract, resulting
in a number of chronic fibrotic conditions. Liver fibrosis is the process of excessive accumulation of extracellular matrix proteins,
predominantly collagen, which occurs as the result of liver injury. In cases of acute temporary damage, these changes are transient and
liver fibrosis may resolve. In chronic cases, however, the liver damage persists and chronic inflammation and accumulation of the extracellular
matrix eventually lead to cirrhosis. The various fibrotic manifestations in conditions like SSc are still not well understood. Disease
progression is characterized by an early inflammatory onset followed by tissue fibrosis, vascular injury and organ damage. Fibrosis, and
specifically lung fibrosis, is the main cause of disease progression and mortality in SSc, although manifestation of the disease in other
organs can cause patients considerable distress and adversely impact their health and their quality of life.
Fibrosis and inflammation are intrinsically
linked; a healthy inflammatory response is necessary for efficient wound healing; however, a prolonged response can contribute to the
pathogenesis of fibrosis. The inflammatory response during chronic liver injury is a dynamic process with intrahepatic accumulation of
diverse immune cells. Recruitment and infiltration of these cells to the liver and their localization is mainly determined by chemokines
and cytokines that are produced by hepatocytes, immune cells, biliary epithelial cells, and endothelial cells. Notably, activated liver
fibroblasts, the hepatic stellate cells, or HSCs, secrete various chemokines, thereby contributing to the ongoing immune response during
fibrotic liver diseases. Similarly, for SSc, the early inflammatory phase leading to fibrosis in multiple organs of the body includes
activation of the immune cell network of lymphocytes, eosinophils, and monocytes, as well as endothelial and endothelial progenitor cells.
In the advanced SSc phase, fibroblasts and myofibroblasts take the lead to generate tissue fibrosis.
Chemokine involvement
in inflammation and fibrosis
Chemokines are a group of small signaling
proteins thought to be involved in the etiology, or causation, of multiple inflammatory diseases. They are not only implicated in immune
cell recruitment during inflammation, but also contribute to immune surveillance, direct cells to target organs in homeostasis, and exert
pleiotropic, or diverse, effects on non-immune cells, for instance, directly influencing the functionality of fibrogenic cells. Chemokines
and their corresponding chemokine receptors are key players in orchestrating the sequential influx of immune cells into damaged or diseased
organs, driving inflammatory responses to specific triggers.
In the liver, chemokines have a key
role in the development of inflammation and wound healing responses, which can lead to either resolution of liver injury or promote, if
ongoing, maladaptive responses with chronic inflammation, fibrosis, and development of clinically manifest liver disease. Although the
pathophysiology underlying PSC has not yet been fully clarified, animal models of PSC have contributed to dissecting the molecular basis
of this disease and highlighting the role of cytokines and chemokines as important pathogenetic mediators of liver inflammation and fibrosis.
Recently published studies demonstrated that in most of the processes suggested for the onset and development of PSC, chemokines and chemokine
receptors play a key role. Hematopoietic stem cells (HSCs) may be the main producers of cytokines and play an initial role in the
progression of liver fibrosis by attracting different types of immune cells, resulting in further production of cytokines and liver injury
in a vicious disease cycle. Extensive proliferation, trans-differentiation and activation of HSCs result in ongoing chronic tissue remodeling
and severe fibrosis. In addition, chemokines are also involved in promoting polarization of the recruited immune cells. Therefore, chemokines
may participate in PSC by promoting migration of inflammatory and fibrotic cells, by activating inflammatory and fibrotic cells locally,
or by inducing cytokines that promote collagen and matrix deposition.
Likewise, in SSc pathogenesis, chemokines
foster migration and activation of inflammatory and fibrotic cells, inducing the secretion of cytokines that promote collagen and matrix
deposition in affected organs. Indeed, patients with SSc exhibit increased systemic levels of proinflammatory chemokines and some of these
have also been shown to correlate with limited or diffuse cutaneous disease phenotype and/or to organ-specific pathology such as lung
disease or skin vascular inflammation.
The role of CCL24
CCL24 is a chemokine that promotes
various types of cellular processes that regulate inflammatory and fibrotic activities through the CCR3 receptor. This chemokine is known
to be expressed by activated T-cells, monocytes, epithelial cells and endothelial cells, as well as by activated fibroblasts. CCL24 induces
chemotaxis and activation of CCR3-expressing cells, including immune cells and fibroblasts.
We have been the driving force in
establishing the role of CCL24 in the pathogenesis of PSC and SSc, however, others have highlighted its contribution to other indications.
For example, published work has shown that both CCL24 and CCR3 are involved in lung and skin inflammation and fibrosis. CCR3 is robustly
expressed on eosinophils and recent data has suggested that eosinophilic inflammation may be involved in the pathogenesis and progression
of SSc. For example, in SSc patients, eosinophil counts, but not total leukocytes, were significantly higher than in patients with other
connective autoimmune diseases. Eosinophil counts correlated positively with both interstitial lung disease severity and the modified
Rodnan skin thickness score, or mRSS.
Notably, CCR3 was shown to be expressed
on oral and dermal fibroblasts where it modulates wound healing and tissue remodeling processes. A recent academic study also demonstrated
overexpression of CCR3 on monocyte populations isolated from SSc patients. CCL24 was shown to be involved in proinflammatory reactions,
specifically contributing to the type 2 immune reaction involving Th2 lymphocytes and M2 macrophages that were shown to be present in
skin lesions of SSc patients. Accordingly, CCL24 was found to play a dominant role in inducing profibrotic effects and to be overexpressed
in fibrotic lungs and bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis, a disease sharing similar lung dysfunction
features with SSc. Furthermore, CCL24 was shown to promote collagen production in human lung fibroblasts and to be constitutively expressed
by dermal fibroblasts.
CCL24 is a critical mediator promoting
inflammation and fibrosis
Challenges to
drug development in fibrosis and inflammation
Successful treatment of fibrotic
disorders has in large part remained elusive, primarily due to incomplete understanding of the complexity and multi-mechanism contributions
to disease progression. This has complicated preclinical investigations for new products and new targets, with animal models having limited
resemblance to human disease. Additionally, preclinical animal data is often of short treatment duration and does not capture the effects
of treating chronic fibrotic indications. This is particularly applicable to complex, orphan indications like PSC and SSc, where
there is still no approved standard of care or proven target mechanism.
Notwithstanding challenges in the
field of fibrosis and inflammation, there is significant and growing industry interest given the associated unmet medical need and the
continuing opportunity to identify better therapeutic targets. For example, in 2024 Gilead acquired Cymabay for its PPAR agonist in Primary
biliary cirrhosis. In 2019 Novartis completed two transactions related to the treatment of MASH, a liver metabolic fibrotic disease.
It acquired IFM Tre for NLRP3 antagonists for a $310 million upfront payment and total potential consideration of $1.5 billion and licensed
an integrin inhibitor from Pliant Therapeutics for an $80 million upfront payment. Additionally, Gilead Sciences licensed two preclinical
programs, one in MASH for a $15 million upfront payment (total potential consideration of $785 million) and the other for TGF-β inhibitors
in fibrosis for an $80 million upfront payment and total potential consideration of $1.4 billion. In 2020, Roche acquired Promedior for
a $390 million upfront payment and total potential consideration of $1 billion in milestones for its Phase 2 product in pulmonary fibrosis,
and Bayer partnered with Recursion Pharmaceuticals to develop and commercialize preclinical-stage small molecule treatments for fibrotic
conditions for a $30 million upfront payment and total potential consideration of $1 billion.
Targeting chemokines
as a treatment for fibrotic indications
We believe that our approach, selectively
targeting fibrotic conditions by attenuating both inflammation and fibrosis, may be an optimal approach for both effectiveness and reduction
of toxicity. As central regulators of initiation and progression of fibrotic disorders, chemokines are an ideal target to impact both
inflammation and fibrosis. Some chemokines are also disease-specific, allowing for potential selectivity.
Chemokine receptors, or CCRs, have
been more extensively studied as drug targets in fibrotic conditions compared to chemokine ligands, however, the therapeutic effects of
CCR inhibitors have generally fallen short in the clinic. Pharmaceutical companies have previously explored the CCL24 ligand receptor,
CCR3, and its other ligands CCL7 and CCL11, with small or large molecule inhibitors. These programs were directed at inhibiting eosinophilic
trafficking in respiratory and allergic inflammation, however, despite promising preclinical data, most programs were discontinued largely
due to poor safety profiles and limited efficacy of the antagonist used. To our knowledge, only Alkahest has an active program that explores
CCR3 inhibition, which is under license from Boehringer Ingelheim and is being developed as a treatment for wet AMD. In contrast, we believe
CCL24 presents a more promising opportunity. Unlike other CCR3 ligands, CCL24 binds only to the CCR3 receptor and is also organ/disease-specific,
which together could provide enhanced selectivity and tolerability. For example, in PSC, CCL24 is elevated in the liver and cholangiocytes
(bile duct epithelia) and immune cells that play a key role in the progression of the disease. Likewise, elevation of CCL24 has
been shown in fibrotic lungs and bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis, a disease sharing similar
lung dysfunction features with SSc and which recently was correlated, by us, with disease severity and lung involvement in a cohort of
SSc patients from the United Kingdom. Furthermore, CCL24 is constitutively expressed by skin and dermal fibroblasts. The use of an antibody
in targeting this chemokine is a novel approach to targeting fibrosis.
Our expertise and approach to drug
discovery
We are a clinical stage biotechnology
company focused on the discovery and development of novel drugs to address fibrotic indications with unmet medical needs. CCL24 is a key
target promoting fibrosis as it regulates the two main processes that drive fibrosis: fibroblast activation and immune cell migration
and activation. Using our expertise in monoclonal antibody, or mAb, development and deep knowledge of chemokine biology, we are developing
nebokitug, a proprietary, first-in-class, fully humanized mAb that through research and studies to date, has been shown to neutralize
CCL24 and by so doing inhibits its disease-related functions in both inflammation and fibrosis. This represents an innovative approach
to anti-fibrotic drug discovery and is a key differentiator for us. The ability of nebokitug to directly attenuate fibroblast activation
and concurrently attenuate recruitment of immune cells is novel and could address a wide range of hard-to-treat fibrotic diseases.
Our ongoing collaborations are complementary
to both preclinical and clinical aspects of research and development. We have created an extensive panel of in vitro, ex vivo and in vivo
assays which we have used to further the understanding of fibrotic processes together with the role of CCL24 in various diseases and the
effects of its neutralization by nebokitug. These assays have allowed us to sequentially explore target validation and proof of mechanism
in disease relevant human and animal samples that we believe help de-risk the translation of nebokitug into the clinic.
Target expression
and engagement
We regularly collaborate with leading
academic centers around the world to investigate the role of CCL24 and nebokitug in various indications. For example, we work with The
Royal Free Hospital, or RFH, in London, and Birmingham University in Birmingham, United Kingdom to access liver biopsy and serum samples
from patients with PSC. Using immunohistochemistry and florescence microscopy to stain CCL24 and CCR3, it explores the expression patterns
of these targets in disease relevant human samples and compares them to healthy volunteers. Similarly, we have tested biopsies of SSc
patients through a collaboration with the University of Florence in Italy and serum samples of SSc patients through a collaboration with
Leeds University in the UK.
Proof of mechanism
We explore fibroblast activation
and immune cell recruitment in response to nebokitug treatment through inhouse ex vivo and in vitro assays. We have executed multiple
validated genetic and treatment-based disease models in fibrotic and inflammatory indications in which we have investigated nebokitug’s
effects. Additionally, as part of a collaboration with Nordic Biosciences, Copenhagen, Denmark, we have gained access to proprietary tools
and expertise to explore the effects of nebokitug on key fibrogenesis and fibrolysis biomarkers. Nordic Biosciences is a world-leading
extracellular matrix specialist and continues to contribute additional analyses to our clinical samples.
We have created
a broad array of biological assays to explore CCL24 and nebokitug
We may explore next-generation biologic
products, and, based on our wide database of patient samples and extensive knowledge and experience in fibrosis, may identify targets
that could complement CCL24 inhibition. Next-generation assets could therefore be dual targeting and would be screened through the panel
of assays available to us that evaluate target expression in fibrotic tissues as well as the anti-fibrotic activity of potential candidates.
Similar to nebokitug, this process would establish proof-of-biological-mechanism in both animal models and human tissue prior to commencing
product development and initiating clinical studies.
Our pipeline
Nebokitug
in PSC and SSc
Our lead product, nebokitug, is a
first-in-class humanized monoclonal antibody targeting CCL24 that is being developed initially for the treatment of PSC and SSc, with
potential future opportunities in other fibrotic-inflammatory indications. We have completed two Phase 1a studies of nebokitug in healthy
volunteers as well as a Phase 1b safety, tolerability and proof-of-mechanism study in MAFLD patients and a Phase 2a liver fibrosis biomarker
study in MASH patients with liver fibrosis, which was reported in 2023. Topline results showed favorable safety and tolerability profiles
for nebokitug in patients with serious liver disease, confirmed early signs of biomarker activity that are also relevant for a number
of fibro-inflammatory disorders, and reinforced tolerability and pharmacokinetic data relevant to the development of our current subcutaneous
formulation.
In the Phase 2 SPRING trial in PSC,
nebokitug met the primary study endpoint, demonstrating that it is well tolerated and nebokitug-treated patients with moderate/advanced
disease showed improvements on a wide range of disease-related secondary endpoints, including liver stiffness, liver fibrosis biomarkers,
such as the Enhanced Liver Fibrosis (ELF) score and PRO-C3 levels; total bilirubin and liver function tests; pruritus (itch) and markers
of inflammation. Dose-dependent responses were observed for multiple disease-related biomarkers. A consistent pattern of greater improvement
on the secondary endpoints was observed in the study arm receiving the 20mg/kg dose of nebokitug, An Open Label Extension portion of this
study was recently reported in which nebokitug showed continued safety and activity over 48 weeks, most notably in the 20mg/kg dose arm
and in patients with moderate to advanced disease.
A global Phase 2 study in SSc that
will assess the safety and activity of nebokitug in this patient population has an open U.S. IND and is Phase 2-ready.
Primary
Sclerosing Cholangitis
PSC is a progressive, rare, and chronic
cholestatic liver disorder that is characterized by thickening, inflammation, and fibrosis of the intra- and extra-hepatic bile ducts.
This generally leads to cholestasis, liver damage, cirrhosis, and eventually liver failure. The exact cause of PSC remains mostly unknown;
however, immune system dysregulation, genes, viruses, and bacteria may be involved. PSC is commonly associated with inflammatory bowel
disease, or IBD. Approximately three in every four individuals with PSC also have ulcerative colitis. Most individuals affected with PSC
are adults with an average age of 40 years at diagnosis; however, it may also occur in children. Disease progression, symptoms, and severity
may vary greatly between individuals. Patients in the initial stages of PSC are generally asymptomatic or have only mild symptoms.
Abdominal discomfort, fatigue, and
pruritus, or itching, are common initial symptoms of PSC that can be severe and debilitating. The initial step in diagnosing PSC is to
evaluate liver enzyme levels through blood tests. Physicians will then confirm a diagnosis with cholangiography ultrasound and, in rare
cases, a liver biopsy. As the disease progresses, bile flow from the liver is obstructed and is subsequently absorbed into the bloodstream
leading to the yellowing of the mucous membranes, whites of the eyes, and skin. Furthermore, individuals may also experience abdominal
pain, malaise, light-colored stools, nausea, dark urine, weight loss, and/or hepatomegaly or splenomegaly. PSC patients have a 40-fold
increased risk of liver cancer and a 400-fold increased risk of cholangiocarcinoma, and the disease may lead to other conditions including
osteoporosis, bacterial cholangitis, portal hypertension, bleeding, as well as vitamin deficiencies.
There are currently no specific medical
therapies that can alter or cure the course of the disease; instead, available treatments are directed towards slowing the progression
of PSC and treating symptoms. In certain individuals, endoscopic surgery may be performed to enlarge the narrowed bile ducts and to remove
blockages. Complications due to vitamin deficiencies can be prevented with the help of vitamin supplements, while infections and inflammation
can be controlled by using antibiotics. Cholestyramine and UCDA can be effective in managing itching and can be used with or without antihistamines.
Patients with advanced symptoms such as end-stage liver disease, recurrent bacterial cholangitis and intractable pruritus, will often
undergo liver transplantation, however, in 20-25% of cases, PSC will recur even after liver transplantation. The median survival is 10-12
years without intervention.
Systemic
Sclerosis
SSc is an autoimmune inflammatory
condition that results in widespread fibrosis and vascular abnormalities affecting the skin, lungs, gastrointestinal tract, heart and
kidneys. Other key features of SSc include thickening and hardening of the skin, autoantibody production and abnormal nail fold capillaries.
The underlying mechanisms that cause SSc are complex and for the most part unknown but most likely involve a combination of factors including
the immune system, genetics, and environmental triggers. Various pathways are involved in the pathogenesis of SSc including cytokines
that injure blood vessels, growth factors that stimulate collagen, integrin signaling, morphogen pathways, and co-stimulatory pathways.
SSc is generally diagnosed between the age of 30 and 50 years and is more prevalent in women.
Given that SSc can affect many different
parts of the body there are a multitude of different symptoms of the disease. The most widely observed symptoms include fatigue, arthralgia,
and myalgia. However, the earliest sign is often the Raynaud phenomenon in which the body’s normal response to cold or emotional
stress is exaggerated, resulting in abnormal spasms in arterioles. Cutaneous features include sclerosis of the skin, particularly the
face and hands. Gastrointestinal symptoms of the upper tract include acid reflux and of the lower tract include bloating, nausea and incontinence.
Cardiopulmonary presentations include interstitial lung disease, pulmonary arterial hypertension and cardiac scleroderma. Renal and ocular
symptoms can also present and 20% of SSc patients have an overlapping diagnosis with other connective tissue diseases and can develop
arthritis, lupus or myositis. SSc is subdivided into two main types related to the distribution of skin involvement: diffuse cutaneous
(two-thirds of cases) and limited cutaneous. Diffuse SSc, or dcSSc, is rapidly progressive with more significant organ involvement.
There is no cure for SSc. Established
treatments can help with symptoms and may modify the disease outcome only if given early in the disease course. Prescribed medications,
used off-label, primarily focus on suppressing inflammation with NSAIDs and dilating abnormal or constricted blood vessels with losartan,
sildenafil, iloprost and SSRIs, or selective serotonin reuptake inhibitors, as well as treatments to manage individual organ involvement.
The only three drugs that are approved for the treatment of SSc symptoms are bosentan by Actelion Pharmaceuticals, approved in Europe
for the prevention of digital ulcer development, nintedanib by Boehringer Ingelheim, and tocilizumab by Roche, approved in the United
States, Europe and Japan for the treatment of SSc associated interstitial lung disease. The clinical course of SSc is determined by the
extent of vascular and fibrosis complications and has the highest mortality rate among the systemic rheumatic diseases. Forty percent
of patients die within 10 years of disease onset, with pulmonary involvement being the leading cause of death.
Nebokitug may have disease-modifying
potential
The dual anti-fibrotic and anti-inflammatory activity of nebokitug
enables the targeting of a wide range of pathogenic mechanisms and may afford patients a new treatment that may have a more impactful
effect on disease progression.

Targeting CCL24
offers a dual activity approach
In order to understand CCL24’s
role in disease pathophysiology, we have collected data on CCL24 levels from patients with multiple fibrotic-inflammatory indications,
including those with PSC, SSc and MASH. PSC patients’ liver biopsies and SSc skin samples were stained for CCL24 and its receptor,
CCR3. Blood samples taken from PSC and SSc patients were used to further evaluate the role of the CCL24-CCR3 axis exploring levels of
circulating CCL24 and CCR3. To explore the influence of CCL24 on disease status, CCL24 serum levels were correlated with fibrotic biomarkers
and disease severity markers.
CCL24 levels
in liver biopsies from PSC patients
PSC pathology generally initiates
with bile duct damage leading to cholestasis, bile duct inflammation and fibrosis and finally to substantial liver damage. We assessed
the accumulation and cellular localization of CCL24 in livers of PSC patients focusing on CCL24 levels in the periductal damaged zone
that is most relevant to disease pathology. CCL24 was mainly found in inflammatory cells in the liver of PSC patients. Due to the robust
liver inflammatory insult in PSC, reflected by massive accumulation of resident and recruited immune cells in the periductal space, CCL24
positive staining was extensive. Specific and robust CCL24 staining was also shown in cholangiocytes, the epithelial cells of the bile
ducts. Activated myofibroblasts that surround the bile ducts, whether they originate from hepatic stellate cells or portal fibroblasts,
are the main drivers of the excess extracellular matrix accumulation in this area, comprising the unique “onion ring” shape
seen in PSC liver sections. The collective expression pattern shows high CCL24 levels in areas that are most affected in PSC and highlights
its central role in PSC related liver pathology.

Elevated CCL24
staining in liver biopsies from PSC patients
CCR24 levels
association with PSC related pathways
To further elucidate the involvement
of CCL24 in PSC and its association with disease-related pathways, sera from healthy controls (n=30) and from patients with PSC (n=45)
were analyzed using the Olink proximity extension assay (PEA) of 3072 proteins. Serum proteomics data were analyzed according to three
comparisons: (1) healthy controls vs. patients with PSC, (2) fibrosis severity in patients, defined by ELF score (9.8 cutoff), and (3)
serum levels of CCL24 in patients.
Differentially expressed proteins
(DEPs) from each of the three comparisons were interpreted using Ingenuity Pathway Analysis (IPA), to identify dysregulated canonical
biological pathways, upstream regulators, and toxicity-functions. The enriched canonical pathways, upstream regulators and toxicity-functions
overlapped between the three comparisons (disease, fibrosis and CCL24), suggesting that there are biological mechanisms related to PSC
and its progression also related to CCL24 expression levels. Overlapping canonical pathways included HSC activation pathway, immune cell
trafficking pathways (granulocyte and agranulocyte adhesion and diapedesis) and inflammation pathways (Th1 and Th2 activation, Th1 activation
and pathogen induced cytokine storm). In patients with PSC, those that had high levels of CCL24 also showed significantly higher
average expression of these pathways.

PSC-related mechanisms are upregulated
in patients with high CCL24 levels. (A) Analysis over-view: sera from patients with PSC and HC were analyzed by the Olink Explore 3072
proteomic platform, and differentially expressed proteins (DEPs) were compared by disease, fibrosis or CCL24. (B) Score plots of principal
component analysis of proteome profiles in HC and Patients with PSC with low or high ELF scores. (C) Correlation of CCL24 to representative
proteins associated with inflammation/chemotaxis (CCL7 or CXCL10), in HC (n = 30) or patients with PSC with ALP > 1.5 ULN (n = 34).
(D-I) Ingenuity Pathway Analysis of canonical pathways, upstream regulators and liver-related toxicity functions. Venn diagrams show top
30 significant canonical pathways (D), top 20 significant upstream regulators (F), and significant liver-related toxicities (H). The average
ex-pression of protein lists of specific canonical pathways (E), upstream regulators (G) and liver-related toxicities (I) is presented
for HC and patients with low and high CCL24 serum levels. Boxes rep-resent interquartile ranges with medians (n = 20-30). *, p < 0.05;
**, p < 0.01; ****, P < 0.0001.
CCR3 levels in
circulating PBMCs in PSC patients
Chronic liver inflammation is driven
in most hepatic injuries by several different immune cell populations originating from either resident hepatic immune cells or recruited
cells from the circulation to the damaged site. In collaboration with the Kaplan Medical Center, Israel, we explored systemic changes
of CCR3, given that this could impact cell recruitment to the PSC damaged liver. Peripheral blood mononuclear cells (PBMCs) from ten PSC
patients and healthy controls were stained for expression of CCR3 and demonstrated that levels were significantly higher in PSC patient
samples compared to healthy donors.
CCL24 and CCR3
levels in skin biopsies from SSc patients
We analyzed skin samples from diffuse
SSc patients and healthy volunteers and the SSc samples showed elevations in CCL24 and CCR3. Specifically, higher accumulation of CCL24
on immune cells skin infiltration was shown in the SSc samples and CCR3 was evident in skin fibroblasts, immune cells and endothelial
cells. These elevations led to a CCL24-mediated robust activation of CCR3 expressing cells, which enhances the recruitment of immune cells
and fibroblasts to the diseased organ.
SSc patients showed
elevated levels of CCL24 in skin tissue
SSc patients showed
elevated levels of CCR3 in skin tissue
CCL24 levels
in serum samples from SSc patients and correlation with fibrotic biomarkers
Our researchers analyzed SSc serum
samples that showed that CCL24 levels were significantly increased in SSc patients compared with healthy individuals. Notably, in diffuse
SSc patients, CCL24 levels were fourfold higher than in healthy control patients. Additionally, the levels of CCL24 were correlated
with a biomarker of SSc severity, anti-topoisomerase, an autoantibody seen in diffuse SSc patients.
CCL24 levels in serum samples from
SSc patients and association with disease manifestations and mortality
The relationship between serum CCL24
levels and disease characteristics in a comprehensive real-life cohort of patients with SSc (n=213) was further studied. The study
highlights the association between higher CCL24 levels with critical clinical variables linked to the most severe forms of SSc. Specifically,
these variables include male gender, anti-Scl70 positivity, severity of skin fibrosis, presence of ILD, presence of digital ulcers and
lung microvascular impairment as measured by DLco. In a longitudinal setting, high serum CCL24 was predictive of lung deterioration. Accordingly,
a higher baseline CCL24 level was associated with SSc-related mortality.
Comparison of baseline serum CCL24
levels based on the occurrence of rapid ILD progression (A) and the relationship between baseline serum CCL24 levels and the relative
change in FVC over the following 12 months (B).
Cumulative incidence curves comparing
SSc-related and other-cause mortality in SSc patients with High and Low baseline CCL24 Status
Preclinical Efficacy
of nebokitug in models of PSC
Preclinical experiments in models
of PSC
• |
Human hepatic stellate cells demonstrated reduced transition to myofibroblasts following
incubation of nebokitug with CCL24. |
|
|
• |
Human hepatic stellate cells showed reduced motility towards CCL24 following treatment
with nebokitug. |
|
|
• |
Nebokitug demonstrated in vivo activity on liver fibrosis and cholangiocyte proliferation
induced by bile duct ligation in the Sprague Dawley rat model. |
|
|
• |
Nebokitug (D8-a murine surrogate of nebokitug) inhibits the progression of liver fibrosis
and bile duct damage in a chronic cholangitis cholestasis model using the hepatobiliary toxin ANIT. |
|
|
• |
Nebokitug (D8) reduces bile duct epithelial cell (cholangiocyte) proliferation, collagen
deposition, macrophage infiltration, liver enzymes, bile acid and circulating inflammatory monocytes in an experimental cholangitis model
in MDR2 knockout mice. |
|
|
• |
Nebokitug reduces liver enzymes, fibrosis, collagen, and fibrotic gene expression
in a TAA-induced liver fibrosis model in rats. |
|
|
• |
Nebokitug (D8) prevented fibrosis and inflammation in a TAA-induced liver fibrosis
model in mice. |
Results from the multi-drug resistant
2, or MDR2, knock out mouse model that reflects sclerosing cholangitis and the thioacetamide (TAA) rat model reflecting liver fibrosis
are described below.
Nebokitug demonstrates anti-cholestatic, anti-inflammatory,
and anti-fibrotic activity in MDR2 knock out mouse model in vivo
Mice with targeted disruption of
the MDR2 transporter gene develop chronic and progressive hepatic sclerosing cholangitis that closely resembles PSC and therefore this
model has been extensively used to study the pathogenesis and progression of PSC. Using MDR2 knockout mice (six weeks of age), we tested
the ability of nebokitug (D8) to attenuate PSC related symptoms. Mice (n=15/group) received either vehicle control, or nebokitug 10 mg/kg
SC twice weekly during weeks 6-12 following established disease and were sacrificed at the end of week 12. In this study mice were tested
for changes in alkaline phosphatase, or ALP, bile acid levels, collagen deposition (histology, Sirius red), macrophage presence in the
liver and cholangiocyte proliferation. We observed a significant decrease in all three core pathologies that play a role in PSC: inflammation,
fibrosis and cholangiocyte proliferation after nebokitug (D8) treatment compared to non-active treatment. Reduction in the serum markers
that represent the cholestatic state, ALP and bile acid, was also observed.

Nebokitug
reduces liver fibrosis, inflammation and bile duct epithelial proliferation in MDR2 knockout model
Nebokitug demonstrates
in vivo activity in a thioacetamide induced liver fibrosis model in rats using a therapeutic model
To assess the potential efficacy
of nebokitug on liver fibrosis, we used the TAA-induced liver fibrosis model. Liver fibrosis was induced by intraperitoneal administration
of TAA at a dose of 250 mg/kg twice weekly for eight weeks. Rats (n=10/group) received either vehicle control or nebokitug 2.5 mg/kg IV
twice weekly during weeks four to eight following established fibrosis and were sacrificed at week eight. After eight weeks of TAA treatment,
all vehicle-treated animals had developed liver fibrosis, as confirmed by Sirius-red-stained liver histology.
nebokitug reduces
fibrosis in rat livers
Plasma ALP, ALT, and AST levels decreased
in the nebokitug study arm. Liver collagen content and fibrotic areas were significantly reduced in the nebokitug-treated group compared
to non-active treatment. nebokitug was also shown to reduce fibrotic markers in the TAA treated rats.
Efficacy of nebokitug in models
of SSc
Preclinical experiments
in models of SSc
• |
Nebokitug reduces SSc serum-induced dermal fibroblast activation and transition to
myofibroblasts and interferes with endothelial cell activation. |
|
|
• |
Nebokitug treatment attenuated skin fibrotic remodeling in the bleomycin (BLM)-induced
dermal fibrosis mouse model. |
|
|
• |
Nebokitug attenuated lung fibrosis and inflammation in the bleomycin (BLM)-induced
pulmonary fibrosis mouse model. |
Results from the bleomycin (BLM)-induced
dermal and lung fibrosis mouse models are discussed below in more detail.
Nebokitug treatment
attenuates skin fibrotic remodeling in the bleomycin (BLM)-induced dermal fibrosis mouse model
The activity of nebokitug (D8) in SSc was tested in the
dermal bleomycin model. Treatment started after the onset of fibrotic signs, eight days following the first BLM injection. Histological
assessment of skin lesions stained with H&E and Masson’s trichrome revealed significant elevation of dermal thickness and collagen
deposition following 21 days of BLM administration. This elevation was significantly reduced when mice were treated with 2.5 mg/kg nebokitug
with significant reductions in both skin thickness and collagen deposition compared with the mouse group treated with BLM alone.
Nebokitug treatment
attenuates skin fibrotic remodeling in the bleomycin-induced dermal fibrosis mouse model
Another feature that characterizes
the BLM model and is representative of human SSc is the development of bronchoalveolar inflammation. To evaluate the effect of nebokitug
on lung inflammation, we collected bronchoalveolar lavage, or, BAL, fluid, and assessed the number of white blood cells, or WBC, and mononuclear
cells. Treatment with BLM for 21 days significantly increased WBC and mononuclear cells in BAL fluid and the number of WBC and mononuclear
cells was decreased significantly following nebokitug treatment compared with the group that was administered only BLM. This data supports
the anti-inflammatory effect of nebokitug in SSc.
Nebokitug inhibits
lung fibrosis in the BLM-induced pulmonary fibrosis mouse model
We also tested nebokitug in the experimental
lung SSc model where mice were given a single intratracheal administration of BLM followed by either nebokitug, non-active treatments
(PBS or control immunoglobulin G (IgG)) or the approved anti-fibrosis drugs, pirfenidone and nintedanib. nebokitug had a significant anti-fibrotic
and anti-inflammatory effect in the experimental BLM-induced lung fibrosis model as compared with non-active treatment-treated animals.
BLM animals treated with non-active treatments showed massive immune cell infiltration, extensive fibrosis and severe tissue injury. nebokitug-treated
mice exhibited significantly reduced levels of lung fibrosis similar to levels in healthy animals and showed superior effects compared
to the approved fibrosis drugs pirfenidone and nintedanib.
Nebokitug attenuates
lung fibrosis and collagen deposition in the bleomycin (BLM)-induced pulmonary fibrosis mouse model
Preclinical safety
and toxicology of nebokitug
Preclinical safety evaluation of
nebokitug included tissue cross reactivity, assessment of the effect of nebokitug on pro-inflammatory cytokine secretion ex-vivo, and
in vivo GLP toxicology studies in mice and non-human primates. No safety concerns were observed in these preclinical assessments.
Immunogenicity may be triggered following
administration of humanized monoclonal antibodies, an effect that is frequently seen with approved mAbs. To date, no meaningful ADA effects
were identified in three completed clinical studies, which supports a preliminary conclusion that nebokitug may have low immunogenic potential.
As summarized below, there were no safety concerns related
to nebokitug in any of the other preclinical safety experiments.
Summary of key preclinical safety experiments
Preclinical findings |
|
Observation |
Ex vivo |
|
|
Antibody dependent cell-cytotoxic (ADCC) and complement
dependent cell-cytotoxic (CDC) activity was tested in PBMCs from healthy volunteers.
|
|
Nebokitug did not have Fc-related effector functions
such as ADCC and CDC.
|
Cytokine release was assessed in human whole blood from
healthy volunteers.
|
|
Nebokitug did not induce pro-inflammatory cytokine secretion.
|
Tissue cross reactivity was evaluated from healthy human
tissues.
|
|
Nebokitug does not bind non-specifically to healthy
tissues, and therefore is expected to only bind to its target, circulating CCL24.
|
In vivo
|
|
|
GLP repeated dose 4-week toxicity study of nebokitug
(IV) in mice.
|
|
1. No obvious treatment related adverse reactions.
2. No gross or microscopic pathological findings.
3. No cases of treatment related mortality were observed.
4. No significant elevation was seen in IL1β, IL2, IL4, IL5, IL10, GM-CSF,
IFN and TNFα. |
GLP repeated dose (up to 50 mg/kg) 6-month toxicity
study of nebokitug (SC) in Cynomolgus Monkey.
|
|
1. No obvious treatment related adverse reactions.
2. No clinical signs or injection site reactions.
3. No cases of treatment related mortality were observed.
4. Blood and urine tests were found to be within normal ranges for monkeys.
5. No treatment-related organ weight changes and no treatment-related necropsy
findings.
6. No treatment-related histopathology findings.
7. Three samples from treated animals were confirmed ADA positive but there
was no obvious correlation between positive ADA results and nebokitug serum concentrations or systemic exposure. |
Preclinical proof
of mechanism studies for nebokitug
We conducted a series of in vitro
and in vivo studies to demonstrate the proposed mechanism of action and provide proof-of-concept for administering nebokitug in the clinic
for target indications.
Affinity, selectivity,
and binding kinetics
We evaluated the kinetic binding
parameters of nebokitug to human CCL24, as well as the specificity of nebokitug binding to other chemokines using commercial binding assays.
nebokitug demonstrated a strong and stable, high affinity binding to CCL24.
Nebokitug reduced CCL24 dependent
CCR3 activation
In an in
vitro assay, nebokitug was shown to robustly attenuate the ability of CCL24 to induce activation of the CCR3 receptor following
pre-incubation of CCL24 with nebokitug.
Clinical Development
of nebokitug
Completed clinical studies
The nebokitug Phase 1 program included
two Phase 1a single administration, or SAD, studies, using IV and SC administration with doses ranging from 0.75-10 mg/kg, in healthy
volunteers and a Phase 1b multiple administration (MAD) study (5 administrations) in MAFLD patients with normal liver function, testing
2.5 mg/kg IV and 5 mg/kg SC. In the Phase 1 studies 42 subjects have received at least one nebokitug dose, the majority by IV infusion
(12/42 subjects received SC).
Safety
The first Phase 1a study, which was
a single-center, randomized double-blind, placebo-controlled, single-dose, dose-escalation study, included four escalating dose groups
of eight subjects each. In each dose group subjects were randomized in a 3:1 ratio to receive a single IV infusion of either nebokitug
(n=6) or placebo (n=2). A total of 24 subjects were enrolled into the study and randomized to the treatment groups (0.75 mg/ kg, 2.5 mg/kg,
5.0 mg/kg, 10 mg/kg) and eight subjects received a placebo. All 32 subjects completed the study as planned. Single, IV doses of nebokitug
were well tolerated up to the highest dose level (10 mg/ kg) in healthy subjects. No severe or serious adverse events, or AEs, occurred
during the study and all nebokitug related AEs were mild, with one moderate AE reported in the placebo group (myalgia).
The second Phase 1a study was also
a single-center, randomized double-blind, placebo-controlled, single-dose study, but evaluated only one dose group. Subjects were randomized
in a 3:1 ratio to receive a single SC injection of either nebokitug 5 mg/kg (n=6) or matching placebo (n=2). A total of eight subjects
were enrolled into the study and randomized; all eight subjects completed the study as planned. Single SC administration of 5 mg/kg of
nebokitug was well tolerated with no severe or serious AEs occurring during the study. A total of 6 AEs were reported in two subjects
treated with nebokitug; only one AE was classified as related to nebokitug (change in diastolic blood pressure) and that AE was classified
as mild in intensity.
In both Phase 1a studies, all AEs
reported were resolved; no subjects discontinued the study prematurely due to AEs, and no concomitant medications were required for treatment
of any drug-related AEs. No clinically significant changes in laboratory tests (hematology, chemistry or urinalysis), vital signs, ECG,
physical examination or infusion site examination were observed. In the first Phase 1a study with nebokitug delivered by IV administration,
the effect on cytokine secretion was tested pre-treatment and one hour, eight hours and 24 hours post drug administration. Serum levels
of a panel of cytokines including IL-6, IFNγ, GM-CSF, TNF-α, IL-2, IL-4, IL-8 and IL-10 showed no significant change at all
tested nebokitug doses and timepoints. These findings suggest that single nebokitug administration does not cause immune activation nor
cytokine secretion. Additionally, none of the subjects in either of the Phase 1a studies tested positive for anti-drug antibodies (ADA).
The multiple administration randomized,
placebo-controlled, Phase 1b study in MAFLD patients with normal liver function tests evaluated two dose levels. The first dose level
of 2.5 mg/kg nebokitug was administered as an IV infusion and the second dose level of 5 mg/kg was administered as an SC injection. Both
dose levels involved five drug administrations over 12 weeks (Q3W), providing 15 weeks of treatment coverage. At both dose levels, subjects
were randomized in a 3:1 ratio to receive either nebokitug (n=6 per cohort) (2.5 mg/kg IV or 5 mg/kg SC) or matching placebo (n=2 per
cohort). Five repeated IV and SC nebokitug administrations were well tolerated and there were no deaths, or severe or serious drug related
AEs reported throughout the study. Only mild to moderate AEs were reported in the nebokitug treatment groups of which only two AEs were
classified as possibly related to nebokitug. No injection site reactions or clinically significant trends in laboratory tests (hematology,
chemistry, or urinalysis), vital signs, ECG or physical examination were observed. One patient experienced a non-drug-related SAE. This
patient was a 61-year-old female that was subsequently diagnosed with a non-treatment related meningioma. The tumor was treated surgically,
and the patient was discontinued from the study.
Pharmacokinetics with single-dose
administration
PK analysis was conducted for the
Phase 1 studies and the quantification of nebokitug in plasma samples was performed using a validated ELISA-based assay by Eurofins (UK).
Following IV infusion in healthy volunteers, nebokitug exhibited a biphasic serum concentration vs. time curve (rapid distribution phase
and slow elimination phase) which is typical for monoclonal antibodies. Target-mediated drug disposition (TMDD), or presence of ADAs,
was not evident in the analyzed concentration vs. time curves of nebokitug, which exhibited linear terminal slope without apparent TMDD
kinetics or other concentration-dependent changes of the elimination kinetics. Comparison of the PK data of 5 mg/kg nebokitug using IV
administration against SC administration indicates consistent distribution and elimination behavior of nebokitug.
At either IV or SC administration,
the values of the PK parameters obtained in the non-compartmental and compartmental analysis of nebokitug concentration vs. time data
appear to be typical for monoclonal antibodies that undergo FcRn-mediated recycling. The terminal half-life of nebokitug was long for
both SC and IV formulations, which supports administration of nebokitug at a frequency of once every 2-4 weeks.
Pharmacokinetics with multiple-dose
administration
PK analysis of the data from the
Phase 1b study was conducted to evaluate nebokitug following multiple IV infusion of 2.5 mg/kg or 5 mg/kg SC injections of nebokitug in
MAFLD patients. Following repeated IV infusions (2.5 mg/kg Q3W) and SC injection (5 mg/kg Q3W), nebokitug exhibited a long terminal half-life,
similar to the terminal half-life seen in the single dose studies. nebokitug accumulated over time, resulting in significant systemic
exposure over time and potentially reaching a steady state.
Overall, nebokitug reached steady
state conditions more slowly following SC injection, as compared to IV infusion. The inter-patient variability in nebokitug serum concentrations
was higher for SC dosing injection, as compared to IV. The trough nebokitug serum concentrations after repeated 5 mg/kg SC injections
were proportionally higher than those after 2.5 mg/kg IV infusions, considering the difference in administration modes. Comparison of
the PK data of nebokitug in the Phase 1b to the Phase 1a studies indicates a consistency in PK behavior of nebokitug.
Pharmacodynamics and target engagement
of nebokitug
Serum was taken from patients in
all three Phase 1 studies at different times and the levels of both CCL24 and nebokitug were measured. Total CCL24 levels represent nebokitug’s
engagement to its target. Total CCL24 levels were increased following administration of the drug, which indicates that nebokitug is effective
in target engagement, as the higher levels of CCL24 correlated significantly with greater doses of nebokitug, and such levels decreased
gradually from the peak of nebokitug administration. These findings demonstrate that nebokitug effectively binds to CCL24 in the circulation,
which reflects a strong drug-target interaction.
In the Phase 1b study, nebokitug
treatment of 2.5mg/kg IV attained the highest levels of total CCL24 by the third administration, maintaining these levels until the end
of treatment. Nebokitug 5mg/kg administered by SC injection reached the highest levels of CCL24 by the fourth treatment and maintained
these levels until the end of treatment. The matching placebo did not have any effect on CCL24 levels.
As exemplified in the in-vitro studies,
binding of CCL24 by nebokitug attenuates the binding of CCL24 to its cognate CCR3 receptor, thereby reducing its downstream activation.
Altogether, CCL24 levels following treatment with nebokitug provide strong evidence for target engagement and pharmacodynamic response
of nebokitug in healthy volunteers and patients.
Phase 1b exploratory endpoints
Fibrotic biomarkers were analyzed
as part of the Phase 1b study in NAFLD patients with normal liver function. Circulating fibrotic biomarkers were tested in serum pre-
and post-treatment. The analysis included data from patients that presented with more active disease, reflected by baseline elastography
(FibroScan) score >4 kPa. Tissue inhibitor of metalloproteinases-1 (TIMP-1) and tissue inhibitor of metalloproteinases-2 (TIMP-2),
considered well established fibrotic biomarkers, were evaluated, and showed that nebokitug treatment led to reductions of both markers
by week 15. The growth factor PDGF-AA, known as a pro-fibrotic secreted factor, was also reduced in nebokitug treated patients. Conversely,
in the placebo group TIMP-1, TIMP-2 and PDGF-AA all increased.
Evaluation of the fibrogenesis and
fibrolysis/inflammatory biomarkers, Pro-C3, Pro-C4 and C3M measured in serum, conducted by Nordic Bioscience, Copenhagen, Denmark, were
also used as sensitive indicators of the liver’s fibrotic state. In accordance with reduced liver stiffness, Pro-C3, Pro-C4 and
C3M were all reduced in the nebokitug treated groups. No reductions were identified in the placebo control group.
Changes in liver stiffness, a measurement
of liver fibrosis, were also evaluated using FibroScan measurements taken at screening and end of treatment (EoT) following 15 weeks of
treatment coverage. 80% of nebokitug treated patients had significant decreases in FibroScan measurements, unlike placebo patients where
there was no significant change from baseline.
Results of investigator-initiated clinical study of nebokitug
in patients with COVID-19-derived lung damage
On November 9, 2022, encouraging
clinical data from an investigator-initiated clinical study assessing nebokitug activity and safety in hospitalized patients with severe
lung injury derived from COVID-19 infection was presented at the 2022 Union Conference, an international conference on lung health. A
key rationale for the study is that some of the mechanisms underlying lung inflammation resulting from COVID-19 infection are similar
to those seen in systemic sclerosis and other chronic diseases involving lung inflammation and fibrosis.
The objective was to evaluate the
safety and activity of nebokitug in hospitalized COVID-19 patients with severe pneumonia, including its impact on biomarkers related to
lung inflammation that are also relevant in SSc. The open label, single arm trial enrolled
16 hospitalized adult COVID-19 patients with severe respiratory involvement. All patients were receiving standard of care therapy. All
were treated with a single 10mg/kg intravenous dose of nebokitug on the first day of the study and followed for 30 days.
Administration of nebokitug to this
acutely ill patient population appeared well tolerated. nebokitug exposures and target engagement profiles were similar to what our researchers
have seen in previous clinical studies of nebokitug.
Importantly, rapid reductions in
serum biomarkers of lung inflammation, fibrogenesis and neutrophil activity were observed post-treatment with nebokitug. Overall,
this study confirmed and extended the safety and tolerability profile of nebokitug and demonstrated clinically relevant changes in biomarkers
associated with lung inflammation and fibrogenesis, further supporting nebokitug’s anti-inflammatory and anti-fibrotic effects.
Moreover, we believe that these results
add to the data suggesting that nebokitug has the potential to attenuate lung inflammation and fibrosis, further strengthening the rationale
for treating SSc patients with this drug. These new clinical data also contribute to a growing body of evidence demonstrating nebokitug’s
anti-fibrotic and anti-inflammatory effects in varied organs including the lung, liver and skin.
Primary endpoints for the study were
safety and tolerability. Secondary endpoints included the evaluation of the pharmacokinetic and target engagement profile of the SC formulation
as well as changes in relevant biomarkers that may provide further mechanistic understanding of nebokitug effects on liver fibrosis. This
trial was primarily designed to assess a subcutaneous formulation of nebokitug and to evaluate the drug’s impact on liver fibrosis
biomarkers relevant to both MASH and fibro-inflammatory conditions that represent the focus for Chemomab, such as PSC and SSc.
The randomized, placebo-controlled
trial enrolled 23 MASH patients with stage F1c, F2 and F3 disease who were randomized to receive either nebokitug or placebo. Patients
received eight doses of 5 mg/kg of study drug administered by subcutaneous injection once every two weeks, for a treatment period of 16
weeks. Key findings of the nebokitug Phase 2a trial included the following.
• |
Nebokitug appeared to be well tolerated when administered subcutaneously. Most reported
adverse events observed were mild, with one unrelated serious adverse event reported. No significant injection site reactions were reported
and no anti-drug antibodies were detected. |
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• |
Nebokitug administered subcutaneously demonstrated favorable pharmacokinetics and
target engagement profiles as expected and were similar to what we have previously reported. |
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• |
Nebokitug-treated patients showed greater improvements than the placebo group in a
number of liver fibrosis-related biomarkers, including ProC-3, ProC-4, ProC-18, TIMP-1 and ELF. |
|
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• |
A majority of nebokitug-treated patients showed improvements in more than one liver
fibrosis-related biomarker—almost 60% of nebokitug patients responded in at least three biomarkers at week 20, compared to no patients
in the placebo group. |
|
|
• |
A higher proportion of patients in the nebokitug-treated group showed improvement
in a physiologic measure of liver stiffness as compared to placebo (reduction of at least one grade of fibrosis score as assessed by the
non-invasive elastography method known as FibroScan®). |
|
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• |
Nebokitug-treated patients with higher CCL24 levels at baseline showed greater reductions
in fibrosis-related biomarkers than patients with lower levels. Multiple fibrosis-related biomarkers showed more pronounced reductions
in nebokitug-treated patients who had higher CCL24 levels at baseline than in patients with lower CCL24 levels at baseline, adding to
the growing body of evidence validating the role of CCL24 in the pathophysiology of fibrotic liver disease. |
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• |
After completion of the study, the unblinded data showed that patients in the nebokitug-treated
group had higher baseline levels of fibrosis compared to placebo patients. The impact of this difference on the results, if any, is unknown.
|
Secondary analysis results of Phase
2a study in patients with liver fibrosis derived from MASH
In June 2023, at the 2023 EASL Congress, Chemomab
researchers reported topline results from secondary analyses of the Phase 2a liver fibrosis trial assessing nebokitug, in patients with
MASH. The results were included in a late-breaking poster presentation.
Overall, the data showed improvements
across an additional set of inflammatory and fibrotic biomarkers that are consistent with the positive clinical results Chemomab released
in January of 2023. Additionally, in MASH patients at greater risk of disease progression, nebokitug treatment resulted in a greater biomarker
response than in MASH patients with lower risk disease or in placebo-treated patients.
The new analyses assessed additional
biomarkers and also used the FibroScan-AST (FAST) score to categorize study patients based on progressive disease risk, thereby enabling
the evaluation of nebokitug activity in the main target population of patients with more active disease. FAST is a validated score
composed of non-invasive FibroScan® and AST
measurements that is used to identify patients with a high risk of MASH progression. The results showed that:
• |
FAST scores were improved in a higher proportion of nebokitug-treated patients than
in placebo patients. |
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• |
Nebokitug-treated patients with higher FAST scores demonstrated greater improvements
in key fibro-inflammatory biomarkers, such as Pro-C3, than patients with lower FAST scores or placebo patients. |
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• |
Nebokitug-treated patients with higher FAST scores showed improvements in several fibro-inflammatory
biomarkers generally comparable to those achieved in several recent successful MASH clinical trials. |
Additionally, in these secondary
analyses, nebokitug-treated patients showed improvements in an additional set of biomarkers associated with active fibrosis and inflammation:
• |
FIB-4, an index for determining MASH status that includes age, platelet count, AST
and ALT levels, was improved in nebokitug-treated patients vs. placebo patients. |
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• |
AST/ALT ratio, a liver enzyme ratio, was improved in nebokitug-treated patients vs.
placebo patients. |
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• |
Neutrophil-to-Lymphocyte Ratio (NLR), an indicator of inflammation, was improved in
nebokitug-treated patients vs. placebo patients, and NLR was further improved in groups with higher FAST scores. |
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• |
PRO-C3, which captures active fibrogenesis and correlates with fibrotic disease severity,
was improved in nebokitug-treated patients vs. placebo patients and was further improved in groups with higher FAST scores. As an overall
indicator of fibrogenesis and fibrotic disease, PRO-C3 is also considered a potential "bridge" to PSC and other anti-fibrotic indications.
|
We believe the that the data analyses
from this trial provide important insights in support of the nebokitug development program, including the favorable safety and tolerability
of nebokitug in patients with serious liver disease, confirmation of early signs of biomarker activity that are relevant for a number
of fibro-inflammatory disorders, and support of the tolerability and pharmacokinetic data needed to assess next steps in the development
of our current subcutaneous formulation.
SPRING Trial: Phase
2 Clinical study in PSC
The Phase 2 SPRING trial in PSC was
a randomized, double-blind, placebo-controlled, study designed to evaluate the safety and efficacy of nebokitug in adult subjects with
PSC. Participants must have a serum alkaline phosphatase, or ALP, level of at least 1.5 times the upper limit of normal (x 1.5 ULN). Subjects
with concomitant inflammatory bowel disease (IBD) are eligible for recruitment if their disease is stable and there is an absence of high-grade
dysplasia in colonic biopsies within 18 months of randomization. Subjects were randomized to receive 10 mg/kg or 20mg/kg of nebokitug
IV, or placebo, in a 2:1 ratio. Patients received a dose of investigational product once every three weeks for a total of five administrations
resulting in a total coverage of 15 weeks during the double-blind portion of the study. The study design also includes a 33-week long
open-label extension period during which all participants receive either 10 mg/kg or 20 mg/kg of nebokitug via IV administration every
three weeks.
The primary endpoint for the study
is safety and tolerability. Secondary endpoints include evaluations of changes from baseline in the fibrotic marker enhanced liver function,
or ELF, score at week 15 as well as evaluation of change in liver stiffness using elastography. ELF score is a biochemical test panel
made up of serum markers that are indicators of the extracellular matrix. Additional secondary endpoints included evaluations of changes
from baseline in liver enzymes and additional fibrotic markers, including ALP, AST, ALT, total bilirubin, Pro-C3, as well as PK, PD and
ADA parameters. Measurements of cholestasis related activity like pruritus were also evaluated.
Nebokitug SPRING Trial – Overview of Key Results
Nebokitug met the primary study endpoint,
demonstrating it is well tolerated over the 15-week treatment period. Nebokitug -treated patients with moderate/advanced disease showed
improvements on a wide range of disease-related secondary endpoints, including assessments of changes from baseline relative to placebo
at Week 15 in liver stiffness; in liver fibrosis biomarkers, including the Enhanced Liver Fibrosis (ELF) score and PRO-C3 levels; in total
bilirubin and liver function tests; in pruritus (itch) and in markers of inflammation.
Dose-dependent responses were observed
for multiple disease-related biomarkers. A consistent pattern of greater improvement on the secondary endpoints was seen in the study
arm receiving 20 mg/kg of nebokitug and in the prespecified subgroup of PSC patients with moderate/advanced disease. Since PSC is a slowly
progressive disease, longer duration of treatment with nebokitug may also result in greater improvement in patient populations with lower
disease burden, with the goal of slowing or preventing disease progression.
Primary Endpoint
Nebokitug demonstrated it was well-tolerated
over the 15-week treatment period. It also exhibited favorable and dose-dependent pharmacokinetic profiles. Adverse events, which most
commonly included fatigue, headache, and pruritus, were generally mild/moderate and distributed similarly between the placebo and nebokitug
-treated dosing arms.
Key Secondary Endpoints
Liver Stiffness Measures
Improved in Nebokitug -Treated PSC Patients
Notably, both doses of nebokitug
improved liver stiffness relative to placebo at Week 15, with a statistically significant improvement achieved in patients with moderate/advanced
disease This is the first time that an investigational drug for the treatment of PSC has demonstrated significant improvements in liver
stiffness in a relatively short study.
ELF Score Improved in Nebokitug
-Treated PSC Patients
Patients treated with the 20 mg/kg
dose of nebokitug with moderate/advanced disease had reduced ELF scores relative to placebo at all time points in the trial. In addition,
in all patients treated with the 20 mg/kg dose of nebokitug, ELF changes from baseline remained consistently below 0.19, a recognized
threshold for predicting long-term PSC-related clinical events.
PRO-C3 Improved in Nebokitug
-Treated in PSC Patients
Reductions in PRO-C3 levels at Week
15 relative to placebo were observed in patients receiving both the 10 mg/kg and 20 mg/kg doses of nebokitug. PRO-C3, a
serum biomarker of type III collagen synthesis, has been shown to be elevated in patients with PSC and has been identified as an independent
predictor of transplant-free survival in PSC.
Total Bilirubin Improved
in Nebokitug -Treated PSC Patients
Bilirubin is a key biomarker that
is an indicator of bile duct health. Nebokitug -treated patients showed a dose-dependent improvement in total bilirubin relative to placebo
at Week 15 that further supports the anti-cholestatic activity of nebokitug
5-D Itch Scale Total
Pruritus Scores Improved in Nebokitug -Treated PSC Patients
Pruritus total scores on the 5-D
Itch Scale relative to placebo improved in nebokitug -treated patients, who demonstrated decreased pruritus scores compared to placebo
starting as soon as six weeks after their first dose. Nebokitug -treated patients experienced decreased pruritus scores across
all timepoints compared to placebo and the decrease reached statistical significance in patients receiving the 10 mg/kg dose at Week 15.
Liver Function Tests
Improved in Nebokitug -Treated PSC Patients
All liver function tests improved
in nebokitug -treated patients relative to placebo at Week 15. Levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT) aspartate
aminotransferase (AST) and gamma-glutamyl transferase (GGT) decreased in nebokitug -treated patients receiving the 20 mg/kg dose.
Anti-inflammatory Activity
Demonstrated in Nebokitug -Treated PSC Patients
Levels of the inflammatory cytokines
IL-6 and TGFβ1, which are known to play an important role in inflammation and fibrosis, were reduced in nebokitug -treated patients
relative to placebo at Week 15. The reduction reached statistical significance in moderate/advanced disease patients receiving the 20
mg/kg dose.
SPRING Trial Open Label Extension
(OLE)
More than 90% of SPRING trial patients
eligible to participate in the OLE (50 out of 54 eligibles) chose to continue. OLE participants who had been in the treatment arms of
the 15-week double-blinded portion of the SPRING trial received another 33 weeks of treatment with nebokitug, for at total of up to 48
weeks of treatment, and former placebo patients crossed over to receive 33-weeks of treatment with nebokitug.
The OLE study confirmed that in PSC
patients receiving 10 mg/kg or 20 mg/kg of nebokitug administered once every three weeks for 48 weeks, the drug was safe and well-tolerated
and resulted in positive effects, including continued improvements in key liver biomarkers such as the ELF score, the fibrosis-related
components of ELF and the fibrosis biomarker PRO-C3. Liver stiffness scores (transient elastography), as measured by FibroScan®
were substantially lower in the nebokitug-treated patients with moderate/advanced disease compared to matching historical controls. Cholestasis-related
markers stabilized over 48 weeks of treatment and total serum bile acids were reduced. OLE patients with moderate/advanced disease treated
with nebokitug for 48 weeks showed a significantly lower number of clinical events (4.8%) compared to matching historical controls (25.8%).
Results from the patients receiving placebo in the double-blinded period who rolled over to receive 33 weeks of treatment with nebokitug
during the OLE were consistent with the results in patients treated with nebokitug in the double-blinded study, including stabilization
of ELF scores and improvements in liver stiffness compared to baseline.
The company views the broad and consistent
stabilization and improvement in disease-related biomarkers for up to 48 weeks of nebokitug treatment in the OLE results, including reductions
in the risk of disease progression as shown by the ELF score, as directly translatable and potentially derisking to the planned nebokitug
PSC Phase 3 study. Additionally, the new data showed a lower rate of clinical events in patients treated with nebokitug for up to
48 weeks compared to historical controls, further increasing confidence in the Phase 3 trial design, where the primary endpoint is reduction
in time to first clinical event. The findings represent an important milestone in Chemomab’s continued clinical progress and reinforce
the rationale for the planned Phase 3 trial that provides a pathway to potential full regulatory approval for nebokitug in PSC.
Phase 2 in SSc
Chemomab has a Phase 2 ready study
in SSc that may enable proof-of-concept and further elucidation of different nebokitug mechanisms of action in treating SSc skin, lung
and vascular damage. The U.S. FDA cleared our IND application to commence the Phase 2 SSc trial
Competition
The development and commercialization
of new drug products is highly competitive across major pharmaceutical companies, specialty pharmaceutical companies and biotechnology
companies worldwide. We face competition with respect to our current product and expect to face competition with respect to any product
candidates that we may develop or commercialize in the future. Specifically, there are a number of companies developing treatments for
fibrotic/inflammatory diseases, including multiple major pharmaceutical and biotechnology companies with substantially greater resources
than us. We are a small biotech company with limited resources compared to the major pharmaceutical companies, however, we believe that
the unique nebokitug platform together with our knowledge and experience in inflammatory-fibrotic research provides us with competitive
advantages.
Therapeutic options for PSC and SSc
are limited and despite significant biopharmaceutical industry investment, the FDA has not approved any disease modifying therapies for
the treatment of PSC or SSc. Liver transplant is currently the only treatment shown to improve clinical outcomes for PSC patients while
SSc patients are being treated with drugs that were approved for different manifestations of the disease like interstitial lung disease
(nintedanib, Boehringer Ingelheim and tocilizumab, Hoffmann-La Roche).
We are assessing nebokitug, a first-in-class
monoclonal antibody that interferes directly with both inflammation and fibrosis, into clinical development for the treatment of PSC and
SSc. There are a number of large biopharmaceutical and biotechnology companies that are currently pursuing the development of products
for the treatment of fibrotic indications like PSC and SSc, such as, Mitsubishi Tanabe Pharma, Horizon Therapeutics, Pliant Therapeutics, and
others. However, we know of no other companies currently in clinical development with a monoclonal antibody that targets CCL24.
Although the approach is novel with
respect to targeting both inflammation and fibrosis, we will need to compete with products further advanced in the pipeline towards market
approval. Investigational products, include:
There are currently no FDA-approved
therapies for the treatment of PSC. Companies currently developing product candidates in Phase 3 clinical studies include Dr. Falk Pharma,
targeting cholestasis and liver metabolism (Dr. Falk; norUrso), rather than anti-fibrotic and anti-inflammatory manifestations of PSC.
Other companies with clinical candidates in earlier stages of development include Mirum Pharmaceuticals and NGM Bio. As shown in the table
below, most competitors are targeting the metabolic or symptomatic aspects of PSC. Only the Chemomab and NGM Bio compounds have disease
modifying potential, and we believe that our unique dual anti-fibrotic and anti-inflammatory activity gives nebokitug a potential advantage.

There are currently two FDA approved
products for the treatment of clinical manifestations of SSc--nintedanib, marketed by Boehringer Ingelheim GmbH and tocilizumab, marketed
by Hoffmann-La Roche for the treatment of interstitial lung disease. Companies currently developing product candidates in SSc in early
clinical stage include Amgen, Merck, GSK, Boehringer Ingelheim , AstraZeneca, and others. Additionally a number of pharmaceutical and
biotechnology companies are in the early stages of assessing new approaches that might be applicable to the treatment of SSc, such as
CAR-T cell therapies.
The availability of reimbursement
from government and other third-party payors will affect the pricing and competitiveness of nebokitug and any future products. More advanced
competitors also may obtain regulatory approval for their products more rapidly than us, which could result in competitors establishing
a strong market position.
Intellectual Property
Overview
We strive to protect and enhance
the proprietary technology, inventions, and improvements that are commercially important to the development of our business, including
seeking, maintaining, and defending patent rights, whether developed internally or licensed from third parties. We also rely on trade
secrets relating to our proprietary technology platform and know-how, continuing technological innovation and in-licensing opportunities
to develop, strengthen, and maintain our proprietary position in the field of inflammation and fibrosis that may present areas of opportunity
for the development of our business. We may also rely on regulatory protection afforded through data exclusivity, market exclusivity,
and patent term extensions, where available.
Our commercial success may depend
in part on our ability to: obtain and maintain patent and other proprietary protection for commercially important technology, inventions
and know-how related to our business; defend and enforce our patents; preserve the confidentiality of our trade secrets; and operate without
infringing the valid enforceable patents and proprietary rights of third parties. Our ability to prevent third parties from making, using,
selling, offering to sell, or importing our products may depend on the extent to which we have rights under valid and enforceable licenses,
patents, or trade secrets that cover these activities. In certain cases, enforcement of these rights may depend on third party licensors.
With respect to both licensed and company-owned intellectual property rights, we cannot be sure that patents will be granted with respect
to any of our pending patent applications or with respect to any patent applications that may be filed by us in the future, nor can we
be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting
our commercial products and methods of manufacturing the same.
As of the date of this Annual Report
on Form 20-F, we owned or licensed seven pending or issued US patents and patent applications as well as patents and patent applications
in other jurisdictions. The first patent family has been issued in each of the United States, Europe (validated in France, Germany and
the United Kingdom) and Israel to the Tel Aviv Souraski Medical Center, whose rights have been licensed to Chemomab on an exclusive basis.
A composition of matter patent was issued in United States and certain corresponding foreign jurisdictions. To date, three additional
patent families were filed concerning the use of anti CCL24 antibodies in specific indications, dosing regimens, and routes of administration.
We will seek United States and foreign patent protection for a variety of additional technologies, including: research compounds and methods,
candidate compounds and antibodies for modulating the activity of CCL24, methods for treating diseases of interest, and methods for treating
our products. We will seek additional protection, in part, through confidentiality and proprietary information agreements.
Company Owned Intellectual
Property
We own multiple families of patent
applications that pertain to anti-CCL24 monoclonal antibody compositions capable of blocking CCL24 activity and methods for treating or
preventing diseases associated with inflammation and fibrosis. Certain applications in these families relate to our nebokitug antibody,
backup variants, various unit dosages, dosing regimens, and other routes of administration. Patents that are or will be issued from these
submissions will expire between the years 2035 to 2041, subject to possible patent term adjustments and/or extensions.
In addition to the above, we have
established expertise and development capabilities focused in the areas of preclinical research and development, manufacturing and manufacturing
process development, quality control, quality assurance, regulatory affairs, and clinical study design and implementation. We believe
that our focus and expertise will help us develop products based on our proprietary intellectual property.
Licensed IP
As mentioned above, we have obtained
an exclusive license from the Tel Aviv Souraski Medical Center for one patent, which is expected to expire in 2029. This patent was issued
in each of the United States, Europe and Israel, and pertains to anti CCL24 inhibitors (specifically, anti CCL24 antibodies) and methods
of using such inhibitors for treating inflammatory, autoimmune and cardiovascular diseases.
Trade Secret
Protection
We may rely, in some circumstances,
on trade secrets to protect our technology. We seek to protect our proprietary technology and processes, in part, by entering into confidentiality
agreements with our employees, consultants, scientific advisors, and contractors. We also seek to preserve the integrity and confidentiality
of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information
technology systems.
Material Agreements
Tel-Aviv Souraski Medical Center
(TASMC) License Agreement
In December 2011, we entered into
a license agreement, or the TASMC Agreement, with the Medical Research, Infrastructure, Health Services Fund of the Tel Aviv Souraski
Medical Center., or TASMC, for the research, development and commercialization of the CCL24 platform and CCR3 blockade platform (nebokitug),
which license includes patent rights covering the foregoing platforms and related know how and products. Under the terms of the TASMC
Agreement, we are responsible for the research, development, manufacturing and commercialization of nebokitug. This license was granted
on an exclusive basis and we were also granted rights to sublicense the instant license to third parties pursuant to certain terms described
therein.
In accordance with the TASMC Agreement,
we paid TASMC a non-refundable and non-creditable payment in four milestone installments, related to TASMC’s past patent maintenance
and prosecution costs.
Certain additional terms of the TASMC Agreement include:
• |
We will be required to pay TASMC non-refundable and non-creditable milestone payments
of up to (i) $300,000 upon the submission of an NDA, BLA or equivalent for each of the licensed products to the FDA and to equivalent
European and Asian foreign regulatory agencies, and (ii) $600,000 upon the grant by the FDA or equivalent European and/or Asian regulatory
agencies of their marketing approval for each licensed product; |
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In the event of an “exit,” as such term is defined therein, we must pay
TASMC an exit fee of 1% of the transaction consideration (which shall be capped at $3 million); |
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In the event we sublicense a licensed product, we must pay TASMC a sublicense fee
of 10% of all attributed income, in addition to a low-single digit percentage tiered royalty payment of our earned royalties. |
Unless terminated earlier, the TASMC
Agreement will expire upon the later of the expiration of the last-to-expire valid patent claim and any extension granted prior thereto.
The termination of the TASMC Agreement will not preclude TASMC from receiving sublicense payments or royalties. In addition to the foregoing,
the TASMC Agreement includes customary termination provisions.
CMC Collaboration Agreement
In June 2015, we entered into a collaboration
agreement, or the CMC Agreement, with CMC ICOS Biologics, Inc. (acquired by AGC Biologics in 2018), or CMC, which, under the terms thereof,
granted the us certain licenses to use proprietary rights, materials and know-how of CMC for purposes of research and development of nebokitug
as well as commercialization thereof. Pursuant to the terms of the CMC Agreement, we received (i) a worldwide, non-exclusive, non-transferable,
non-sublicensable license for research purposes, or the Research License, and (ii) an option, or the Option License, to a worldwide, non-exclusive,
non-transferable, sublicensable license for commercialization purposes, subject to a fee schedule in addition to that described below.
In accordance with the terms of the
CMC Agreement, we agreed to pay in exchange for the foregoing license payments to CMC upon the achievement of certain pre-determined clinical
and regulatory events, an amount stipulated in the CMC Agreement, aggregating a six-digit number. Additionally, for any product that is
commercialized pursuant to the CMC Agreement, we are required to pay CMC a royalty payment based on annual aggregate worldwide net sales
thresholds for such products. In the event CMC exclusively manufactures our products, CMC agrees to waive the foregoing royalty.
Unless terminated earlier pursuant
to the customary termination provisions set forth in the CMC Agreement, the Research License will expire upon the conclusion of the term
as defined therein, and the Option License will expire upon the later of (a) the tenth anniversary following our obtainment of regulatory
approval, or (b) the last to expire of the patent rights and country-by-country basis.
Manufacturing
Our product candidate, nebokitug,
is a monoclonal antibody amenable to standard formulation technologies. We have developed the biological process and manufactured kilogram
quantities through processes similar to the manufacturing processes that will be required to provide drug product for the Phase 2 clinical
studies. The manufacturing process of the drug substance used for such product candidates is robust, well established and requires the
use of readily available starting materials. The biological route is amenable to large-scale production and does not require unconventional
equipment or handling during the manufacturing process. We have obtained an adequate supply chain of the drug substance for nebokitug
from our contract manufacturing organization, or CMO, to satisfy both our clinical and preclinical requirements for this year. We rely
on a sole supplier for the manufacture of nebokitug. Our manufacturer has the capabilities to support late stage clinical studies as well
as product launch and marketing.
We do not own or operate facilities
for clinical drug manufacturing, storage, distribution or quality testing. Currently, all of our clinical manufacturing is outsourced
to third-party manufacturers. As our development programs expand and we build new process efficiencies, we expect to continually evaluate
this strategy with the objective of satisfying demand for our clinical studies and, if approved, the manufacture, sale and distribution
of commercial products.
Commercialization
We intend to develop and, if approved
by the FDA, to commercialize our product candidates alone or in collaboration with others. We may work in combination with one or more
large pharmaceutical partners for certain indications, where specialist capabilities are needed. We intend to enter into distribution
or licensing arrangements for global or regional commercialization rights. We will, however, continuously review our partnering strategy
in the light of new clinical data and market understanding.
The Food and Drug Administration,
or FDA, and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial and burdensome
requirements upon companies involved in the clinical development, manufacture, marketing and distribution of drugs, such as those that
we are developing. These agencies and other federal, state and local entities regulate, among other things, the research and development,
testing, manufacture, quality control, safety, effectiveness, labelling, storage, record keeping, approval, advertising and promotion,
distribution, post-approval monitoring and reporting, sampling and export and import of our product candidates.
United States
government regulation of drug products
Drugs in the United States are subject
to rigorous regulation under the Food, Drug, and Cosmetic Act, or FDCA, and its implementing regulations. The FDA also regulates biological
products under the FDCA and the Public Health Service Act, or PHSA. The process of obtaining regulatory approvals and the subsequent compliance
with applicable federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial
resources. Failure to comply with the applicable United States requirements at any time during the product development process, approval
process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal
to approve a pending New Drug Application, or NDA, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters,
product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government
contracts, restitution, disgorgement or civil or criminal penalties.
The process required by the FDA before
a drug or biologic may be marketed in the United States generally involves the following:
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completion of preclinical laboratory tests, animal studies and formulation studies
in compliance with the FDA’s Good Laboratory Practice, or GLP, regulations; |
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submission to the FDA of an Investigational New Drug application, or IND, which must
become effective before human clinical studies may begin; |
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approval by an Institutional Review Board, or IRB, at each clinical site before each
study may be initiated; |
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performance of adequate and well-controlled human clinical studies in accordance with
Good Clinical Practice, or GCP requirements to establish the safety and efficacy of the proposed drug product for each indication;
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completion of all manufacturing requirements to ensure robust manufacturing process,
and product quality and safety as per Good Manufacturing Practice, or cGMP guidelines; |
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completion of non-clinical reproductive studies, as applicable, prior to late stage
clinical studies and NDA or Biologics License Application, or BLA, submission; |
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development of an appropriate pediatric plan for clinical testing or exclusion, pre-
or post-approval, as applicable; |
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submission to the FDA of an NDA or BLA; |
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satisfactory completion of an FDA advisory committee review, if applicable;
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satisfactory completion of an FDA inspection of the manufacturing facility or facilities
at which the product is produced to assess compliance with cGMP requirements and to assure that the facilities, methods and controls are
adequate to preserve the drug’s identity, strength, quality and purity; |
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satisfactory completion of FDA audits of clinical study sites to assure compliance
with GCPs and the integrity of the clinical data; |
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payment of user fees and securing FDA approval of the NDA; |
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FDA review and approval of an NDA or BLA; and |
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compliance with any post-approval requirements, including the potential requirement
to implement a Risk Evaluation and Mitigation Strategies, or REMS, and the potential requirement to conduct post-approval studies.
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Preclinical studies
Preclinical studies include laboratory
evaluation of product chemistry, toxicity and formulation, as well as animal studies to assess potential safety and efficacy. An IND sponsor
must submit the results of the preclinical tests, together with manufacturing information, analytical data and any available clinical
data or literature, among other things, to the FDA as part of an IND. Some preclinical testing may continue even after the IND is submitted.
An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions
related to one or more proposed clinical studies and places the clinical study on a clinical hold. In such a case, the IND sponsor and
the FDA must resolve any outstanding concerns before the clinical study can begin. As a result, submission of an IND may not result in
the FDA allowing clinical studies to initiate.
Clinical studies
Clinical studies involve the administration
of the investigational new drug to human subjects under the supervision of qualified investigators in accordance with GCP requirements,
which include the requirement that all research subjects provide their informed consent in writing for their participation in any clinical
study. Clinical studies are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be
used in monitoring safety, and the effectiveness criteria to be evaluated. A protocol for each clinical study and any subsequent protocol
amendments must be submitted to the FDA as part of the IND. In addition, an IRB at each institution participating in the clinical study
must review and approve the plan for any clinical study before it initiates at that institution. Information about certain clinical studies
must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on their www.clinicaltrials.gov
website.
Human clinical studies are typically
conducted in three sequential phases, which may overlap or be combined. A fourth, or post-approval, phase may include additional clinical
studies. These phases generally include the following:
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Phase 1: The
drug or biologic is initially introduced into healthy human subjects or patients with the target disease or condition and tested for safety,
dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness.
For some products for severe or life-threatening diseases, especially if the product may be too toxic to administer to healthy humans,
the initial clinical trials may be conducted in individuals having a specific disease for which use the tested product is indicated.
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Phase 2: The
drug or biologic is administered is administered to a limited patient population to identify possible adverse effects and safety risks,
to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage.
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Phase 3: The
drug or biologic is administered to an expanded patient population, generally at geographically dispersed clinical study sites, in well-controlled
clinical studies to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the
overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product. |
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Phase 4: Phase
4 clinical trials are studies required of, or agreed to by, a sponsor that are conducted after the FDA has approved a product for marketing.
These studies are used to gain additional experience from the treatment of patients in the intended therapeutic indication and to document
a clinical benefit in the case of drugs approved under accelerated approval regulations. If the FDA approves a product while a company
has ongoing clinical trials that were not necessary for approval, a company may be able to use the data from these clinical trials to
meet all or part of any Phase 4 clinical trial requirement. Failure to promptly conduct Phase 4 clinical trials where necessary could
result in withdrawal of approval for products approved under accelerated approval regulations. |
Progress reports detailing the results
of the clinical studies must be submitted at least annually to the FDA and more frequently if serious adverse events occur. Phase 1, Phase
2 and Phase 3 studies may not be completed successfully within any specified period, or at all. Furthermore, the FDA or the sponsor may
suspend or terminate a clinical study at any time on various grounds, including a finding that the research subjects are being exposed
to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical study at its institution if the clinical
study is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious
harm to patients.
Marketing approval
Assuming successful completion of
the required clinical testing, the results of the preclinical and clinical studies, together with detailed information relating to the
product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA
or BLA requesting approval to market the product for one or more indications. In most cases, the submission of an NDA or BLA is subject
to a substantial application user fee. Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the
FDA has a goal of ten months from the date of “filing” of a standard NDA, for a new molecular entity to review and act on
the submission. This review typically takes twelve months from the date the NDA or BLA is submitted to FDA because the FDA has approximately
two months to make a “filing” decision.
In addition, under the Pediatric
Research Equity Act of 2003, or PREA, as amended and reauthorized, certain NDAs/BLAs or supplements thereof must contain data that are
adequate to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations, and
to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may, on its
own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of
the product for use in adults, or full or partial waivers from the pediatric data requirements. An Agreed Initial Pediatric Study Plan
requesting a waiver from the requirement to conduct clinical studies may be submitted to the FDA.
The FDA also may require submission
of a REMS plan to ensure that the benefits of the drug outweigh its risks. The REMS plan could include medication guides, physician communication
plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, or other risk
minimization tools.
The FDA conducts a preliminary review
of all NDAs/BLAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently
complete to permit substantive review. The FDA may request additional information rather than accept an NDA/BLA for filing. In this event,
the application must be resubmitted with the additional information. The resubmitted application is also subject to review before the
FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA reviews
an NDA/BLA to determine, among other things, whether the drug is safe and effective and whether the facility in which it is manufactured,
processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.
The FDA may refer an application
for a novel drug to an advisory committee. An advisory committee is a panel of independent experts, including clinicians and other scientific
experts, which reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions.
The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
Before approving an NDA, the FDA
typically will inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it
determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent
production of the product within required specifications. Additionally, before approving an NDA, the FDA may inspect one or more clinical
study sites to assure compliance with GCP requirements.
After evaluating the NDA/BLA and
all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities
and clinical study sites, the FDA may issue an approval letter, or, in some cases, a complete response letter. A complete response letter
generally contains a statement of specific conditions that must be met in order to secure final approval of the NDA/BLA and may require
additional clinical or preclinical testing in order for the FDA to reconsider the application. Even with submission of this additional
information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval. If and when those
conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter. An approval letter authorizes
commercial marketing of the drug with specific prescribing information for specific indications.
Even if the FDA approves a product, it may limit the approved
indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require
that post-approval studies, including Phase 4 clinical studies, be conducted to further assess a drug’s safety after approval, require
testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and
use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability
of the product. The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance
programs. After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes, and additional
labeling claims, are subject to further testing requirements and FDA review and approval.
FDA Expedited
Development and Review Programs
The FDA has various programs, including
fast track designation, priority review, accelerated approval, and breakthrough therapy designation,
which are intended to expedite or simplify the process for the development and FDA review of drugs that are intended for the treatment
of serious or life-threatening diseases or conditions and demonstrate the potential to address unmet medical needs. The purpose of these
programs is to provide important new drugs to patients earlier than under standard FDA review procedures.
The FDA has a fast track designation
program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria. Specifically,
new drugs are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and
demonstrate the potential to address unmet medical needs for the disease or condition. With regard to a fast track product, the FDA may
consider for review sections of the NDA/BLA on a rolling basis before the complete application is submitted, if the sponsor provides a
schedule for the submission of the sections of the NDA/BLA, the FDA agrees to accept sections of the NDA/BLA and determines that the schedule
is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA/BLA. In November 2023, the
Company announced that the FDA had awarded Fast Track status to nebokitug for the treatment of PSC in adult patients.
Any product submitted to the FDA
for approval, including a product with a fast track designation, may also be eligible for other types of FDA programs intended to expedite
development and review, such as priority review and accelerated approval. A product is eligible for priority review if it has the potential
to provide safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the treatment,
diagnosis, or prevention of a disease compared to marketed products. The FDA will attempt to direct additional resources to the evaluation
of an application for a new drug designated for priority review in an effort to facilitate the review.
In addition, a product may be eligible
for accelerated approval. Drug products intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated
approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit,
or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict
an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of
the condition and the availability or lack of alternative treatments. As a condition of approval, the FDA may require a sponsor of a drug
receiving accelerated approval to perform post-marketing studies to verify and describe the predicted effect on irreversible morbidity
or mortality, or other clinical endpoint and to submit promotional materials for preapproval and pre-use review, which could adversely
impact the timing of the commercial launch of the product. In addition, the drug may be subject to accelerated withdrawal procedures.
The Food and Drug Administration
Safety and Innovation Act established a category of drugs referred to as “breakthrough therapies” that may be eligible to
receive breakthrough therapy designation. A sponsor may seek FDA designation of a product candidate as a “breakthrough therapy”
if the product is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or
condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies
on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation
includes all of the fast track program features, as well as more intensive FDA interaction and guidance. The breakthrough therapy designation
is a distinct status from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria
are met. If a product is designated as breakthrough therapy, the FDA will work to expedite the development and review of such drug.
Fast track designation, priority
review, accelerated approval, and breakthrough therapy designation do not change the standards for approval but may expedite the development
or approval process. Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer
meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.
Orphan drug designation
and exclusivity
Under the Orphan Drug Act, the FDA
may designate a drug product as an “orphan drug” if it is intended to treat a rare disease or condition (generally meaning
that it affects fewer than 200,000 individuals in the United States, or more in cases in which there is no reasonable expectation that
the cost of developing and making a drug product available in the United States for treatment of the disease or condition will be recovered
from sales of the product). A company must request orphan product designation before submitting an NDA. If the request is granted, the
FDA will disclose the identity of the therapeutic agent and its potential use. Orphan product designation does not convey any advantage
in or shorten the duration of the regulatory review and approval process. As of the current date, we have obtained orphan drug designation
for three indications, PSC, SSc and IPF.
If a product with orphan status receives
the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare
disease or condition for which it was designated, the product generally will be receiving orphan product exclusivity. Orphan product exclusivity
means that the FDA may not approve any other applications for the same product for the same indication for seven years, except in certain
limited circumstances. If a drug or drug product designated as an orphan product ultimately receives marketing approval for an indication
broader than what was designated in its orphan product application, it may not be entitled to exclusivity. Orphan exclusivity will not
bar approval of another product under certain circumstances, including if a subsequent product with the same active ingredient for the
same indication is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a
major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand. Further, the FDA
may approve more than one product for the same orphan indication or disease as long as the products contain different active ingredients.
Moreover, competitors may receive approval of different products for the indication for which the orphan product has exclusivity or obtain
approval for the same product but for a different indication for which the orphan product has exclusivity.
In Catalyst
Pharms., Inc. v. Becerra, 14 F.4th 1299 (11th Cir. 2021), the court disagreed with the FDA’s longstanding position that the
orphan drug exclusivity only applies to the approved use or indication within an eligible disease. This decision created uncertainty in
the application of the orphan drug exclusivity. On January 24, 2023, the FDA published a notice in the Federal Register to clarify that
while the agency complies with the court’s order in Catalyst, FDA intends to continue to
apply its longstanding interpretation of the regulations to matters outside of the scope of the Catalyst
order – that is, the agency will continue tying the scope of orphan-drug exclusivity to the uses or indications for which a drug
is approved, which permits other sponsors to obtain approval of a drug for new uses or indications within the same orphan designated disease
or condition that have not yet been approved. It is unclear how future litigation, legislation, agency decisions, and administrative actions
will impact the scope of the orphan drug exclusivity.
United States
marketing exclusivity
Market exclusivity provisions under
the FDCA also can delay the submission or the approval of certain applications. The FDCA provides a five-year period of non-patent marketing
exclusivity within the United States to the first applicant to gain approval of an NDA for a new chemical entity. A drug is a new chemical
entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible
for the action of the drug substance. During the exclusivity period, the FDA may not accept for review an Abbreviated New Drug Application,
or ANDA, or a 505(b)(2) NDA submitted by another company for another version of such drug where the applicant does not own or have a legal
right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification
of patent invalidity or non-infringement. The FDCA also provides three years of marketing exclusivity for an NDA, 505(b)(2) NDA or supplement
to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant
are deemed by the FDA to be essential to the approval of the application, for example, new indications, dosages or strengths of an existing
drug. This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not prohibit
the FDA from approving ANDAs for the original non-modified version of the drug. Five-year and three-year exclusivity will not delay the
submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference
to all of the preclinical studies and adequate and well-controlled clinical studies necessary to demonstrate safety and effectiveness.
Abbreviated Licensure Pathway of Biological
Products as Biosimilars or Interchangeable Biosimilars
The Patient Protection and Affordable
Care Act (Affordable Care Act or ACA), signed into law in 2010, includes the Biologics Price Competition and Innovation Act of 2009 (BPCIA),
which created an abbreviated approval pathway for biological products shown to be highly similar to an FDA-licensed reference biological
product. The BPCIA attempts to minimize duplicative testing, and thereby lower development costs and increase patient access to affordable
treatments.
Biosimilarity means that the biological
product is highly similar to the reference product notwithstanding minor differences in clinically inactive components, and that there
are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and potency
of the product. In addition, the law provides for a designation of “interchangeability” between the reference and biosimilar
products, whereby the biosimilar may be substituted for the reference product without the intervention of the healthcare provider who
prescribed the reference product.
A biosimilar product sponsor may
not submit an application for four years from the date of first licensure of the reference product. A reference product may also be entitled
to exclusivity under other statutory provisions. For example, a reference product designated for a rare disease or condition (an orphan
drug) may be entitled to seven years of exclusivity, in which case no product that is biosimilar to the reference product may be approved
until either the end of the twelve-year period provided under the biosimilarity statute or the end of the seven-year orphan drug exclusivity
period, whichever occurs later. In certain circumstances, a regulatory exclusivity period can extend beyond the life of a patent, and
thus block biosimilarity applications from being approved on or after the patent expiration date.
Pediatric exclusivity is another
type of regulatory market exclusivity in the United States. Pediatric exclusivity, if granted, adds six months to existing regulatory
exclusivity periods. This six-month exclusivity may be granted based on the voluntary completion of a pediatric study in accordance with
an FDA-issued “Written Request” for such a study.
Post-approval
requirements
Drugs and biologics manufactured
or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things,
requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting
of adverse experiences with the product. After approval, most changes to the approved product, such as adding new indications or other
labeling claims are subject to prior FDA review and approval. There are continuing, annual user fee requirements for any marketed products
and the establishments where such products are manufactured, as well as new application fees for supplemental applications with clinical
data.
The FDA may impose a number of post-approval
requirements as a condition of approval of an NDA. For example, the FDA may require post-marketing testing, including Phase 4 clinical
studies, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.
In addition, drug and biologic manufacturers
and other entities involved in the manufacture and distribution of approved drugs and biologics are required to register their establishments
with the FDA and state agencies, and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance
with cGMP requirements. Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being
implemented. FDA regulations also require investigation and correction of any deviations from cGMP requirements and impose reporting and
documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use. Accordingly, manufacturers
must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.
Once an approval of a drug or biologic
is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems
occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of
unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in
mandatory revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical studies to assess
new safety risks; or imposition of distribution or other restrictions under a REMS program. Other potential consequences include, among
other things:
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Restrictions on the marketing or manufacturing of the product, complete withdrawal
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Fines, warning letters or holds on post-approval clinical studies; |
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Refusal of the FDA to approve pending NDAs or BLAs or supplements to approved NDAs
or BLAs, or suspension or revocation of product approvals; |
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Product seizure or detention, or refusal to permit the import or export of products;
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The FDA strictly regulates marketing,
labeling, advertising and promotion of products that are placed on the market. Drugs and biologics may be promoted by a manufacturer and
any third parties acting on behalf of a manufacturer only for the approved indications and in a manner consistent with the approved label
for the product. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and
a company that is found to have improperly promoted off-label uses may be subject to significant liability.
Other U.S. healthcare
laws
Healthcare providers, physicians,
and third party payors play a primary role in the recommendation and prescription of drug products for which we obtain marketing approval.
Arrangements with third party payors, healthcare providers and physicians, in connection with the clinical research, sales, marketing
and promotion of products, once approved, and related activities, may expose a pharmaceutical manufacturer to broadly applicable fraud
and abuse and other healthcare laws and regulations. In the United States, these laws include, without limitation, state and federal anti-kickback,
physician self-referral prohibitions, false claims, physician transparency, and patient data privacy and security laws and regulations,
including but not limited to those described below:
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The federal Anti-Kickback Statute, or AKS, which makes it illegal for any person,
including a prescription drug manufacturer (or a party acting on its behalf) to knowingly and willfully solicit, receive, offer or pay
any remuneration (including any kickback, bribe, or rebate), directly or indirectly, overtly or covertly, in cash or in kind, that is
intended to induce or reward, referrals including the purchase recommendation, order or prescription of a particular drug for which payment
may be made under a federal healthcare program, such as the Medicare and Medicaid programs. A person or entity does not need to have actual
knowledge of the statute or specific intent to violate it in order to have committed a violation. In addition, the government may assert
that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent
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The federal civil and criminal false claims laws, including the FCA, which can be
enforced through “qui tam” or “whistleblower” actions, and civil monetary penalty laws, which impose criminal
and civil penalties against individuals or entities for, among other things, knowingly presenting, or causing to be presented, claims
for payment or approval from Medicare, Medicaid, or other federal health care programs that are false or fraudulent; knowingly making
or causing a false statement material to a false or fraudulent claim or an obligation to pay or transmit money or property to the federal
government; or knowingly concealing or knowingly and improperly avoiding or decreasing such an obligation. Similar to the AKS, a person
or entity does not need to have actual knowledge of these statutes or specific intent to violate them in order to have committed a violation;
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|
• |
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA,
which created additional federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme
to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the
money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public
or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially
false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters;
|
|
|
• |
HIPAA, as amended by the Health Information Technology for Economic and Clinical Health
Act of 2009, or HITECH, and their respective implementing regulations, which impose requirements on certain covered healthcare providers,
health plans, and healthcare clearinghouses as well as their respective business associates and their subcontractors that perform services
for them that involve the creation, use, receipt, maintenance or disclosure of individually identifiable health information, relating
to the privacy, security and transmission of individually identifiable health information; |
|
|
• |
The federal Physician Payments Sunshine Act, created under Patient Protection and
Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the ACA, and its implementing
regulations, which require manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare,
Medicaid or the Children’s Health Insurance Program to report annually to the Centers for Medicare and Medicaid Services, or CMS,
under the Open Payments Program, information related to payments or other transfers of value made to physicians (defined to include doctors,
dentists, optometrists, podiatrists and chiropractors), certain non-physician healthcare professionals (such as physician assistants and
nurse practitioners, among others), and teaching hospitals, as well as ownership and investment interests held by physicians and
their immediate family members; and |
|
|
• |
Analogous state and foreign laws and regulations, such as state and foreign anti-kickback,
physician self-referral prohibitions, false claims, consumer protection and unfair competition laws which may apply to pharmaceutical
business practices, including but not limited to, research, distribution, sales and marketing arrangements as well as submitting claims
involving healthcare items or services reimbursed by any third-party payor, including commercial insurers; state laws that require pharmaceutical
companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated
by the federal government that otherwise restricts payments that may be made to healthcare providers and other potential referral sources;
state laws that require drug manufacturers to file reports with states regarding pricing and marketing information, such as the tracking
and reporting of gifts, compensations and other remuneration and items of value provided to healthcare professionals and entities; state
and local laws requiring the registration of pharmaceutical sales representatives; and state and foreign laws governing the privacy and
security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the
same effect, thus complicating compliance efforts. |
Because of the breadth of these laws
and the narrowness of the statutory exceptions and regulatory safe harbors available, it is possible that some of a pharmaceutical manufacturer’s
business activities could be subject to challenge under one or more of such laws. Efforts to ensure that business arrangements comply
with applicable healthcare laws involve substantial costs. It is possible that governmental and enforcement authorities will conclude
that a pharmaceutical manufacturer’s business practices do not comply with current or future statutes, regulations or case law interpreting
applicable fraud and abuse or other healthcare laws and regulations. If any such actions are instituted against a pharmaceutical manufacturer,
and it is not successful in defending itself or asserting its rights, those actions could have a significant impact on its business, including
the imposition of significant civil, criminal and administrative penalties, damages, disgorgement, imprisonment, monetary fines, possible
exclusion from participation in Medicare, Medicaid and other federal healthcare programs, reporting obligations and oversight if we become
subject to integrity and oversight agreements to resolve allegations of non-compliance, contractual damages, reputational harm, diminished
profits and future earnings, and curtailment of operations, any of which could adversely affect a pharmaceutical manufacturer’s
ability to operate its business and the results of operations. In addition, commercialization of any drug product outside the United States
will also likely be subject to foreign equivalents of the healthcare laws mentioned above, among other foreign laws.
Prescription drug advertising is
subject to federal, state and foreign regulations. In the United States, the FDA regulates prescription drug promotion, including direct-to-consumer
advertising. Prescription drug promotional materials must be submitted to the FDA in conjunction with their first use. Any distribution
of prescription drug products and pharmaceutical samples must comply with the United States Prescription Drug Marketing Act, or PDMA,
a part of the FDCA. In addition, Title II of the Federal Drug Quality and Security Act of 2013, known as the Drug Supply Chain Security
Act, or DSCSA, has imposed new “track and trace” requirements on the distribution of prescription drug products by manufacturers,
distributors, and other entities in the drug supply chain. The DSCSA requires product identifiers (i.e., serialization) on prescription
drug products in order to eventually establish an electronic interoperable prescription product system to identify and trace certain prescription
drugs distributed in the United States and preempts existing state drug pedigree laws and regulations on this topic. The DSCSA also establishes
new requirements for the licensing of wholesale distributors and third-party logistic providers. The FDA is in the process of finalizing
regulations addressing national standards for the licensure of wholesale distributors and third-party logistics providers.
In the United States, numerous federal
and state laws and regulations, including state data breach notification laws, state health information privacy laws, and federal and
state consumer protection laws, govern the collection, use, disclosure, and protection of health-related and other personal information.
For example, in June 2018, the State of California enacted the California Consumer Privacy Act of 2018, or the CCPA, which came into
effect on January 1, 2020 and provides new data privacy rights for consumers and new operational requirements for companies, which
may increase our compliance costs and potential liability. The CCPA gives California residents expanded rights to access and delete their
personal information, opt out of certain personal information sharing, and receive detailed information about how their personal information
is used. The CCPA provides for civil penalties for violations, as well as a private right of action for data breaches that is expected
to increase data breach litigation. While there is currently an exception for protected health information that is subject to HIPAA and
clinical study regulations, as currently written, the CCPA may impact certain of our business activities. The CCPA could mark the beginning
of a trend toward more stringent state privacy legislation in the United States, which could increase our potential liability and adversely
affect our business.
In the event we decide to conduct
clinical studies or continue to enroll subjects in our ongoing or future clinical studies, we may be subject to additional privacy restrictions.
The collection, use, storage, disclosure, transfer, or other processing of personal data regarding individuals in the European Economic
Area, or EEA, including personal health data, is subject to the EU General Data Protection Regulation, or GDPR, which became effective
on May 25, 2018. The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including
requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates,
providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality
of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors. The GDPR
also imposes strict rules on the transfer of personal data to countries outside the EEA, including the United States, and permits
data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million
or 4% of annual global revenues, whichever is greater. The GDPR also confers a private right of action on data subjects and consumer associations
to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations
of the GDPR. In addition, the GDPR includes restrictions on cross-border data transfers. The GDPR may increase our responsibility and
liability with respect to personal data that we process where such processing is subject to the GDPR, and we may be required to put in
place additional mechanisms to ensure compliance with the GDPR, including as implemented by individual countries. Compliance with the
GDPR will be a rigorous and time-intensive process that may increase our cost of doing business or require us to change our business practices,
and despite those efforts, there is a risk that we may be subject to fines and penalties, litigation, and reputational harm in connection
with our European activities. Further, the United Kingdom’s decision to leave the EU, often referred to as Brexit, has created uncertainty
with regard to data protection regulation in the United Kingdom and transfers of personal data to the UK and from the UK to both the EEA
and countries outside the UK/EEA. For the time being, transfers of personal data from the EU to the UK are covered by an adequacy decision
of the EU Commission, and the UK has recently implemented its own regime for safeguarding transfers from the UK to countries outside the
UK/EEA which sit alongside the new EU safeguards which were brought in during 2021. However, both the adequacy decision and the
UK regime remain vulnerable to withdrawal or legal challenge. Further both the new UK and EU personal data transfer regimes remain
relatively untested and therefore impose risk that a transfer of personal data and/or its subsequent processing would be held unlawful
and give rise to liabilities from administrative fines and/or damages claims from data subjects.
Current and future
healthcare reform legislation
In both the United States and certain
foreign jurisdictions, there have been a number of legislative and regulatory changes to the health care system. In particular, in 2010
the ACA was enacted, which, among other things, increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug
Rebate Program, extended the Medicaid Drug Rebate Program to utilization of prescriptions of individuals enrolled in Medicaid managed
care organizations, subjected manufacturers to new annual fees and taxes for certain branded prescription drugs, and provided incentives
to programs that increase the federal government’s comparative effectiveness research.
In addition, other legislative changes
have been proposed and adopted in the United States since the ACA was enacted. In August 2011, the Budget Control Act of 2011, among
other things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with recommending
a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby
triggering the legislation’s automatic reduction to several government programs. This includes aggregate reductions of Medicare
payments to providers of 2% per fiscal year, which went into effect in 2013, and, due to subsequent legislative amendments, will remain
in effect through 2032. The American Taxpayer Relief Act of 2012 further reduced Medicare payments to several providers, including hospitals
and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers
from three to five years. The Bipartisan Budget Act of 2018, also amended the ACA, effective January 1, 2019, by increasing
the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and closing the coverage
gap in most Medicare drug plans, commonly referred to as the “donut hole”.
Additionally, there has been heightened
governmental scrutiny in the United States of pharmaceutical pricing practices in light of the rising cost of prescription drugs and biologics.
In August 2022, Congress passed the Inflation Reduction Act of 2022, which includes prescription drug provisions that have significant
implications for the pharmaceutical industry and Medicare beneficiaries, including allowing the federal government to negotiate a maximum
fair price for certain high-priced single source Medicare drugs that have been on the market for at least 7 years and biologics that have
been on the market for at least 11 years, and, imposing penalties and excise tax for manufacturers that fail to comply with the drug price
negotiation requirements; requiring inflation rebates for all Medicare Part B and Part D drugs, with limited exceptions, if their drug
prices increase faster than inflation; and redesigning Medicare Part D to reduce out-of-pocket prescription drug costs for beneficiaries,
among other changes. The impact of these legislative, executive, and administrative actions and any future healthcare measures and agency
rules implemented by the second Trump administration on us and the pharmaceutical industry as a whole is unclear. The implementation of
cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize
any of the product candidates for which we receive approval. At the state level, legislatures have increasingly passed legislation and
implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts,
restrictions on certain product access and marketing cost disclosure and transparency measures and, in some cases, designed to encourage
importation from other countries and bulk purchasing.
Legislative and regulatory proposals,
executive orders, and enactment of laws, at the foreign, federal and state levels, directed at containing or lowering the cost of healthcare,
will continue into the future.
Rest of World
Regulation
For other countries outside of the
European Union and the United States, such as countries in Eastern Europe, Latin America or Asia, the requirements governing product development,
the conduct of clinical studies, manufacturing, distribution, marketing approval, product licensing, pricing and reimbursement vary from
country to country. Additionally, clinical studies must be conducted in accordance with GCP requirements and the applicable regulatory
requirements and the ethical principles that have their origin in the Declaration of Helsinki.
If we fail to comply with applicable
foreign regulatory requirements, we may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product
recalls, seizure of products, operating restrictions and criminal prosecution.
Additionally, to the extent that
any of our product candidates, once approved, are sold in a foreign country, we may be subject to applicable post-marketing requirements,
including safety surveillance, anti-fraud and abuse laws and implementation of corporate compliance programs and reporting of payments
or other transfers of value to healthcare professionals.
Coverage and
reimbursement
Successful commercialization of new
drug products depends in part on the extent to which reimbursement for those drug products will be available from government health administration
authorities, private health insurers, and other organizations. Government authorities and third-party payors, such as private health insurers
and health maintenance organizations, decide which drug products they will pay for and establish reimbursement levels. The availability
and extent of reimbursement by governmental and private payors is essential for most patients to be able to afford a drug product. Sales
of drug products depend substantially, both domestically and abroad, on the extent to which the costs of drugs products are paid for by
health maintenance, managed care, pharmacy benefit and similar healthcare management organizations, or reimbursed by government health
administration authorities, private health coverage insurers and other third-party payors.
A primary trend in the United States
healthcare industry and elsewhere is cost containment. Government authorities and third-party payors have attempted to control costs by
limiting coverage and the amount of reimbursement for particular drug products. In many countries, the prices of drug products are subject
to varying price control mechanisms as part of national health systems. In general, the prices of drug products under such systems are
substantially lower than in the United States. Other countries allow companies to fix their own prices for drug products but monitor and
control company profits. Accordingly, in markets outside the United States, the reimbursement for drug products may be reduced compared
with the United States.
In the United States, the principal
decisions about reimbursement for new drug products are typically made by CMS, an agency within the U.S. Department of Health and Human
Services. CMS decides whether and to what extent a new drug product will be covered and reimbursed under Medicare, and private payors
tend to follow CMS to a substantial degree. However, no uniform policy of coverage and reimbursement for drug products exists among third-party
payors and coverage and reimbursement levels for drug products can differ significantly from payor to payor.
The Medicare Prescription Drug, Improvement,
and Modernization Act of 2003, or the MMA, established the Medicare Part D program to provide a voluntary prescription drug benefit
to Medicare beneficiaries. Under Part D, Medicare beneficiaries may enroll in prescription drug plans offered by private entities
that provide coverage of outpatient prescription drugs. While all Medicare drug plans must give at least a standard level of coverage
set by Medicare, Part D prescription drug plan sponsors are not required to pay for all covered Part D drugs, and each Part D
prescription drug plan can develop its own drug formulary that identifies which drugs it will cover and at what tier or level. However,
Part D prescription drug formularies must include drugs within each therapeutic category and class of covered Part D drugs,
though not necessarily all the drugs in each category or class. Any formulary used by a Part D prescription drug plan must be developed
and reviewed by a pharmacy and therapeutic committee. Government payment for some of the costs of prescription drugs may increase demand
for drugs for which we obtain marketing approval. Any negotiated prices for any of our products covered by a Part D prescription
drug plan will likely be lower than the prices it might otherwise obtain. Moreover, while the MMA applies only to drug benefits for Medicare
beneficiaries, private payors often follow Medicare coverage policy and payment limitations in setting their own payment rates. Any reduction
in payment that results from the MMA may result in a similar reduction in payments from non-governmental payors.
For a drug product to receive federal
reimbursement under the Medicaid or Medicare Part B programs or to be sold directly to United States government agencies, the manufacturer
must extend discounts to entities eligible to participate in the 340B drug pricing program. The required 340B discount on a given product
is calculated based on the average manufacturer price, or AMP, and Medicaid rebate amounts reported by the manufacturer. As of 2010, the
ACA expanded the types of entities eligible to receive discounted 340B pricing, although under the current state of the law these newly
eligible entities (with the exception of children’s hospitals) will not be eligible to receive discounted 340B pricing on orphan
drugs. As 340B drug pricing is determined based on AMP and Medicaid rebate data, the revisions to the Medicaid rebate formula and AMP
definition described above could cause the required 340B discount to increase. If third-party payors do not consider our drugs to be cost-effective
compared to other available therapies, they may not cover our drugs after approval as a benefit under their plans or, if they do, the
level of payment may not be sufficient to allow us to sell our drugs on a profitable basis.
These laws, and state and federal
healthcare reform measures that may be adopted in the future, may result in additional reductions in Medicare and other healthcare funding
and otherwise affect the prices we may obtain for any product candidates for which we may obtain regulatory approval or the frequency
with which any such product candidate is prescribed or used.
Outside of the United States, the
pricing of pharmaceutical products and medical devices is subject to governmental control in many countries. For example, in the European
Union, pricing and reimbursement schemes vary widely from country to country. Some countries provide that products may be marketed only
after a reimbursement price has been agreed. Some countries may require the completion of additional studies that compare the cost effectiveness
of a particular therapy to currently available therapies or so-called health technology assessments, in order to obtain reimbursement
or pricing approval. Other countries may allow companies to fix their own prices for products, but monitor and control product volumes
and issue guidance to physicians to limit prescriptions. Efforts to control prices and utilization of pharmaceutical products and medical
devices will likely continue as countries attempt to manage healthcare expenditures.
Employees and Human Capital Resources
As of December 31, 2024, we had 16
employees / consultants, including 6 with Ph.D. or M.D. degrees and including 11 who are engaged in research and development activities.
We are dependent on our management and scientific personnel, and it is crucial that we continue to attract and retain valuable employees.
To facilitate attraction and retention, we strive to make ourselves an inclusive and safe workplace, with opportunities for our employees
to grow and develop in their careers, supported by strong compensation and benefits programs. None of our employees are represented by
labor unions or covered by collective bargaining agreements.
Corporate Information and History
We were incorporated on November
30, 2011, under the laws of the State of Israel. In March 2021, in connection with the Merger, we changed our name from Anchiano Therapeutics
Ltd. to Chemomab Therapeutics Ltd. Our principal executive offices are located at Kiryat Atidim, Building 7, Tel Aviv, Israel 6158002,
and our phone number is +972-77-331-0156. Our website is: www.chemomab.com. The information
contained on, or that can be accessed through, our website is not incorporated by reference into this Annual Report.
Available Information
Our investor relations website is
https://investors.chemomab.com/. We promptly make available on our investor relations website, free of charge, the reports that
we file or furnish with the SEC, corporate governance information (including our Code of Business Conduct and Ethics) and all press releases.
The SEC maintains a website at www.sec.gov that contains reports, proxy and information statements and other information regarding Chemomab
and other issuers that file electronically with the SEC.
Item 4A.
Unresolved Staff Comments
None.
Item 5. Operating
and Financial Review and Prospects
You should
read the following discussion together with the consolidated financial statements and related notes included elsewhere in this Annual
Report. The statements contained in this discussion regarding industry outlook, our expectations regarding our future performance, planned
investments in our expansion into additional geographies, research and development, sales and marketing and general and administrative
functions as well as other non-historical statements contained in this discussion are forward-looking statements. These forward-looking
statements are subject to numerous risks and uncertainties, including, but not limited to, the risks and uncertainties described in Item
3.D. entitled “Risk factors” and “Special note regarding forward-looking statements” included elsewhere in this
Annual Report. Our actual results may differ materially from those contained in or implied by any forward-looking statements.
Overview
We are a clinical-stage biotechnology
company focused on the discovery and development of innovative therapeutics for fibrotic and inflammatory diseases with high unmet needs.
Based on the unique and pivotal role of the soluble protein CCL24 in promoting fibrosis and inflammation, we have developed nebokitug,
a monoclonal antibody designed to bind and block CCL24 activity. nebokitug has demonstrated the potential to treat multiple severe and
life-threatening fibrotic and inflammatory diseases.
We have pioneered the therapeutic
targeting of CCL24, a chemokine also known as eotaxin-2, which promotes various types of cellular processes that regulate inflammatory
and fibrotic activities through the CCR3 receptor. CCL24 is expressed in various types of cells, including immune cells, endothelial cells
and epithelial cells. We have developed a novel CCL24 inhibiting product candidate with dual anti-fibrotic and anti-inflammatory activity
that modulates the complex interplay of these inflammatory and fibrotic mechanisms, which drive abnormal states of fibrosis and fibrotic
diseases. This innovative approach is currently being developed for difficult-to-treat rare diseases, also known as orphan indications
or diseases, such as primary sclerosing cholangitis (PSC) and systemic sclerosis (SSc) for which patients have no established disease-modifying
or standard-of-care treatment options. We estimate that there are approximately 77 thousand patients suffering from PSC in the United
States., European Union and Japan, representing a more than $1 billion market opportunity, and approximately 170,000 patients suffering
from SSc in those same markets, representing a more than $1.5 billion market opportunity.
Nebokitug, our lead clinical product
candidate, is a first-in-class humanized monoclonal antibody that attenuates the basic function of CCL24 as a regulator of major inflammatory
and fibrotic pathways. We have demonstrated that nebokitug interferes with the underlying biology of inflammation and fibrosis through
a novel and differentiated mechanism of action. We are currently concluding a Phase 2 clinical study of nebokitug in PSC, a rare
obstructive and cholestatic liver disease, with sites in the United States, Europe and Israel. Positive topline results from the double-blinded
and open label portions of this trial were reported in July, 2024 and March 2025, respectively.
The randomized, placebo-controlled
study design included two doses of nebokitug (10 or 20mg/kg) vs placebo, administered once every three weeks for 15 weeks, as well as
an open label extension in which all eligible patients could receive nebokitug for an additional 33 weeks. In the Phase 2 study, nebokitug
achieved its primary endpoint of safety and tolerability and demonstrated anti-fibrotic, anti-inflammatory and anti-cholestatic effects
across a broad range of disease-related secondary efficacy endpoints, including statistically significant improvements in liver stiffness,
a key PSC disease marker, after just 15-weeks of treatment. Moreover, nebokitug is among the first investigational drugs to show a reduction
in total bilirubin, an important marker of cholestasis and liver health, as well as reductions in pruritus, a cholestatic indicator of
great relevance to patients. Nebokitug is the first investigational drug being developed for PSC to exhibit broad, clinically relevant
effects on all three components of the disease, establishing clinical proof-of-concept and providing further evidence of its multifactorial
mechanism of action and disease-modifying potential. Data from the open label extension portion of the trial was recently reported
showing continued safety and anti-fibrotic, anti-inflammatory and anti-cholestatic activity of nebokitug over 48 weeks of treatment .
The company had an End of Phase 2 meeting with the FDA in December, 2024 to discuss the Phase 2 SPRING trial results and the path forward
to Phase 3 and potential regulatory approval for PSC. Chemomab and the FDA aligned on the design of a single, clinical-events-driven Phase
3 trial. If successful in finalizing a strategic partnership or a major financing, Chemomab could initiate this pivotal trial in
PSC before the end of 2025.
The nebokitug SSc clinical program
is Phase 2-ready and we have an open IND in the United States for a Phase 2 clinical trial. However, Chemomab has suspended initiation
of this study while we focus our resources on the nebokitug PSC program. We believe that nebokitug could have disease-modifying
potential in this poorly treated condition. While our primary focus is on these two rare indications, we previously reported results from
a completed Phase 2a clinical study in patients with liver fibrosis due to metabolic dysfunction-associated steatohepatitis (MASH).
This trial provided safety and pharmacokinetic (“PK”) data and information useful for assessing our current subcutaneous formulation
of nebokitug. Additionally, the trial measured a number of biomarkers that may be relevant to the activity of nebokitug in other fibro-inflammatory
conditions. The results showed that the trial met its primary endpoint of safety and tolerability, and that nebokitug demonstrated consistent
data trends and positive activity across secondary endpoints that included a range of liver fibrosis biomarkers and physiologic assessments.
A secondary analysis, that further confirmed and extended these initial results was reported at the 2023 EASL Congress in June 2023.
Fibrosis is the abnormal and excessive
accumulation of collagen and extracellular matrix, the non-cellular component in all tissues and organs, which provides structural and
biochemical support to surrounding cells. When present in excessive amounts, collagen and extracellular matrix lead to scarring and thickening
of connective tissues, affecting tissue properties and potentially leading to organ dysfunction and failure. Fibrosis can occur in many
different tissues, including lung, liver, kidney, muscle, skin, and the gastrointestinal tract, resulting in a wide array of progressive
fibrotic conditions. Fibrosis and inflammation are intrinsically linked. While a healthy inflammatory response is necessary for efficient
tissue repair; after disease or injury, an excessive, uncontrolled inflammatory response can lead to tissue fibrosis that in turn can
further stimulate inflammatory processes in a fibro-inflammatory vicious cycle.
A. Components
of Operating Results
Revenues
To date, we have not generated any
revenue from product sales and do not expect to generate any revenue from product sales in the near future. If development efforts for
our product candidates are successful and result in our receipt of necessary regulatory approvals, or if our development efforts otherwise
lead to any commercialized products or additional license agreements with third parties, then we may generate revenue in the future from
product sales.
Research and
Development Expenses, net
Research and development expenses
consist primarily of costs incurred in connection with the development of our product candidates. These expenses include:
• |
expenses incurred under agreements with clinical research organizations and contract
manufacturing organizations, as well as investigative sites and consultants that conduct our clinical trials, preclinical studies and
other scientific development services; |
• |
manufacturing scale-up expenses and the cost of acquiring and manufacturing preclinical
and clinical trial materials; |
• |
employee-related expenses, including salaries, related benefits, travel and share-based
compensation expenses for employees engaged in research and development functions, as well as external costs, such as fees paid to outside
consultants engaged in such activities; |
|
license maintenance fees and milestone fees incurred in connection with various license
agreements; |
• |
costs related to compliance with regulatory requirements; and |
• |
depreciation and other expenses. |
We recognize external development
costs based on an evaluation of the progress to completion of specific tasks using information provided to us by our service providers.
We do not allocate employee costs
or facility expenses, including depreciation or other indirect costs, to specific programs because these resources are deployed across
multiple programs and, as such, the related costs are not separately classified. We use internal resources primarily to oversee our research,
as well as for managing our preclinical development, process development, manufacturing and clinical development activities. Our employees
work across multiple programs; therefore, we do not track the related expenses by program.
Research and development activities
are fundamental to our business. Product candidates in later stages of clinical development generally have higher development costs than
those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. As a
result, we expect that our research and development expenses will increase substantially over the next several years as we continue to
advance the development of our product candidates. We also expect to incur additional expenses related to milestone and royalty payments
payable to third parties with whom we have entered into license agreements.
General and Administrative Expenses
General and administrative expenses
consist primarily of salaries and related benefits, share-based compensation expenses for personnel in executive and administrative functions,
insurance and professional fees for legal, consulting, accounting and audit services.
We anticipate that our general and
administrative expenses will increase in the future due to increased headcount and professional fees to support our continued research
activities and development of our product candidates. We also anticipate that we will continue to incur accounting, audit, legal, regulatory,
compliance, director and officer insurance costs, as well as investor and public relations expenses associated with being a public company.
Additionally, once we believe that regulatory approval of a product candidate appears likely, we will begin to incur a material increase
in payroll and related expenses as a result of preparation for commercial operations, particularly in respect of sales and marketing.
Financing Expenses,
Net
Financing expenses, net consist primarily
of income or expenses related to revaluation of foreign currencies and interest income on our bank deposits.
Results of Operations
The following table summarizes our
results of operations for the years ended December 31, 2024, 2023 and 2022:
|
|
Year ended December 31, |
|
|
|
2024 |
|
|
2023 |
|
|
2022 |
|
|
|
(in thousands)
|
|
Operating Expenses: |
|
|
|
Research and development |
|
$ |
11,327 |
|
|
$ |
18,381 |
|
|
$ |
16,977 |
|
General and administrative |
|
|
3,412 |
|
|
|
7,078 |
|
|
|
11,556 |
|
Total operating expenses |
|
|
14,739 |
|
|
|
25,459 |
|
|
|
28,533 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Financing income, net |
|
|
(794 |
) |
|
|
(1,238 |
) |
|
|
(353 |
) |
Loss before taxes |
|
|
13,945 |
|
|
|
24,221 |
|
|
|
28,180 |
|
Taxes benefit |
|
|
- |
|
|
|
- |
|
|
|
(534 |
) |
|
|
|
|
|
|
|
|
|
|
|
|
|
Net loss |
|
$ |
13,945 |
|
|
$ |
24,221 |
|
|
$ |
27,646 |
|
Our results of operations have varied
in the past and can be expected to vary in the future due to numerous factors. We believe that period-to-period comparisons of our operating
results are not necessarily meaningful and should not be relied upon as indications of future performance.
Year ended December
31, 2024, Compared to the Year Ended December 31, 2023
Research and development expenses
Research and development expenses
decreased by approximately $7.1 million, or 38%, to approximately $11.3 million for the year ended December 31, 2024, compared to approximately
$18.4 million for the year ended December 31, 2023. The decrease resulted due to production for clinical trial done in 2023 and decrease
in clinical related expenses due to completion of phase 2 clinical study in Q3 2024.
General and administrative expenses
General and administrative expenses
decreased by approximately $3.7 million, or 52%, to approximately $3.4 million for the year ended December 31, 2024, compared to approximately
$7.1 million for the year ended December 31, 2023. The decrease was primarily due to a decrease in headcount, professional fees, insurance
expenses and share-based compensation.
Financing income, net
Financing income, net, decreased
by approximately $444 thousand, or 36%, to net income of $794 thousand for the year ended December 31, 2024, compared to a net income
of $1,238 thousand for the year ended December 31, 2023. The decrease was primarily due to a reduction in the amount of deposits and cash
and cash equivalents between the periods. Financing income, net for the year ended December 31, 2024, was primarily related to interest
income on deposits offset by foreign currency exchange rate differences.
Year ended December
31, 2023, Compared to the Year Ended December 31, 2022
Research and development expenses
Research and development expenses
increased by approximately $1.4 million, or 8.3%, to approximately $18.4 million for the year ended December 31, 2023, compared to approximately
$17.0 million for the year ended December 31, 2022. The increase resulted primarily from an increase in from a continued investment
in the clinical programs of the Company.
General and administrative expenses
General and administrative expenses
decreased by approximately $4.5 million, or 38.8%, to approximately $7.1 million for the year ended December 31, 2023, compared to approximately
$11.6 million for the year ended December 31, 2022. This decrease was primarily due to decrease in headcount and professional fees and
insurance expenses and share-based compensation.
Financing income, net
Financing income, net, increased by approximately
$885 thousand, or 251%, to net income of $1,238 thousand for the year ended December 31, 2023, compared to a net income of $353 thousand
for the year ended December 31, 2022. Financing income , net for the year ended December 31, 2023, was primarily related interest income
on deposits offset by foreign currency exchange rate differences.
Taxes on Income
The tax benefit in 2022 is related
to a tax return of Chemomab Therapeutics Inc., a wholly owned subsidiary of ours, derived by carryback of net operating losses
Cash Flows
The following table summarizes our
cash flows for the years ended December 31, 2024, 2023 and 2022:
|
|
Year ended December 31, |
|
|
Increase/(decrease) |
|
|
|
2024 |
|
|
2023 |
|
|
2022 |
|
|
|
|
|
% |
|
|
|
(in thousands) |
|
|
|
|
Net cash used in operating activities |
|
$ |
(15,386 |
) |
|
$ |
(23,611 |
) |
|
$ |
(20,370 |
) |
|
$ |
8,225 |
|
|
|
35 |
% |
Net cash provided by investing activities |
|
|
2,297 |
|
|
|
15,879 |
|
|
|
19,533 |
|
|
|
(13,582 |
) |
|
|
(86 |
)% |
Net cash provided by (used in) financing activities |
|
|
9,868 |
|
|
|
3,504 |
|
|
|
(808 |
) |
|
|
6,364 |
|
|
|
182 |
% |
Net decrease in cash, cash equivalents and restricted cash
|
|
$ |
(3,221 |
) |
|
$ |
(4,228 |
) |
|
$ |
(1,645 |
) |
|
$ |
1,007 |
|
|
|
24 |
% |
Year ended December
31, 2024, Compared to the Year Ended December 31, 2023
Operating activities
Net cash used in operating activities
for the year ended December 31, 2024, was approximately $15 million and included net loss of $13.9 million, and by net cash used by changes
in operating assets and liabilities of approximately $2.1 million offset by non-cash charges of $0.7 million, which mainly included share-based
compensation expenses.
Net cash used in operating activities
for the year ended December 31, 2023, was approximately $23.6 million and included net loss of $24.2 million, partially offset by net
cash used by changes in operating assets and liabilities of approximately $0.9 million and non-cash charges of $1.6 million, which mainly
included share-based compensation expenses.
Net cash provided by investing activities
for the year ended December 31, 2024, was approximately $2.3 million, due to decrease in short term deposits.
Net cash provided in investing activities
for the year ended December 31, 2023, was $15.9 million, due to decrease in short term deposits.
Financing activities
Net cash provided by financing activities
for the year ended December 31, 2024, was approximately $9.9 million due to proceeds from issuance of shares net of issuance costs.
Net cash provided by financing activities
for the year ended December 31, 2023, was $3.5 million, consisting of $2.9 million of proceeds from issuance of shares net of issuance
costs , $0.6 of proceeds from the sale of treasury shares.
Year ended December
31, 2023, Compared to the Year Ended December 31, 2022
Operating activities
Net cash used in operating activities
for the year ended December 31, 2023, was approximately $23.6 million and included net loss of $24.2 million, partially offset by net
cash used by changes in operating assets and liabilities of approximately $0.9 million and non-cash charges of $1.6 million, which mainly
included share-based compensation expenses.
Net cash used in operating activities for the year ended
December 31, 2022 was approximately $20.4 million and included net loss of $27.6 million, partially offset by net cash used by changes
in operating assets and liabilities of approximately $4.0 million and non-cash charges of $3.3 million, which mainly included share-based
compensation expenses.
Investing activities
Net cash provided by investing activities
for the year ended December 31, 2023, was $15.9 million, which was primarily related to funds received from bank deposits.
Net cash provided by investing activities
for the year ended December 31, 2022, was approximately $19.5 million, which was primarily related to investment in short-term deposits
offset by purchasing of fixed assets.
Financing activities
Net cash provided by financing activities
for the year ended December 31, 2023, was approximately $3.5 million, consisting of $2.9 million of proceeds from the sale of ADSs, $0.6
of proceeds from the sale of treasury shares.
Net cash used in financing activities for
the year ended December 31, 2022, was approximately $0.8 million, consisting of $0.3 million of proceeds from the sale of ADSs, $0.14
million of proceeds from the exercise of stock options offset by the repurchase of shares in the amount of $1.2 million.
Funding Requirements
We expect our expenses to increase
substantially as we advance the clinical trials of our product candidate. In addition, we expect to continue to incur additional costs
associated with operating as a public company.
We believe that our existing cash, cash
equivalents and bank deposits will enable us to fund our operating expenses and capital expenditure requirements through March 31, 2026.
This means that there is a substantial doubt about our ability to continue as a going concern, and that we will be required to raise additional
funds to support our operations and continue as a going concern. While we believe that we can raise additional funds, there can be no
assurance that these efforts will be successful or sufficient. We have based these estimates on assumptions that may prove to be wrong,
and we could expend our capital resources sooner than we expect. If we receive regulatory approval for any of our product candidates,
we expect to incur significant commercialization expenses related to product manufacturing, sales, marketing and distribution.
Until such time, if ever, that we
generate product revenue sufficient to achieve profitability, we expect to finance our cash needs through the sales of our securities
and through other outside funding sources. Debt financing and preferred equity financing, if available, may involve agreements that include
covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures
or declaring dividends. If we raise additional funds through government and other third-party funding, collaboration agreements, strategic
alliances, licensing arrangements or marketing and distribution arrangements, then we may have to relinquish valuable rights to our technologies,
future revenue streams, research programs or product candidates or grant licenses on terms that may not be favorable to us. If we are
unable to raise additional funds through equity or debt financings when needed, then we may be required to delay, limit, reduce or terminate
our product development or future commercialization efforts or grant rights to develop and market products or product candidates that
we would otherwise prefer to develop and market.
B. Liquidity
and Capital Resources
In connection with the Merger, on
March 15, 2021, we entered into Securities Purchase Agreements with certain investors, pursuant to which we agreed to sell approximately
$45.5 million of the ADSs in a private placement transaction (the Private Placement). The Private Placement closed on March 22, 2021,
at which time we sold 2,619,270 ADSs together with warrants to purchase up to 261,929 ADSs at an exercise price of $17.35 per ADS. The
warrants expire five years from the date of issuance, and, if exercised in full, will provide proceeds of approximately $4.5 million.
On April 30, 2021, we entered into
the Sales Agreement with Cantor Fitzgerald & Co. (Cantor). Pursuant to the Sales Agreement, we may offer and sell, from time to time,
ADSs having an aggregate offering price of up to $75 million through Cantor (the “Cantor ATM Facility”). Sales of ADSs, if
any, under the Sales Agreement will be issued and sold pursuant to our Registration Statement on Form S-3 which was declared effective
on May 17, 2021, and will be made in sales deemed to be an “at the market offering” as defined in Rule 415(a)(4) promulgated
under the Securities Act. Pursuant to the Sales Agreement, Cantor has agreed to act as sales agent on a best efforts basis and use
commercially reasonable efforts to sell on our behalf all of the ADSs we requested to be sold in accordance with the Sales Agreement,
consistent with Cantor’s normal trading and sales practices, on mutually agreed terms.
On April 25, 2022, we filed a prospectus
supplement with the SEC for the issuance and sale of up to $18,125,000 of ADSs in connection with the reactivation of the Cantor ATM Facility
and pursuant to General Instruction I.B.6 of Form S-3, which, subject to certain exceptions, limits the amount of securities we are able
to offer and sell under such registration statement during any twelve month period to one-third of our unaffiliated public float.
In October 2023, we entered into
an At the Market Offering Agreement (the “Roth ATM Agreement”) with Roth Capital Partners, LLC, (“Roth”). Pursuant
to the Roth ATM Agreement, we may offer and sell, from time to time, our ADSs having an aggregate offering price of up to $2,863,664 through
Roth or the Roth ATM Agreement (the “Roth ATM Facility”). Accordingly, in October 2023, we filed a prospectus supplement with
the SEC for the issuance and sale of up to $2,863,664 of our ADSs in connection with the reactivation of the Roth ATM Facility.
On November 15, 2024, we filed a
prospectus supplement with the SEC for the issuance and sale of up to $8,626,564 of ADSs in connection with the Roth ATM .Facility and
pursuant to General Instruction I.B.6 of Form S-3, which, subject to certain exceptions, limits the amount of securities we are able to
offer and sell under such registration statement during any twelve month period to one-third of our unaffiliated public float.
On July 25, 2024, we entered into
a Securities Purchase Agreement with the Purchasers as identified therein, pursuant to which we sold to the Purchasers: (i) 4,148,867
ADSs, at a purchase price of $1.235 per ADS; and (ii), in lieu of ADSs, Pre-Funded Warrants to purchase up to 3,948,300 ADSs at a purchase
price of $ 1.2349 per warrant (the July 2024 Private Placement). The Pre-Funded Warrants will have an exercise price of $0.0001 per ADS,
be immediately exercisable and remain exercisable until exercised in full. The July 2024 Private Placement closed on July 30, 2024, and
we received gross proceeds from the July 2024 Private Placement of approximately $10.0 million before deducting any offering expenses.
On August 23, 2024, we filed a Registration Statement on Form F-3 with the SEC for the issuance and sale of the 8,097,167 of ADSs sold
to the Purchasers in the July 2024 Private Placement.
During the year ended December 31,
2022, we sold 130,505 ADSs at an average price of USD 2.11 per ADS, through the Cantor ATM Facility, resulting in gross proceeds
of $275,000.
During the year ended December 31, 2023, we sold 1,800,000ADSs
at an average price of USD 0.96 per ADS, through the Roth ATM Facility, resulting in gross proceeds of USD1.73 million and 772,900 ADSs
at an average price of USD 1.83 per ADS, through the Cantor ATM Facility, resulting in gross proceeds of approximately USD1.4 million
During the year ended December 31,
2023, we sold 582,023 ADSs which were held in treasury for consideration of approximately $580 thousand.
During the year ended December 31,
2024, we sold 503,009 ADSs at an average price of USD 1.65 per ADS, through the Roth ATM Facility, resulting in gross proceeds of approximately
$0.8 million shown in the accompanying consolidated financial statements, we have incurred losses and cash flow deficits from operations
since inception, resulting in an accumulated deficit as of December 31, 2024, of $102.6 million. We have financed operations to date primarily
through public and private placements of equity securities. We anticipate that we will continue to incur net losses for the foreseeable
future. We believe that our existing cash, cash equivalents and bank deposits will be sufficient to fund our projected cash needs through
March 31, 2026. To meet future capital needs we would need to raise additional capital through equity or debt financing or other strategic
transactions. However, any such financing may not be available to us on favorable terms or at all. Our failure to obtain sufficient funds
on commercially acceptable terms when needed would have a material adverse effect on our business, results of operations and financial
condition.
Current Outlook
We estimate that our current liquidity
resources will allow us to execute our business plans through March 31, 2026.
Developing drugs, conducting preclinical
and clinical trials, obtaining commercial manufacturing capabilities and commercializing products is expensive, and we will need to raise
substantial additional funds to achieve our strategic objectives. We will require significant additional financing in the future to fund
our operations, including if and when we progress into clinical trials of our product candidates, obtain regulatory approval for one or
more of our product candidates, obtain commercial manufacturing capabilities and commercialize one or more of our product candidates.
Our future capital requirements will depend on many factors, including, but not limited to:
• |
the progress and costs of our preclinical and clinical trials and other research and
development activities; |
• |
the scope, prioritization and number of our preclinical and clinical trials and other
research and development programs; |
• |
the amount of revenues and contributions we receive under future licensing, collaboration,
development and commercialization arrangements with respect to our product candidates; |
• |
the costs of development and expansion of our operational infrastructure; |
• |
the costs and timing of obtaining regulatory approval for one or more of our product
candidates; |
• |
our ability, or that of our collaborators, to achieve development milestones, marketing
approval and other events or developments under potential future licensing agreements; |
• |
the costs of filing, prosecuting, enforcing and defending patent claims and other
intellectual property rights; |
• |
the costs and timing of securing manufacturing arrangements for clinical or commercial
production; |
• |
the costs of contracting with third parties to provide sales and marketing capabilities
for us or establishing such capabilities ourselves; |
• |
the costs of acquiring or undertaking development and commercialization efforts for
any future products, product candidates or technology; |
• |
the magnitude of our general and administrative expenses; and |
• |
any additional costs that we may incur under future in- and out-licensing arrangements
relating to one or more of our product candidates. |
Until we can generate significant
recurring revenues, we expect to satisfy our future cash needs through capital raising or by out-licensing and/or co-developing applications
of one or more of our product candidates. We cannot be certain that additional funding will be available to us on acceptable terms, if
at all. If funds are not available, we may be required to delay, reduce the scope of or eliminate research or development plans for, or
commercialization efforts with respect to, one or more of our product candidates and make the necessary change to our operations to reduce
the level of our expenditures in line with available resources.
We are a development-stage company
and it is not possible for us to predict with any degree of accuracy the outcome of our research and development efforts. As such, it
is not possible for us to predict with any degree of accuracy any significant trends, uncertainties, demands, commitments or events that
are reasonably likely to have a material effect on our net loss, liquidity or capital resources, or that would cause financial information
to not necessarily be indicative of future operating results or financial condition. However, to the extent possible, certain trends,
uncertainties, demands, commitments and events are described in this item.
C. |
Research and Development, Patents and Licenses |
For information concerning our research
and development policies and a description of the amount spent during each of the last three fiscal years on company-sponsored research
and development activities, see “Item 5. Operating and Financial Review and Prospects—Results of Operations.”
Other than as disclosed elsewhere
in this Annual Report, we are not aware of any trends, uncertainties, demands, commitments or events for the period from January 1, 2024
to December 31, 2024 that are reasonably likely to have a material adverse effect on our revenue, profitability, liquidity or capital
resources, or that caused the disclosed financial information to be not necessarily indicative of future operating results or financial
condition.
E. |
Critical Accounting Estimates |
Our financial statements are prepared
in accordance with generally accepted accounting principles in the United States (GAAP). The preparation of our financial statements and
related disclosures in accordance with GAAP requires us to make estimates and judgments that affect the reported amounts of assets, liabilities,
revenue, costs and expenses, and the disclosure of contingent assets and liabilities in our financial statements. We base our estimates
on historical experience, known trends and events and various other factors that we believe are reasonable under the circumstances, the
results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent
from other sources. We evaluate our estimates and assumptions on an ongoing basis. Our actual results may differ from these estimates
under different assumptions or conditions.
Our significant accounting policies are described in more detail in Note 2 to our consolidated
financial statements
Item 6.
Directors, Senior Management and Employees
A. |
Directors and Senior Management |
The following table sets
forth the name and position of each of our executive officers and directors as of March 31, 2025:
Name |
|
Age |
|
Position |
Executive Officers: |
|
|
|
|
Adi Mor |
|
43 |
|
Director, Chief Executive Officer and Chief Scientific Officer |
Sigal Fattal |
|
54 |
|
Chief Financial Officer |
Matthew Frankel |
|
56 |
|
Chief Medical Officer |
Non-Employee Directors: |
|
|
|
|
Nissim Darvish†(2)(3) |
|
59 |
|
Chairman of the Board |
Alan Moses†(1) |
|
76 |
|
Director |
Claude Nicaise†(1) |
|
71 |
|
Director |
Neil Cohen†(2)(3) |
|
60 |
|
Director |
Jill Quigley†(1) |
|
49 |
|
Director |
† Independent Director
(1) |
Member of Audit Committee |
|
|
(2) |
Member of Compensation Committee |
|
|
(3) |
Member of Corporate Governance and Nominating Committee |
Executive Officers
Dr.
Adi Mor is the co-founder of Chemomab Ltd., the wholly-owned subsidiary of the Company, and served as Chemomab Ltd.’s Chief
Executive Officer, Chief Scientific Officer and a member of Chemomab Ltd.’s board of directors from its formation in 2011 until
the Chemomab Ltd.–- Anchiano Therapeutics Ltd. merger that was consummated on March 16, 2021 (the “Merger”). Dr. Mor
previously served as Chief Executive Officer of the Company through October 25, 2021. Dr. Mor has in-depth knowledge in immunology focusing
on rare diseases and broad experience in designing, developing and patenting a novel class of monoclonal antibodies to treat inflammatory
and fibrotic diseases. Dr. Mor received her Ph.D. in immunology from Tel Aviv University in the Department of Neurobiochemistry in Israel
and is the lead author of numerous scientific journal publications regarding immunology and inflammatory disorders.
Sigal
Fattal previously served as Chemomab Ltd.’s interim Chief Financial Officer from October 2020 until the Merger and continued
in that capacity for the Company following the Merger until November 8, 2021, following which she became the Company’s VP of Finance.
Prior to joining Chemomab Ltd., from March 2017 to December 2019, Ms. Fattal served as Chief Financial Officer at BiomX (NYSE American:
PHGE), a clinical stage microbiome product discovery company. Prior to joining BiomX, Ms. Fattal served as Chief Financial Officer at
Evogene (Nasdaq and TASE: EVGN), a computational biology company, from 2013 to 2016. Prior to that time, Ms. Fattal served in multiple
financial and operational executive roles in various companies. Ms. Fattal also currently serves as co-founder of Simbiz, which was founded
in September 2020 and which offers one-stop-shop corporate services to startup companies. Ms. Fattal is a certified CPA (Isr.), and holds
a BA in Accounting and Economics, and an MBA, both from Tel Aviv University.
Dr.
Matthew B. Frankel has 20 years of experience in the pharmaceutical industry, encompassing clinical development and medical affairs.
From 2018 until November 2022, Dr. Frankel served as Vice President, Clinical Development and Medical Affairs, Specialty Pharma at Boehringer-Ingelheim
Pharmaceuticals, Inc. Prior to that, he served as the Vice President & Head, Immunology and Dermatology Medical Unit at Novartis Pharmaceuticals
Corporation from 2016 to 2018. From 2012 to 2016, Dr. Frankel served as the Executive Medical Director of Sandoz and from 2010 through
2012 held the role of Global Medical Director, Clinical Development at Reata Pharmaceuticals (RETA). From 2003 through 2010, he held various
senior roles across different companies in the research field. Dr. Frankel received his undergraduate degree from Vassar College, his
MD from the University of California, Los Angeles School of Medicine, and his MBA from the J. L. Kellogg Graduate School of Management.
Directors
Nissim
Darvish, M.D., Ph.D. has served on our Board since March 16, 2021 and as chairman of the Board since June 2023. Dr. Darvish is
a General Partner at Eliraz Ventures, a venture capital fund. Dr. Darvish currently serves as a director of several private companies.
Prior to his current position, Dr. Darvish served as a Venture Partner at OrbiMed Israel and as a member of the boards of directors of
9 Meters Biopharma Inc. and Medigus Ltd. Previously, Dr. Darvish was employed at Pitango Venture Capital, where he was a General Partner
managing life sciences investments. He was also the founder and CEO of Impulse Dynamics, where he oversaw a $250 million realization event.
Dr. Darvish obtained his M.D. and Ph.D. in Biophysics and Physiology from the Technion in Israel, and subsequently conducted his post-doctoral
research at NIH. He has published over 100 patents and authored over 20 publications.
Alan
Moses, MD, FACP has served on our Board since March 16, 2021. Dr. Moses is board certified by the ABIM with subspecialty certification
in Endocrinology and Metabolism and is a Fellow of the American College of Physicians. Dr. Moses serves as a Director for BiomX/APT
Inc. He also serves as Chair of the Board of Trustees of The diaTribe Foundation, a nonprofit located in San Francisco and as a
member of the Board of Trustees of the Joslin Diabetes Center. Prior to that time, from 2008 to 2018, Dr. Moses served as the Global Chief
Medical Officer of Novo Nordisk A/S (CPH: NOVO-B), a company he joined in 2004. Dr. Moses served as a Professor of Medicine at Harvard
Medical School from 2002 to 2006, and in collaboration with MIT, he co-founded and co-directed the Clinical Investigator Training Program,
which focused on training physician-scientists in translational research. Dr. Moses previously served as the Senior Vice President and
Chief Medical Officer of the Joslin Diabetes Center from 1998 to 2004. Dr. Moses holds a BS from Duke University, North Carolina and an
MD from Washington University School of Medicine, Missouri. He received additional postgraduate training at the National Institutes of
Health and completed his endocrinology Fellowship at Tufts-New England Medical Center.
Claude
Nicaise, MD has served on our Board since March 16, 2021. Dr. Nicaise is a physician with extensive U.S. and international
experience in clinical drug development, strategic management, worldwide regulatory strategy, pharmaceuticals, biotechnology, including
clinical cancer research, infectious diseases and neuroscience. Dr. Nicaise is the owner and founder of Clinical Regulatory Services,
which provides consulting services to the life science and biotechnology industry in support of all aspects of clinical and regulatory
development. Since 2015, Dr. Nicaise has served on the board of directors and as the Chairman of the Compensation Committee of Sarepta
Therapeutics, Inc. (NASDAQ: SRPT). Dr Nicaise has also served on the board of directors of Mynoryx Therapeutics since 2017. Prior to that
time, from 2008 to 2014, Dr. Nicaise served as the Senior Vice President of Alexion Pharmaceuticals Inc. (NASDAQ: ALXN), and between 1984
and 2008, he held numerous senior management roles at Bristol Myers Squibb (NYSE: BMY). Dr. Nicaise holds an MD and a degree in Internal
Medicine, Clinical Oncology, from Brussels University, Belgium.
Neil
Cohen has served as a member of our Board since April 2020 and served as our interim Chief Executive Officer from October
2020 until the consummation of the Merger. Mr. Cohen has served as the Chairman and Chief Executive Officer of Castel Partners Ltd. since
January 2012. In 1994, he co-founded Israel Seed Partners, a leading venture capital firm, and managed the firm until 2019. Mr. Cohen
has invested in and served on the boards of directors of many private technology companies, including a large number which were acquired
or completed successful initial public offerings, including Compugen (Nasdaq: CGEN), Shopping.com (Nasdaq: SHOP, acquired by EBAY), Broadlight
(acquired by Broadcom, Nasdaq: AVGO) and Cyota (acquired by RSA). He is a venture partner at SKY, an Israeli middle-market private equity
firm, Hetz Ventures Management Ltd., an early-stage Israeli venture capital fund, and Shavit Capital. Mr. Cohen was previously the Business
Editor of The Jerusalem Post and began his career in the private equity group at N M Rothschild & Sons Limited in London. Mr. Cohen
received a B.A. and M.A. in Oriental Studies, with first class honors, from Oxford University.
Jill
M. Quigley has served as a member of our Board since June 2022. Since September 2023 Ms. Quigley serves as CEO of a stealth biotech
company. Since December 2020, Ms. Quigley has served as a member of the board of directors of Terns Pharmaceuticals, Inc. (Nasdaq: TERN),
including her role as chairperson of its audit committee. From November 2018 until December 2021, Ms. Quigley served as Chief Operating
Officer of Passage BIO, Inc. (Nasdaq: PASG). Previously, she served as the Interim Chief Executive Officer and General Counsel of Nutrinia,
Inc., from January 2016 to November 2018. From July 2012 to January 2016, Ms. Quigley served in various roles at Shire plc, most recently
as Senior Legal Counsel. Ms. Quigley received her undergraduate degree in Communications, Legal Institutions, Economics & Governance
(CLEG) from American University and J.D. from Rutgers School of Law.
Directors. Under the Companies Law, the compensation of our directors requires the approval of our compensation committee, the
subsequent approval of the board of directors and, unless exempted under regulations promulgated under the Companies Law, the approval
of the shareholders at a general meeting. If the compensation of our directors is inconsistent with our stated compensation policy, then,
those provisions that must be included in the compensation policy according to the Companies Law must have been considered by the compensation
committee and board of directors, and shareholder approval by a simple majority will also be required, provided that:
• |
at least a majority of the shares held by all shareholders who are not controlling
shareholders and do not have a personal interest in such matter, present and voting at such meeting, are voted in favor of the compensation
package, excluding abstentions; or |
|
|
• |
the total number of shares of non-controlling shareholders and shareholders who do
not have a personal interest in such matter voting against the compensation package does not exceed two percent (2%) of the aggregate
voting rights in the Company. |
Executive Officers other than the Chief Executive Officer. The Companies Law requires the approval of the compensation of a public
company’s executive officers (other than the chief executive officer) in the following order: (1) the compensation committee, (2)
the company’s board of directors, and (3) if such compensation arrangement is inconsistent with the company’s stated compensation
policy, the company’s shareholders (by a special majority vote as discussed above with respect to the approval of director compensation).
However, if the shareholders of the company do not approve a compensation arrangement with such executive officer that is inconsistent
with the company’s stated compensation policy, the compensation committee and board of directors may override the shareholders’
decision if each of the compensation committee and the board of directors provide detailed reasons for their decision.
An amendment to an existing arrangement
with an office holder (who is not a director) requires only the approval of the compensation committee, if the compensation committee
determines that the amendment is not material in comparison to the existing arrangement. However, under the Companies Law, an amendment
to an existing arrangement with an office holder (who is not a director) who is subordinate to the chief executive officer will not require
the approval of the compensation committee, if (1) the amendment is approved by the chief executive officer, (2) the company’s compensation
policy provides that a non-material amendment to the terms of service of an office holder (other than the chief executive officer) may
be approved by the chief executive officer and (3) the engagement terms are consistent with the company’s compensation policy.
Chief
Executive Officer. Under the Companies Law, the compensation of a public company’s chief executive officer is required to
be approved by: (1) the company’s compensation committee; (2) the company’s board of directors, and (3) the company’s
shareholders (by a special majority vote as discussed above with respect to the approval of director compensation). However, if the shareholders
of the company do not approve the compensation arrangement with the chief executive officer, the compensation committee and board of directors
may override the shareholders’ decision if each of the compensation committee and the board of directors provide detailed reasons
for their decision. The approval of each of the compensation committee and the board of directors should be in accordance with the company’s
stated compensation policy; however, in special circumstances, they may approve compensation terms of a chief executive officer that are
inconsistent with such policy provided that they have considered those provisions that must be included in the compensation policy according
to the Companies Law and that shareholder approval is obtained (by a special majority vote as discussed above with respect to the approval
of director compensation). In addition, the compensation committee may waive the shareholder approval requirement with regards to the
approval of the engagement terms of a candidate for the chief executive officer position, if they determine that the compensation arrangement
is consistent with the company’s compensation policy and that the chief executive officer candidate did not have a prior business
relationship with the company or a controlling shareholder of the company and that subjecting the approval of the engagement to a shareholder
vote would impede the company’s ability to employ the chief executive officer candidate.
Compensation of Directors and Executive
Officers
The aggregate compensation paid
by us and our subsidiaries to our directors and executive officers, including share-based compensation expenses recorded in our financial
statements, for the year ended December 31, 2024, was approximately $2.5 million (including $0.4 million in share-based compensation).
This amount includes deferred or contingent compensation accrued for such year (and excludes deferred or contingent amounts accrued for
during the year ended December 31, 2023 and paid during the year ended December 31, 2024). This amount includes amounts set aside
or accrued to provide pension, severance, retirement or similar benefits or expenses, but does not include business travel, relocation,
professional and business association dues and expenses reimbursed to our directors and executive officers.
During the year ended December 31,
2024, our directors and officers were granted options to purchase an aggregate of 1,645,020 ordinary shares (equal to 82,251 ADSs),
at a weighted average exercise price of $0.037 per share (equal to approximately $0.7 per ADS). In addition, 4,363,580 restricted ordinary
shares (equal to 218,179 restricted ADSs) were granted to executive officers of the Company.
The following is a summary of the
salary expenses, bonus and social benefit costs of our three executive officers in 2024, or the “Covered Executives”. All
amounts reported reflect the cost to us as recognized in our financial statements for the year ended December 31, 2024.
• |
Adi Mor, Chief Executive Officer, Chief Scientific
Officer and Director. Compensation expenses recorded in 2024 were $0.7 million in salary expenses. |
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• |
Sigal Fattal, Chief Financial Officer. Compensation expenses recorded
in 2024 were $0.5 million in salary expenses. |
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• |
Matthew Frankel, Chief Medical Officer. Compensation expenses recorded
in 2024 were $0.7 million in salary expenses and $77 thousand in social benefits. |
The salary expenses summarized
above include the gross salary paid to the Covered Executives, severance and bonus. The benefit costs include the social benefits
paid by us on behalf of the Covered Executives, contributions made by us to an insurance policy, pension fund or 401(K) fund.
We also recorded equity-based
compensation expenses in our financial statements for the year ended December 31, 2024, of $0.6 million.
All equity-based compensation
grants to our Covered Executives were made in accordance with the parameters of our compensation policy and were approved by our compensation
committee and board of directors. Assumptions and key variables used in the calculation of such amounts are described in Note 8 to our
audited consolidated financial statements included in Item 18 of this Annual Report.
Additionally,
we annually pay to each of our non-employee directors a cash retainer of $40,000 (or $65,000 for the Chairperson) with an additional annual
payment for service on board committees as follows: $15,500 for the chairperson of the audit committee and $7,625 for the other committee
members. $11,000 for the chairperson of the compensation committee and $5,500 for the other committee members. $9,000 for the chairperson
of the corporate governance and nominating committee or any other board committee and $4,500 for the other committee members.
In addition, upon election,
non-employee directors (other than the Chairperson), will be granted equity awards equal to 0.1% of our share capital on a fully diluted
basis, under our incentive plan, which will vest on a monthly basis over a period of three years. In addition, each non-employee director
will be granted equity awards under our incentive plan (provided the director is still in office) equal to 0.06% of our share capital
on a fully diluted basis, which will vest on the first anniversary of the date on which such options were granted, subject to such director’s
continued service through such date.
The non-employee Chairperson, on
election, will be granted an equity award equal to 0.2% of our share capital on a fully diluted basis, under our incentive plan, which
will vest on a monthly basis over a period of three years. In addition, the non-employee Chairperson will be granted equity awards under
our incentive plan (provided the Chairperson is still in office) equal to 0.1% of our share capital on a fully diluted basis, which will
vest on the first anniversary of the date on which such options were granted, subject to such Chairperson continued service through such
date.
Equity Incentive Plans
We maintain (i) the 2011 Share Option Plan
(the “2011 Plan”), (ii) the 2017 Plan and (iii) the 2015 Plan, which was assumed by our company from the Subsidiary upon the
effectiveness of the Merger. At that time, outstanding options under the 2015 Plan became exercisable for such number of ADSs of our company
(formerly known as Anchiano Therapeutics Ltd.) as was determined based on the exchange ratio in the Merger Agreement, with a reciprocal
adjustment to exercise price. As of December 31, 2024, a total of 1,422,153 ADSs were reserved for issuance under the 2015 Plan, of which
172,276 ADSs had been issued pursuant to previous exercises options, and 456,745 ADSs were issuable under outstanding options.
Of such outstanding options, options to purchase 333,869 ADSs had vested and were exercisable as of that date, with a weighted average
exercise price of $$6.17 per ADS.
As of December 31, 2024, a total
of 1,153,069 of ADSs were reserved for issuance under the 2017 Plan, of which 1,145,770 ADSs were issuable under outstanding
options. Of such outstanding options, options to purchase 573,013 ADSs had vested and were exercisable as of that date, with a weighted
average exercise price of $2.63 per ADS. No ADSs had been issued pursuant to previous exercises options.
2011 Plan
On December 19, 2011, our board of
directors adopted the 2011 Plan to allocate options to purchase our ordinary shares to our directors, officers, employees and consultants,
and those of our affiliated companies (as such term is defined under the 2011 Plan), or the Grantees. The 2011 Plan is administered by
our board of directors or a committee that was designated by our board of directors for such purpose (the “Administrator”).
Under the 2011 Plan, we may grant
options to purchase ordinary shares (“Options”), under four tracks: (i) Approved 102 capital gains Options through a trustee,
which was approved by the Israeli Tax Authority in accordance with Section 102(a) of the Israeli Income Tax Ordinance (“ITO”),
and granted under the tax track set forth in Section 102(b)(2) of the ITO, or the Approved 102 Capital Gains Options. The holding period
under this tax track is 24 months from the date of allocation of Options to the trustee or such period as may be determined in any amendment
of Section 102 of the ITO, or any applicable tax ruling or guidelines; (ii) Approved 102 Earned Income Options through a trustee, granted
under the tax track set forth is Section 102(b)(1) of the ITO, or the Approved 102 Earned Income Options. The holding period under this
tax track is 12 months from the date of allocation of Options to the trustee or such period as may be determined in any amendment of Section
102 of the ITO; (iii) Unapproved 102 Options (the Options will not be allocated through a trustee and will not be subject to a holding
period), or the Unapproved 102 Options; and (iv) 3(i) Options (the Options will not be subject to a holding period). These Options shall
be subject to taxation pursuant to Section 3(i) of the ITO, or Section 3(i).
Options pursuant to the first three
tax tracks (under Section 102 of the ITO) can be granted to our employees and directors and the grant of Options under Section 3(i) can
be granted to our consultants and controlling shareholders (a controlling shareholder is defined under the Section 102 of the ITO is a
person who holds, directly or indirectly, alone or together with a “relative,” (i) the right to at least 10% of the company’s
issued capital or 10% of the voting power; (ii) the right to hold at least 10% of the company’s issued capital or 10% of the voting
power, or the right to purchase such rights; (iii) the right to receive at least 10% of the company’s profits; or (iv) the right
to appoint a company’s director). Grantees who are not Israeli residents may be granted options that are subject to the applicable
tax laws in their respective jurisdictions.
We determine, in our sole discretion,
under which of the first three tax tracks above the Options are granted and we notify the Grantee in a grant letter, as to the elected
tax track. As mentioned above, consultants and controlling shareholders can only be granted Section 3(i) Options.
The number of ordinary shares authorized
to be issued under the 2011 Plan will be proportionately adjusted for any increase or decrease in the number of ordinary shares issued
as a result of a distribution of bonus shares, change in our capitalization (split, combination, reclassification of the shares or other
capital change), or issuance of rights to purchase ordinary shares or payment of a dividend. We will not allocate fractions of ordinary
shares and the number of ordinary shares shall be rounded up to the closest number of ordinary shares.
Unless otherwise determined by the
Administrator, the exercise price of an Option granted under the 2011 Plan will be the average of the market price of our ordinary shares
during the 22 business days prior to the date on which our board of directors authorized the grant of Options; provided, however, that
such exercise price cannot be lower than the market price at the close of the trading day at which it was granted by our board of directors.
The exercise price will be specified in the grant letter every Grantee received from us in which the Grantee notifies of the decision
to grant him/her Options under the 2011 Plan.
Unless otherwise determined by the
Administrator, the Options granted under the 2011 Plan will become vested and may be exercised in 16 equal portions of 6.25% of the total
number of Options, at the end of each quarter following the day the Options were granted. Unless otherwise determined by our board of
directors, the Options may be exercised for ten years following the date of grant, unless terminated earlier, and as long as the Grantee
is employed by us (or by an affiliated company), or provides service to us (or an affiliated company).
The Administrator may, in its absolute
discretion, accelerate the time at which Options granted under the 2011 Plan or any portion of which will vest.
Unless otherwise determined by the
Administrator, in the event that the Grantee’s employment was terminated, not for Cause (as defined in the 2011 Plan), the Grantee
may exercise that portion of the Options that had vested as of the date of such termination until the end of the specified term in the
grant letter or the 2011 Plan. The portion of the Options that had not vested at such date, will be forfeited and can be re-granted according
to the terms of the 2011 Plan.
2015 Plan
In November 2015, the Subsidiary’s
board of directors adopted, and its shareholders subsequently approved, the 2015 Plan. The 2015 Plan provides for the grant of options,
restricted shares, restricted share units and other share-based awards to the Subsidiary’s (following the Merger, the Company’s)
and its subsidiaries’ and affiliates’ directors, employees, officers, consultants, advisors, and any other person whose services
are considered valuable to us or our affiliates. Any such grants are intended to incentivize the foregoing persons to continue as service
providers, to increase their efforts on our behalf or on behalf of our subsidiaries or affiliates, and to promote the success of our business.
The 2015 Plan is administered by
our board of directors or by a committee designated by the board of directors, which determines, subject to Israeli law, the grantees
of awards and the terms of the grant, including, exercise prices, vesting schedules, acceleration of vesting and the other matters necessary
in the administration of the 2015 Plan. The 2015 Plan enables us to issue awards under various tax regimes, including, without limitation,
pursuant to Section 102 of the Israeli Income Tax Ordinance, or the Ordinance, and under Section 3(i) of the Ordinance and Section 422
of the United States Internal Revenue Code of 1986, as amended, or the Code.
The 2015 Plan provides that options
granted to our employees, directors and officers who are not controlling shareholders and who are considered Israeli residents are intended
to qualify for special tax treatment under the “capital gain track” provisions of Section 102(b) of the Ordinance. Our Israeli
non-employee service providers and controlling shareholders may only be granted options under Section 3(i) of the Ordinance, which does
not provide for similar tax benefits.
Options granted under the 2015 Plan
to U.S. residents may qualify as “incentive stock options” within the meaning of Section 422 of the Code, or may be non-qualified.
The exercise price for “incentive stock options” must not be less than the fair market value on the date on which an option
is granted, or 110% of the fair market value if the option holder holds more than 10% of our share capital.
Options and other awards granted
under the 2015 Plan generally vest over four years commencing on the date of grant, such that 25% vests on the first anniversary of the
date of grant and an additional 6.25% vests at the end of each subsequent calendar quarter over the course of the next three years, provided
that the participant remains continuously employed or engaged by us.
Options, other than certain incentive
share options, that are not exercised within ten years from the grant date expire, unless otherwise determined by our board of directors
or our designated committee, as applicable. Share options that qualify as “incentive stock options” and are granted to a person
holding more than 10% of our voting power will expire within five years from the date of the grant. In the event of the death of a grantee
while employed by or performing service for us or our subsidiary or within three months after the date of the employee’s termination,
or the termination of a grantee’s employment or services for reasons of disability, the grantee, or in the case of death, his or
her legal successor, may exercise options or other awards that have vested prior to termination within a period of one year from the date
of disability or death. If we terminate a grantee’s employment or service for cause, all of the grantee’s vested and unvested
options or other awards will expire on the date of termination. If a grantee’s employment or service is terminated for any other
reason, the grantee may generally exercise his or her vested options or other award within three months of the date of termination. Any
expired or unvested options return to the pool and become available for reissuance. From time to time, we may consider issuing options
with slightly different terms or accelerating, extending or otherwise modifying options in accordance with applicable law and regulation
and the terms of the 2015 Plan.
In the event of a merger or consolidation,
or a sale of all, or substantially all, of our shares or assets or other transaction having a similar effect on us, then without the consent
of the option holder, our board of directors or our designated committee, as applicable, may, but is not required, to (i) cause any outstanding
award to be assumed or an equivalent award to be substituted by such successor corporation, or (ii) in case the successor corporation
does not assume or substitute the award (a) provide the grantee with the option to exercise the award as to all or part of the shares
or (b) cancel the options and pay in cash an amount determined by the board of directors or the committee as fair in the circumstances.
Notwithstanding the foregoing, our board of directors or our designated committee may upon such event amend, modify or terminate the terms
of any award, including conferring the right to purchase any other security or asset that the board of directors or the committee shall
deem, in good faith, appropriate.
The 2015 plan was assumed by our
company from the Subsidiary upon the effectiveness of the Merger.
2017 Plan
On February 22, 2017, our board of
directors adopted the 2017 Plan to allocate a variety of share-based awards to our directors, officers, employees, consultants, advisors
and service providers, and those of our affiliates (companies that control us, are controlled by us or are under common control with us)
(the “Participants”). The 2017 Plan is currently administered by our board of directors and may be administered by a committee
designated by our board of directors for such purpose.
Under the 2017 Plan, we may grant
options to purchase ordinary shares or ADSs, restricted shares or ADSs, restricted share units and other awards based on our ordinary
shares, all of which are referred to as Awards. We may grant Awards under the same four tracks as described above with respect to the
2011 Plan, subject to the same conditions as apply for the 2011 Plan. In addition, we may grant incentive stock options and nonqualified
stock options to Participants who are residents of the United States, and we may grant awards to Participants who are residents of other
countries that comply with the laws of those jurisdictions.
The number of ordinary shares authorized
to be issued under the 2017 Plan will be proportionately adjusted for any increase or decrease in the number of ordinary shares issued
as a result of a distribution of bonus shares, change in our capitalization (split, combination, reclassification of the shares or other
capital change), issuance of rights to purchase ordinary shares or payment of a dividend. We will not allocate fractions of ordinary shares
and the number of ordinary shares shall be rounded down to the closest number of ordinary shares.
Corporate Governance Practices
As an Israeli company, we are subject
to various corporate governance requirements under the Companies Law. However, pursuant to regulations promulgated under the Companies
Law, companies with securities traded on certain U.S. stock exchanges, including Nasdaq, may, subject to certain conditions, “opt
out” from the Companies Law requirements to appoint external directors and related Companies Law rules concerning the composition
of the audit committee and compensation committee of the board of directors (other than the gender diversification rule under the Companies
Law, which requires the appointment of a director from the other gender if at the time a director is appointed all members of the board
of directors are of the same gender). In accordance with these regulations, we elected to “opt out” from those requirements
of the Companies Law. Under these regulations, the exemptions from such Companies Law requirements will continue to be available to us
so long as: (i) we do not have a “controlling shareholder” (as such term is defined under the Companies Law), (ii) our ADSs
are traded on a U.S. stock exchange, Nasdaq, and (iii) we comply with the director independence requirements and the audit committee and
compensation committee composition requirements under U.S. laws (including applicable rules of Nasdaq) applicable to U.S. domestic issuers.
We are a “foreign private issuer”
(as such term is defined in Rule 3b-4 under the Exchange Act). As a foreign private issuer, we are permitted to comply with Israeli corporate
governance practices instead of the corporate governance rules of Nasdaq, provided that we disclose which requirements we are not following
and the equivalent Israeli requirement. We rely on this “foreign private issuer exemption” with respect to the following:
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(i) |
Quorum for Shareholder Meetings. Whereas under the corporate
governance rules of Nasdaq, a quorum requires the presence, in person or by proxy, of holders of at least 33 1/3% of the total issued
and outstanding voting power of our shares at each general meeting of shareholders, pursuant to the Articles, and as permitted under the
Companies Law, the quorum required for a general meeting of shareholders will consist of at least two shareholders present in person or
by proxy in accordance with the Companies Law who hold or represent at least 33 1/3% of the total outstanding voting power of our shares,
except if (i) any such general meeting of shareholders was initiated by and convened pursuant to a resolution adopted by the board of
directors and (ii) at the time of such general meeting, we qualify as a “foreign private issuer,” then in such case, the requisite
quorum will consist of two or more shareholders present in person or by proxy who hold or represent at least 25% of the total outstanding
voting power of our shares (and if the meeting is adjourned for a lack of quorum, the quorum for such adjourned meeting will be, subject
to certain exceptions, any number of shareholders). |
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(ii) |
Shareholder approval. We do not intend to follow Nasdaq
Stock Market rules which require shareholder approval in order to enter into any transaction, other than a public offering, involving
the sale, issuance or potential issuance by the Company of ordinary shares (or securities convertible into or exercisable for ordinary
shares) equal to 20% or more of the outstanding share capital of the Company or 20% or more of the voting power outstanding before the
issuance for less than the greater of book or market value of the ordinary shares. We will follow Israeli law with respect to any requirement
to obtain shareholder approval in connection with any private placements of equity securities. |
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(iii) |
Adoption or Amendment of Equity-Based Compensation Plans.
We have elected to follow Israeli corporate governance practice instead of the Nasdaq Listing Rule 5635(c), which requires listed issuers
to obtain shareholder approval for the establishment or material amendment of certain equity-based compensation plans and arrangements.
Under Israeli law and practice, in general, the approval of the board of directors is required for the establishment or amendment of equity-based
compensation plans and arrangements. |
Board of Directors
Under the Israeli Companies
Law, 5759-1999 (the “Companies Law”), our board of directors is responsible for setting our general policies and supervising
the performance of management. Our board of directors may exercise all powers and may take all actions that are not specifically granted
by the Companies Law or our articles of association to our shareholders or to management. Our executive officers are responsible for our
day-to-day management and have individual responsibilities established by our board of directors.
Under the Companies Law,
the chief executive officer of a public company, or a relative of the chief executive officer, may not serve as the chairperson of the
board of directors of such public company, and the chairperson of the board of directors of a public company, or a relative of the chairperson,
may not be vested with authorities of the chief executive officer of such public company without obtaining shareholder approval pursuant
to special majority requirements set forth in the Companies Law.
Our board of directors is
currently composed of six (6) members. Our board of directors consists of three classes of directors (as illustrated below), each serving
staggered three-year terms. Upon expiration of the term of a class of directors, directors in that class will be elected for a three-year
term at the Annual General Meeting of shareholders in the year in which that term expires. Each director’s term continues until
the election and qualification of his or her successor, or his or her earlier death, resignation or removal. Any increase or decrease
in the number of directors will be distributed among the three classes so that, as nearly as possible, each class will consist of one-third of
the directors. The division of our board of directors into three classes with staggered three-year terms may delay or prevent a change
of management or a change of control of our company.
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Class I consists of Nissim Darvish and Jill Quigley, each with a term expiring at the 2025 annual meeting
of shareholders. |
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Class II consists of Neil Cohen and Claude Nicaise, each with a term expiring at the 2026 annual meeting
of shareholders. |
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Class III consists of Adi Mor and Alan Moses, each with a term expiring at the 2027
annual meeting of shareholders. |
Our directors are appointed by a
simple majority vote of holders of our ordinary shares, participating and voting at an annual general meeting of our shareholders, provided
that (i) in the event of a contested election, the method of calculation of the votes and the manner in which the resolutions will be
presented to our shareholders at the general meeting will be determined by our board of directors in its discretion, and (ii) in the event
that our board of directors does not or is unable to make a determination on such matter, then the directors will be elected by a plurality
of the voting power represented at the general meeting in person or by proxy and voting on the election of directors.
Each director will hold office until
the annual general meeting of our shareholders for the year in which such director’s term expires, unless the tenure of such director
expires earlier pursuant to the Companies Law or unless such director is removed from office as described below.
Under our Articles of Association,
the approval of the holders of at least 65% of the total voting power of our shareholders is generally required to remove any of our directors
from office or any amendment to this provision shall require the approval of at least 65% of the total voting power of our shareholders
to remove any of our directors from office. In addition, vacancies on our board of directors may only be filled by a vote of a simple
majority of the directors then in office. A director so appointed will hold office until the next annual general meeting of our shareholders
for the election of the class of directors in respect of which the vacancy was created, or in the case of a vacancy due to the number
of directors being less than the minimum number of directors stated in our Articles of Association, the new director filling the vacancy
will serve until the next annual general meeting of our shareholders for the election of the class of directors to which such director
was assigned by our board of directors.
Chairperson of
the Board
Our Articles of Association provide
that the Chairperson of our board of directors is appointed by the members of our board of directors from among them. Under the Companies
Law, the chief executive officer of a public company, or a relative of the chief executive officer, may not serve as the chairperson of
the board of directors of such public company, and the chairperson of the board of directors of a public company, or a relative of the
chairperson, may not be vested with authorities of the chief executive officer of such public company without shareholder approval consisting
of a majority vote of the shares present and voting at a shareholders meeting, and in addition, either:
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at least a majority of the shares of non-controlling shareholders and shareholders
that do not have a personal interest in the approval voted at the meeting are voted in favor (disregarding abstentions); or |
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the total number of shares of non-controlling shareholders and shareholders who do
not have a personal interest in such appointment that re voted against such appointment does not exceed two percent (2%) of the aggregate
voting rights in the company. |
The shareholders’ approval
can be effective for a period of up to five years following an initial public offering, and subsequently, for additional periods of up
to three years.
In addition, a person who is subordinated,
directly or indirectly, to the chief executive officer may not serve as the chairperson of the board of directors; the chairperson of
the board of directors may not be vested with authorities that are granted to persons who are subordinated to the chief executive officer;
and the chairperson of the board of directors may not serve in any other position in the company or in a controlled subsidiary, but may
serve as a director or chairperson of a controlled subsidiary.
External Directors
Under the Companies Law, companies
incorporated under the laws of the State of Israel that are “public companies,” including companies with shares listed on
Nasdaq, are required to appoint at least two external directors. Pursuant to regulations promulgated under the Companies Law, companies
with shares traded on certain U.S. stock exchanges, including Nasdaq, which do not have a “controlling shareholder,” may,
subject to certain conditions, “opt out” from the Companies Law requirements to appoint external directors and related Companies
Law rules concerning the composition of the audit committee and compensation committee of the board of directors. In accordance with these
regulations, we have elected to “opt out” from the Companies Law requirement to appoint external directors and related Companies
Law rules concerning the composition of the audit committee and compensation committee of our board of directors.
Committees of our Board of Directors
Audit Committee
Under the Companies Law, the Exchange
Act and Nasdaq rules, we are required to establish an audit committee, and we have a separately-designated standing audit committee established
in accordance with section 3(a)(58)(A) of the Exchange Act.
The responsibilities of an audit
committee under the Companies Law include identifying and addressing flaws in the business management of the company, reviewing and approving
related party transactions, establishing whistleblower procedures, overseeing the company’s internal audit system and the performance
of its internal auditor, and assessing the scope of the work and recommending the fees of the company’s independent accounting firm.
In addition, the audit committee is required to determine whether certain related party actions and transactions are “material”
or “extraordinary” for the purpose of the requisite approval procedures under the Companies Law and to establish procedures
for considering proposed transactions with a controlling shareholder.
In accordance with U.S. law and Nasdaq
requirements, our audit committee is also responsible for the appointment, compensation and oversight of the work of our independent auditors
and for assisting our board of directors in monitoring our financial statements, the effectiveness of our internal controls and our compliance
with legal and regulatory requirements.
Under the Companies Law and related
regulations, the audit committee must consist of at least three directors who meet certain independence criteria. Under the Nasdaq rules,
we are required to maintain an audit committee consisting of at least three independent directors, all of whom are financially literate
and one of whom has accounting or related financial management expertise. Each of the members of the audit committee is required to be
“independent” as such term is defined in Rule 10A-3(b)(1) under the Exchange Act.
The members of the audit committee are Jill
Quigley, Alan Moses and Claude Nicaise. Claude Nicaise is the chairperson of the audit committee and is a financial expert under the rules
of the SEC. Our board of directors has concluded that each member of the audit committee is independent under the rules and regulations
of Nasdaq and the SEC.
Compensation
Committee
Under both the Companies Law and
Nasdaq rules, we are required to establish a compensation committee.
The responsibilities of a compensation
committee under the Companies Law include recommending to the board of directors, for ultimate shareholder approval by a special majority,
a policy governing the compensation of directors and officers based on specified criteria, reviewing modifications to and implementing
such compensation policy from time to time, and approving the actual compensation terms of directors and officers prior to approval by
the board of directors.
In accordance with U.S. law and Nasdaq
requirements, our compensation committee is also responsible for the appointment, compensation and oversight of the work of any compensation
consultant, independent legal counsel and other advisors retained by the compensation committee.
The Companies Law and related regulations
require the appointment of a compensation committee that complies with the requirements of Nasdaq. Under Nasdaq rules, we are required
to maintain a compensation committee consisting of at least two independent directors; each of the members of the compensation committee
is required to be independent under Nasdaq rules relating to compensation committee members, which are different from the general test
for independence of board and committee members. The members of the compensation committee are Nissim Darvish and Neil Cohen. Nissim Darvish
is the chairperson of the compensation committee. Our board of directors has determined that each member of the compensation committee
is independent within the meaning of the independent director guidelines of Nasdaq and under Rule 10C-1 under the Exchange Act.
Compensation Policy under the Companies
Law
In general, under the Companies Law,
a public company must have a compensation policy approved by the board of directors after receiving and considering the recommendations
of the compensation committee. In addition, our compensation policy must be approved at least once every three years, first, by our board
of directors, upon the recommendation of our compensation committee, and second, by a simple majority of the ordinary shares present,
in person or by proxy, and voting (excluding abstentions) at a general meeting of shareholders, provided that either:
• |
such majority includes at least a majority of the shares held by shareholders who
are not controlling shareholders and shareholders who do not have a personal interest in such compensation policy; or |
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• |
the total number of shares of non-controlling shareholders and shareholders who do
not have a personal interest in the compensation policy and who vote against the policy does not exceed two percent (2%) of the aggregate
voting rights in the Company. |
Under special circumstances, the
board of directors may approve the compensation policy despite the objection of the shareholders on the condition that the compensation
committee and then the board of directors decide, on the basis of detailed grounds and after discussing again the compensation policy,
that approval of the compensation policy, despite the objection of shareholders, is for the benefit of the company.
If a company that initially offers
its securities to the public, like us, adopts a compensation policy in advance of its initial public offering, and describes it in its
prospectus for such offering, then such compensation policy shall be deemed a validly adopted policy in accordance with the Companies
Law requirements described above. Furthermore, if the compensation policy is established in accordance with the aforementioned relief,
then it will remain in effect for a term of five years from the date such company becomes a public company.
The compensation policy must be based
on certain considerations, include certain provisions and reference certain matters as set forth in the Companies Law. The compensation
policy must serve as the basis for decisions concerning the financial terms of employment or engagement of office holders, including exculpation,
insurance, indemnification or any monetary payment or obligation of payment in respect of employment or engagement. The compensation policy
must be determined and later reevaluated according to certain factors, including: the advancement of the company’s objectives, business
plan and long-term strategy; the creation of appropriate incentives for office holders, while considering, among other things, the company’s
risk management policy; the size and the nature of the company’s operations; and with respect to variable compensation, the contribution
of the office holder towards the achievement of the company’s long-term goals and the maximization of its profits, all with a long-term
objective and according to the position of the office holder. The compensation policy must furthermore consider the following additional
factors:
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the education, skills, experience, expertise and accomplishments of the relevant office
holder; |
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• |
the office holder’s position and responsibilities; |
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• |
prior compensation agreements with the office holder; |
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•
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the ratio between the cost of the terms of employment of an office holder and the
cost of the employment of other employees of the company, including employees employed through contractors who provide services to the
company, in particular the ratio between such cost to the average and median salary of such employees of the company, as well as the impact
of disparities between them on the work relationships in the company; |
|
|
• |
if the terms of employment include variable components - the possibility of reducing
variable components at the discretion of the board of directors and the possibility of setting a limit on the value of non-cash variable
equity-based components; and |
|
|
•
|
if the terms of employment include severance compensation - the term of employment
or office of the office holder, the terms of the office holder’s compensation during such period, the company’s performance
during such period, the office holder’s individual contribution to the achievement of the company goals and the maximization of
its profits and the circumstances under which he or she is leaving the company. |
The compensation policy must also include, among other things:
• |
with regards to variable components: |
|
|
•
|
with the exception of office holders who report to the chief executive officer, a
means of determining the variable components on the basis of long-term performance and measurable criteria; provided that the company
may determine that an immaterial part of the variable components of the compensation package of an office holder shall be awarded based
on non-measurable criteria, or if such amount is not higher than three months’ salary per annum, taking into account such office
holder’s contribution to the company; |
|
|
• |
the ratio between variable and fixed components, as well as the limit of the values
of variable components at the time of their payment, or in the case of equity-based compensation, at the time of grant; |
|
|
•
|
a condition under which the office holder will return to the company, according to
conditions to be set forth in the compensation policy, any amounts paid as part of the office holder’s terms of employment, if such
amounts were paid based on information later to be discovered to be wrong, and such information was restated in the company’s financial
statements; |
|
|
• |
the minimum holding or vesting period of variable equity-based components to be set
in the terms of office or employment, as applicable, while taking into consideration long-term incentives; and |
|
|
• |
a limit to retirement grants. |
Our compensation policy is designed
to promote retention and motivation of directors and executive officers, incentivize superior individual excellence, align the interests
of our directors and executive officers with our long-term performance and provide a risk management tool. To that end, a portion of our
executive officer compensation package is targeted to reflect our short and long-term goals, as well as the executive officer’s
individual performance. On the other hand, our compensation policy includes measures designed to reduce the executive officer’s
incentives to take excessive risks that may harm us in the long-term, such as limits on the value of cash bonuses and equity-based compensation,
limitations on the ratio between the variable and the total compensation of an executive officer and minimum vesting periods and performance
based vesting for equity-based compensation.
Our compensation policy also addresses
our executive officers’ individual characteristics (such as their respective position, education, scope of responsibilities and
contribution to the attainment of our goals) as the basis for compensation variation among our executive officers and considers the internal
ratios between compensation of our executive officers and directors and other employees. Pursuant to our compensation policy, the compensation
that may be granted to an executive officer may include: base salary, annual bonuses and other cash bonuses (such as a signing bonus and
special bonuses with respect to any special achievements, such as outstanding personal achievement, outstanding personal effort or outstanding
company performance), equity-based compensation, benefits and retirement and termination of service arrangements. All cash bonuses are
limited to a maximum amount linked to the executive officer’s base salary.
An annual cash bonus may be awarded
to executive officers upon the attainment of pre-set periodic objectives and individual targets. The annual cash bonus that may be granted
to our executive officers other than our Chief Executive Officer will be based on performance objectives and a discretionary evaluation
of the executive officer’s overall performance by our Chief Executive Officer and subject to minimum thresholds. The annual cash
bonus that may be granted to executive officers other than our Chief Executive Officer may alternatively be based entirely on a discretionary
evaluation. Furthermore, our Chief Executive Officer will be entitled to approve performance objectives for executive officers who report
to her.
The measurable performance objectives
of our Chief Executive Officer will be determined annually by our compensation committee and board of directors. A non-material portion
of the Chief Executive Officer’s annual cash bonus, as provided in our compensation policy, may be based on a discretionary evaluation
of the Chief Executive Officer’s overall performance by the compensation committee and the board of directors.
The equity-based compensation under
our compensation policy for our executive officers (including members of our board of directors) is designed in a manner consistent with
the underlying objectives in determining the base salary and the annual cash bonus, with its main objectives being to enhance the alignment
between the executive officers’ interests with our long-term interests and those of our shareholders and to strengthen the retention
and the motivation of executive officers in the long term. Our compensation policy provides for executive officer compensation in the
form of share options or other equity-based awards, such as restricted shares and restricted share units, in accordance with our equity
incentive plan then in place. The equity-based compensation shall be granted from time to time and be individually determined and awarded
according to the performance, educational background, prior business experience, qualifications, role and the personal responsibilities
of the executive officer.
In addition, our compensation policy
contains compensation recovery provisions which allow us under certain conditions to recover bonuses paid in excess, enable our Chief
Executive Officer to approve an immaterial change in the terms of employment of an executive officer who reports directly to her (provided
that the changes of the terms of employment are in accordance with our compensation policy) and allow us to exculpate, indemnify and insure
our executive officers and directors to the maximum extent permitted by Israeli law subject to certain limitations set forth therein.
Our compensation policy also provides
for compensation to the members of our board of directors either (i) in accordance with the amounts provided in the Companies Regulations
(Rules Regarding the Compensation and Expenses of an External Director) of 2000, as amended by the Companies Regulations (Relief for Public
Companies Traded in Stock Exchange Outside of Israel) of 2000, as such regulations may be amended from time to time, or (ii) in accordance
with the amounts determined in our compensation policy.
Our compensation policy was approved
by our board of directors and shareholders and became effective on July 19, 2021.
Corporate Governance and Nominating
Committee
We have established a Corporate Governance
and Nominating Committee, responsible for making recommendations to the board of directors regarding candidates for directorships and
the size and composition of the board. In addition, the committee is responsible for overseeing our corporate governance guidelines and
reporting and making recommendations to the board concerning corporate governance matters. Under the Companies Law, nominations for director
may also, under certain circumstances, be made by shareholders in accordance with the conditions prescribed by applicable law and our
articles of association. The members of the Corporate Governance and Nominating Committee are Neil Cohen and Nissim Darvish. Neil Cohen
is the chairperson of the Corporate Governance and Nominating Committee. Our board of directors has determined that each member of the
Corporate Governance and Nominating Committee is independent within the meaning of the independent director guidelines of Nasdaq.
Internal Auditor
Under the Companies Law, the board
of directors is required to appoint an internal auditor recommended by the audit committee. The role of the internal auditor is to examine,
among other things, whether the company’s actions comply with applicable law and proper business procedures. The internal auditor
may not be an interested party, a director or an officer of the company, or a relative of any of the foregoing, nor may the internal auditor
be our independent accountant or a representative thereof. Yisrael Gewirtz of Grant Thornton Israel currently serves as our internal auditor.
Approval of Related Party Transactions
under Israeli Law
Fiduciary duties
of directors and Executive Officers
An office holder’s fiduciary
duties consist of a duty of care and a duty of loyalty. The duty of care requires an office holder to act with the level of care with
which a reasonable office holder in the same position would have acted under the same circumstances. The duty of care includes, among
other things, a duty to use reasonable means, in light of the circumstances, to obtain:
• |
information on the business advisability of a given action brought for his, her or
its approval or performed by virtue of his, her or its position; and |
|
|
• |
all other important information pertaining to such action. |
The duty of loyalty requires that
an office holder act in good faith and in the best interests of the company, and includes, among other things, the duty to:
• |
refrain from any act involving a conflict of interest between the performance of his,
her or its duties in the company and his, her or its other duties or personal affairs; |
|
|
• |
refrain from any activity that is competitive with the business of the company;
|
|
|
• |
refrain from exploiting any business opportunity of the company for the purpose of
gaining a personal advantage for himself, herself or itself or others; and |
|
|
• |
disclose to the company any information or documents relating to the company’s
affairs which the office holder received as a result of his, her or its position as an office holder. |
Under the Companies Law, a company
may approve an act specified above which would otherwise constitute a breach of the office holder’s duty of loyalty, provided that
the office holder acted in good faith, neither the act nor its approval harms the company, and the office holder discloses his, her or
its personal interest a sufficient time before the approval of such act. Any such approval is subject to the terms of the Companies Law
setting forth, among other things, the appropriate bodies of the company required to provide such approval and the methods of obtaining
such approval.
Disclosure of
Personal Interests of an Office Holder and Approval of Certain Transactions
The Companies Law requires that an
office holder promptly disclose to the board of directors any personal interest that such office holder may have and all related material
information known to such office holder concerning any existing or proposed transaction with the company. A personal interest includes
an interest of any person in an act or transaction of a company, including a personal interest of one’s relative or of a corporate
body in which such person or a relative of such person is a 5% or greater shareholder, director or general manager or in which such person
has the right to appoint at least one director or the general manager, but excluding a personal interest stemming solely from one’s
ownership of shares in the company. A personal interest includes the personal interest of a person for whom the office holder holds a
voting proxy or the personal interest of the office holder with respect to the officer holder’s vote on behalf of a person for whom
he or she holds a proxy even if such shareholder has no personal interest in the matter.
If it is determined that an office
holder has a personal interest in a non-extraordinary transaction, meaning any transaction that is in the ordinary course of business,
on market terms or that is not likely to have a material impact on the company’s profitability, assets or liabilities, approval
by the board of directors is required for the transaction unless the company’s articles of association provide for a different method
of approval. Any such transaction that is adverse to the company’s interests may not be approved by the board of directors.
Approval first by the company’s
audit committee and subsequently by the board of directors is required for an extraordinary transaction (meaning any transaction that
is not in the ordinary course of business, not on market terms or that is likely to have a material impact on the company’s profitability,
assets or liabilities) in which an office holder has a personal interest.
A director and any other office holder
who has a personal interest in a transaction which is considered at a meeting of the board of directors or the audit committee may generally
(unless it is with respect to a transaction which is not an extraordinary transaction) not be present at such a meeting or vote on that
matter unless a majority of the directors or members of the audit committee, as applicable, have a personal interest in the matter. If
a majority of the members of the audit committee or the board of directors have a personal interest in the matter, then all of the directors
may participate in deliberations of the audit committee or board of directors, as applicable, with respect to such transaction and vote
on the approval thereof and, in such case, shareholder approval is also required.
Certain disclosure and approval requirements
apply under Israeli law to certain transactions with controlling shareholders, certain transactions in which a controlling shareholder
has a personal interest and certain arrangements regarding the terms of service or employment of a controlling shareholder. For these
purposes, a controlling shareholder is any shareholder that has the ability to direct the company’s actions, including any shareholder
holding 25% or more of the voting rights if no other shareholder owns more than 50% of the voting rights in the company. Two or more shareholders
with a personal interest in the approval of the same transaction are deemed to be one shareholder.
For a description of the approvals
required under Israeli law for compensation arrangements of officers and directors, see “-Compensation of Directors and Executive
Officers.”
Shareholder Duties
Pursuant to the Companies Law, a
shareholder has a duty to act in good faith and in a customary manner toward the company and other shareholders and to refrain from abusing
his or her power with respect to the company, including, among other things, in voting at a general meeting and at shareholder class meetings
with respect to the following matters:
• |
an amendment to the company’s articles of association; |
|
|
• |
an increase of the company’s authorized share capital; |
|
|
• |
a merger; or |
|
|
• |
interested party transactions that require shareholder approval. |
In addition, a shareholder has a
general duty to refrain from discriminating against other shareholders.
Certain shareholders also have a
duty of fairness toward the company. These shareholders include any controlling shareholder, any shareholder who knows that it has the
power to determine the outcome of a shareholder vote and any shareholder who has the power to appoint or to prevent the appointment of
an office holder of the company or exercise any other rights available to it under the company’s articles of association with respect
to the company. The Companies Law does not define the substance of this duty of fairness, except to state that the remedies generally
available upon a breach of contract will also apply in the event of a breach of the duty of fairness.
Exculpation,
Insurance and Indemnification of Office Holders
Under the Companies Law, a company
may not exculpate an office holder from liability for a breach of the duty of loyalty. An Israeli company may exculpate an office holder
in advance from liability to the company, in whole or in part, for damages caused to the company as a result of a breach of duty of care
but only if a provision authorizing such exculpation is included in its articles of association. Our Articles of Association include such
a provision. An Israeli company may not exculpate a director from liability arising out of a prohibited dividend or distribution to shareholders.
An Israeli company may indemnify
an office holder in respect of the following liabilities and expenses incurred for acts performed as an office holder, either in advance
of an event or following an event, provided a provision authorizing such indemnification is contained in its articles of association:
•
|
a financial liability imposed on him or her in favor of another person pursuant to
a judgment, including a settlement or arbitrator’s award approved by a court. However, if an undertaking to indemnify an office
holder with respect to such liability is provided in advance, then such an undertaking must be limited to events which, in the opinion
of the board of directors, can be foreseen based on the company’s activities when the undertaking to indemnify is given, and to
an amount or according to criteria determined by the board of directors as reasonable under the circumstances, and such undertaking shall
detail the above mentioned events and amount or criteria; |
|
|
•
|
reasonable litigation expenses, including legal fees, incurred by the office holder
(1) as a result of an investigation or proceeding instituted against him or her by an authority authorized to conduct such investigation
or proceeding, provided that (i) no indictment was filed against such office holder as a result
of such investigation or proceeding; and (ii) no financial liability, such as a criminal penalty, was imposed upon him or her as a substitute
for the criminal proceeding as a result of such investigation or proceeding or, if such financial liability was imposed, it was imposed
with respect to an offense that does not require proof of criminal intent; and (2) in connection with a monetary sanction; |
•
|
reasonable litigation expenses, including legal fees, incurred by the office holder
or imposed by a court in proceedings instituted against him or her by the company, on its behalf or by a third-party or in connection
with criminal proceedings in which the office holder was acquitted or as a result of a conviction for an offense that does not require
proof of criminal intent; and |
|
|
•
|
expenses, including reasonable litigation expenses and legal fees, incurred by an
office holder in relation to an administrative proceeding instituted against such office holder, or certain compensation payments made
to an injured party imposed on an office holder by an administrative proceeding, pursuant to certain provisions of the Israeli Securities
Law. |
An Israeli company may insure an
office holder against the following liabilities incurred for acts performed as an office holder if and to the extent provided in the company’s
articles of association:
• |
a breach of the duty of loyalty to the company, to the extent that the office holder
acted in good faith and had a reasonable basis to believe that the act would not prejudice the company; |
|
|
• |
a breach of the duty of care to the company or to a third-party, including a breach
arising out of the negligent conduct of the office holder; |
|
|
• |
a financial liability imposed on the office holder in favor of a third-party;
|
|
|
• |
a financial liability imposed on the office holder in favor of a third-party harmed
by a breach in an administrative proceeding; and |
|
|
• |
expenses, including reasonable litigation expenses and legal fees, incurred by the
office holder as a result of an administrative proceeding instituted against him or her, pursuant to certain provisions of the Israeli
Securities Law. |
An Israeli company may not indemnify
or insure an office holder against any of the following:
• |
a breach of the duty of loyalty, except to the extent that the office holder acted
in good faith and had a reasonable basis to believe that the act would not prejudice the company; |
|
|
• |
a breach of the duty of care committed intentionally or recklessly, excluding a breach
arising out of the negligent conduct of the office holder; |
|
|
• |
an act or omission committed with intent to derive illegal personal benefit; or
|
|
|
• |
a fine, monetary sanction or forfeit levied against the office holder. |
Under the Companies Law, exculpation,
indemnification and insurance of office holders must be approved by the compensation committee and the board of directors (and, with respect
to directors and the chief executive officer, by the shareholders). However, under regulations promulgated under the Companies Law, the
insurance of office holders does not require shareholder approval and may be approved by only the compensation committee if the engagement
terms are determined in accordance with the company’s compensation policy, which was approved by the shareholders by the same special
majority required to approve a compensation policy, provided that the insurance policy is on market terms and the insurance policy is
not likely to materially impact the company’s profitability, assets or obligations.
Our Articles of Association allow
us to exculpate, indemnify and insure our office holders for any liability imposed on them as a consequence of an act (including any omission)
which was performed by virtue of being an office holder. Our office holders are currently covered by a directors and officers’ liability
insurance policy.
We have entered into indemnification
agreements with each of our directors and executive officers exculpating them in advance, to the fullest extent permitted by law, from
liability to us for damages caused to us as a result of a breach of duty of care, and undertaking to indemnify them to the fullest extent
permitted by law. This indemnification is limited to events determined as foreseeable by the board of directors based on our activities,
and to an amount or according to criteria determined by the board of directors as reasonable under the circumstances.
In the opinion of the SEC, indemnification
of directors and office holders for liabilities arising under the Securities Act, however, is against public policy and therefore unenforceable.
As of December 31, 2024, we had 16 employees/consultants,
including 6 with Ph.D. or M.D. degrees and including 10 who are engaged in research and development activities. We are dependent on our
management and scientific personnel, and it is crucial that we continue to attract and retain valuable employees. To facilitate attraction
and retention, we strive to make ourselves an inclusive and safe workplace, with opportunities for our employees to grow and develop in
their careers, supported by strong compensation and benefits programs. None of our employees are represented by labor unions or covered
by collective bargaining agreements.
For information regarding the share
ownership of directors and officers, see Item 7.A. “Major Shareholders and Related Party Transactions-Major Shareholders.”
For information as to our equity incentive plans, see Item 6.B. “Director, Senior Management and Employees-Compensation- Equity
incentive plans.”
F. |
Disclosure of a Registrant’s Action to Recover Erroneously
Awarded Compensation
|
Item 7.
Major Shareholders and Related Party Transactions
The beneficial ownership of ordinary
shares is determined in accordance with the SEC rules and generally includes any ordinary shares over which a person exercises sole or
shared voting or investment power. For purposes of the table below, we deem shares subject to options or warrants that are currently exercisable
or exercisable within 60 days of December 31, 2024, to be outstanding and to be beneficially owned by the person holding the options or
warrants for the purposes of computing the percentage ownership of that person but we do not treat them as outstanding for the purpose
of computing the percentage ownership of any other person. The percentage of shares beneficially owned is based on 377,132,220 ordinary
shares outstanding as of December 31, 2024.
All of our shareholders, including
the shareholders listed below, have the same voting rights attached to their ordinary shares.
A description of any material relationship
that our principal shareholders have had with us or any of our affiliates within the past three years is included under “Certain
relationships and related party transactions.”
NAME OF BENEFICIAL OWNER |
|
Total
Beneficial
Ownership (ADSs) |
|
|
Percentage of
ADSs Beneficially
Owned |
|
5% and Greater Shareholders |
|
|
|
|
|
|
OrbiMed Israel (1) |
|
|
1,860,906 |
|
|
|
9.99 |
% |
Sphera Funds Management Ltd. (2) |
|
|
1,214,575 |
|
|
|
6.4 |
%
|
Apeiron Group (3) |
|
|
1,175,246 |
|
|
|
6.2 |
% |
Erik Otto (4) |
|
|
1,155,000 |
|
|
|
6.1 |
%
|
Rivendell Investments 2017-9 (5) |
|
|
1,131,563 |
|
|
|
6.0 |
% |
Directors and Executive Officers |
|
|
|
|
|
|
|
|
Adi Mor (6) |
|
|
874,739 |
|
|
|
4.6 |
% |
Sigal Fattal (7) |
|
|
93,264 |
|
|
|
* |
|
Matthew Frankel (8) |
|
|
96,392 |
|
|
|
* |
|
Neil Cohen (9) |
|
|
167,467 |
|
|
|
* |
|
Nissim Darvish (10) |
|
|
48,312 |
|
|
|
* |
|
Alan Moses (11) |
|
|
25,561 |
|
|
|
* |
|
Claude Nicaise (12) |
|
|
25,561 |
|
|
|
* |
|
Jill Quigley (13) |
|
|
18,981 |
|
|
|
* |
|
All current executive officers and directors as a group (8 persons) |
|
|
1,350,277 |
|
|
|
6.9 |
% |
* Less than one percent (1%)
(1)
|
Pursuant to a Schedule 13D/A filed with the SEC by OrbiMed Israel BioFund GP Limited
Partnership (“OrbiMed BioFund”) and OrbiMed Israel GP Ltd. (“OrbiMed GP”, and together with OrbiMed BioFund, “OrbiMed
Israel”) on September 16, 2024, such amount consists of (i) 1,741,274 ADSs, (ii) 28,817 ADSs issuable upon the exercise of warrants
to purchase ADSs and (iii) 90,816 ADSs issuable upon the exercise of pre-funded warrants to purchase ADSs. The foregoing pre-funded warrants
are subject to an exercise limitation that prohibits the holder from exercising the pre-funded warrants to the extent that after giving
effect to the issuance of ADSs after such exercise, the holder (together with the holder’s affiliates) would beneficially own in
excess of 9.99% of the ADSs outstanding. OrbiMed GP, a company that acts as general partner of certain limited partnerships, is the general
partner of OrbiMed BioFund, which is the general partner of OrbiMed Israel Partners Limited Partnership, which is the entity that holds
the foregoing securities. The address of OrbiMed Israel is 5 Hahoshlim St., Herzliya Pituach, Israel. Telephone: +972 73 2822600.
|
|
|
(2) |
Pursuant to a Schedule 13G filed with the
SEC on August 20, 2024 by Sphera Funds Management Ltd., Sphera Global Healthcare GP Ltd. and Sphera Global Healthcare Management LP, the
foregoing beneficially own 1,214,575 ADSs, which are held directly by Sphera Biotech Master Fund, which has delegated its investment management
authority to Sphera Global Healthcare Management LP. Sphera Global Healthcare Management LP is managed, controlled, and operated
by its general partner, Sphera Global Healthcare GP Ltd., the shares of which are owned 90% by Sphera Funds Management Ltd. |
|
|
(3)
|
The Apeiron Group consists of (i) Apeiron SICAV Ltd. - Presight Capital Fund One,
of which owns 438,993 ADSs, (ii) Apeiron Presight Capital Fund II, LP, of which owns 693,028 ADSs and 28,817 ADSs issuable upon the exercise
of warrants and (iii) Apeiron Investment Group Ltd., of which owns 14,408 ADSs issuable upon the exercise of warrants. Each of Fabian
Hansen and Christian Angermayer may be deemed to share voting and investment power with respect to the ADSs held by the Apeiron Group.
|
|
|
(4) |
Pursuant to a Schedule 13G filed with the SEC by Erik Otto on November 30, 2024, Mr.
Otto is the beneficial owner of 1,155,000 ADSs. |
(5)
|
Represents 1,108,509 ADSs held by Rivendell
Investments 2017-9 LLC, or Rivendell, as reported by Rivendell on Schedule 13G filed with the SEC on March 26, 2021, and 23,054 ADSs,
issuable upon the exercise of warrants. Rivendell is the shareholder of record. Peter Thiel is the beneficial owner of Rivendell and has
sole voting and investment power over the securities held by Rivendell. The address of Rivendell is 1209 Orange Street, Wilmington, Delaware
19801. |
|
|
(6) |
Consists of (i) 317,075 ADSs owned directly by Dr. Mor, (ii) 200,236 ADSs owned by
Dr. George, (Dr. Mor’s spouse), (iii) 323,703 ADSs issued to Dr. Mor, issuable upon the exercise of options within 60 days of the
date hereof, and (iv) 33,725 options to purchase 33,725 ADSs issued to Dr. George, (Dr. Mor’s spouse) issuable upon the exercise
thereof within 60 days of the date hereof. |
|
|
(7) |
Includes 2,555ADSs, and 90,709 ADSs issuable upon the exercise of options within 60
days of the date hereof. |
|
|
(8) |
Represents 96,392ADSs issuable upon the exercise of options within 60 days of the
date hereof. |
|
|
(9) |
Includes 141,218 ADSs, and 26,249 ADSs issuable upon the exercise of options within
60 days of the date hereof. |
|
|
(10) |
Includes 1,200 ADSs, and 47,112 ADSs issuable
upon the exercise of options within 60 days of the date hereof. |
|
|
(11) |
Represents 25,561 ADSs issuable upon the exercise of options within 60 days of the
date hereof. |
|
|
(12) |
Represents 25,561 ADSs issuable upon the exercise of options within 60 days of the
date hereof. |
|
|
(13) |
Represents 18,981 ADSs issuable upon the exercise of options within 60 days of the
date hereof. |
Significant Changes in Ownership
To our knowledge, other than as disclosed
in the table above, our other filings with the SEC and this Annual Report, there has been no significant change in the percentage ownership
held by any major shareholder during the past three years.
Voting Rights
Neither our major shareholders nor
our directors and executive officers will have different or special voting rights with respect to their ordinary shares.
Registered Holders
As of the date of this Annual Report,
there are seven shareholders of record of our ordinary shares, of whom five are in the United States. The number of record holders is
not representative of the number of beneficial holders of our ordinary shares, as most of the shares we have issued, including those represented
by ADSs are currently recorded in the name of our ADS registrar, The Bank of New York Mellon.
Change in Control Arrangements
We are not aware of any arrangement
that may at a subsequent date, result in a change of control of the Company.
B. |
Related Party Transactions |
Other Transactions
Agreements with Directors and Officers
Employment
and Consulting Agreements. We have entered into written employment agreements with each of our executive officers. See Item 6.
“Management-Employment and Consulting Agreements with Executive Officers.”
Awards.
Since our inception, we have granted options to purchase our ordinary shares to our executive officers and certain of our directors. Such
option agreements may contain acceleration provisions upon certain merger, acquisition or change of control transactions and other circumstances.
We describe our option plans under “Equity Incentive Plans.”
Exculpation,
Indemnification and Insurance. Our Articles of Association permit us to exculpate, indemnify and insure certain of our office holders
to the fullest extent permitted by the Companies Law. We have entered into agreements with certain office holders, exculpating them from
a breach of their duty of care to us to the fullest extent permitted by law and undertaking to indemnify them to the fullest extent permitted
by law, subject to certain exceptions, including with respect to liabilities resulting from the IPO to the extent that such liabilities
are not covered by insurance. See Item 6. “Directors, Senior Management and Employees-Exculpation, Insurance and Indemnification
of Directors and Officers.”
The
Repurchase Agreement. As previously reported in our Registration Statement on Form S-4 (File No. 333-252070), filed with SEC
on January 13, 2021 and declared effective by the SEC on February 10, 2021, Chemomab Ltd. filed an application with the Israel Tax Authority
for a tax ruling (the “Tax Ruling”) in connection with the Merger, pursuant to which certain of Chemomab Ltd.’s shareholders
were entitled to defer an immediate Israeli tax liability resulting from the exchange of shares that otherwise would have been deemed
a sale. The deferral of the aforementioned tax liability is set to lapse on March 16, 2023, which is the two-year anniversary of the closing
date of the Merger. Dr. Adi Mor, co-founder of Chemomab Ltd. and both our Chief Scientific Officer and a Class III director, and Professor
Kobi George, co-founder of Chemomab Ltd. (together with Dr. Adi Mor, the “Co-Founders”), will be required to pay a substantial
tax liability to the Israeli Tax Authority upon the expiration date of the deferral period. In order to pay this tax liability, the Co-Founders
had to sell part of their holdings in the Company. In light of the foregoing, we elected to enter into a share purchase agreement
(the “Repurchase Arrangement”) with the Co-Founders whereby we agreed, subject to the requisite court approval required under
Section 303(a) of the Companies Law, which we received on November 14, 2022, to repurchase up to 582,023 of our ADSs owned by the Co-Founders,
for consideration not to exceed an aggregate amount of $2,500,000, depending on the market price of the ADSs at the time of any repurchase.
Accordingly, on November 16, 2022, we repurchased the entire amount of 582,023 ADSs from the Co-Founders at a price of $2.0848 and for
total consideration of approximately $1,218,000.
Related Party Transaction Policy
Our board of directors has adopted
a written related party transaction policy that sets forth the policies and procedures for the review and approval or ratification of
related person transactions. This policy covers interested party transactions under the Companies Law, interested party transactions as
defined in Part I, Item 7.B of Form 20-F and transactions between the Company and an interested party, which are material to the Company
or the interested party, and any such transactions between the Company and an interested party that are unusual in their nature or conditions,
involving goods, services, or tangible or intangible assets.
C. |
Interests of Experts and Counsel
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Item 8. Financial
Information
A. |
Consolidated Statements and Other Financial Information |
Consolidated
Financial Statements
See Item 18. “Financial Statements.”
Legal and Arbitration
Proceedings
From time to time, we may be involved
in various claims and legal proceedings arising from the normal course of our business activities and operations. Other than as noted
below, we are not presently a party to any litigation the outcome of which, we believe, if determined adversely to us, would individually
or taken together have a material adverse effect on our business, operating results, cash flows or financial condition. Defending such
proceedings is costly and can impose a significant burden on management and employees. The outcomes of any such claims or proceedings,
regardless of the merits, is inherently uncertain and can have an adverse impact on us because of defense and settlement costs, diversion
of management resources and other factors.
Dividend Policy
We do not anticipate paying any dividends
in the foreseeable future. We currently intend to retain future earnings, if any, to finance operations and expand our business. Our board
of directors has sole discretion whether to pay dividends. If our board of directors decides to pay dividends, the form, frequency and
amount will depend upon our future operations and earnings, capital requirements and surplus, general financial condition, contractual
restrictions, restrictions under our Credit Facility and other factors that our directors may deem relevant. The Companies Law imposes
restrictions on our ability to declare and pay dividends.
Payment of dividends may be subject
to Israeli withholding taxes. See Item 10.E. “Taxation-Israeli Tax Considerations” for additional information.
Item 9.
The Offer and Listing
A. |
Offer and Listing Details
Our ADSs are listed on Nasdaq under the symbol “CMMB”. |
C. |
Markets
Our ADSs are listed on Nasdaq under the symbol “CMMB”. |
Item 10.
Additional Information
B. |
Memorandum and Articles of Association |
A copy of our Articles of Association is attached as Exhibit 1.1
to this Annual Report. Other than as set forth below, the information called for by this Item is set forth in Exhibit 2.1 to this Annual
Report and is incorporated by reference into this Annual Report.
Except as disclosed below or otherwise
disclosed in this Annual Report (including the Exhibits), we are not currently, nor have we been for the two years immediately preceding
the date of this Annual Report, party to any material contract, other than contracts entered into in the ordinary course of business.
•
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Form of Deposit Agreement between Chemomab Therapeutics Ltd. (f/k/a Anchiano Therapeutics
Ltd.), the Bank of New York Mellon as Depositary, and owners and holders from time to time of ADSs issued by the Company, dated February
14, 2019 (incorporated by reference to Exhibit 4.1 to the Registrants registration statement on Form S-1 filed with the SEC on January
13, 2023).
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Form of Indemnification Agreement (incorporated by reference
to Exhibit 10.7 of the Company’s Amendment No. 1 to its Registration Statement on Form S-4 filed with the Securities and Exchange
Commission on February 10, 2021). See Item 6, "Directors, Senior Management and Employees" for more information about this document.
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Compensation Policy for Officers and Directors (incorporated
by reference to Exhibit 10.2 of the Company’s Annual Report on Form 10-K for the fiscal year ended December 31, 2021, filed with
the SEC on March 30, 2022). See Item 6, "Directors, Senior Management and Employees" for more information about this document.
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2011 Incentive Plan for Employees, Officers and Consultants
(previously filed as Exhibit 10.6 of our Registration Statement on Form F-1 (File No. 333-229155) as filed with the SEC on January 7,
2019 and incorporated by reference herein). See Item 6, "Directors, Senior Management and Employees" for more information about this document.
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2017 Equity-Based Incentive Plan (previously filed as
Exhibit 10.8 of our Registration Statement on Form F-1 (File No. 333-229155) as filed with the SEC on January 7, 2019 and incorporated
by reference herein). See Item 6, "Directors, Senior Management and Employees" for more information about this document.
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Chemomab Ltd. 2015 Share Incentive Plan (incorporated
by reference to Exhibit 10.4 to the Registrant’s registration statement on Form S-4 (SEC file number 333- 252070), filed with the
SEC on January 13, 2021) See Item 6, "Directors, Senior Management and Employees" for more information about this document.
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Tel-Aviv Souraski Medical Center (TASMC) License Agreement
between Chemomab Ltd. and the Medical Research, Infrastructure, Health Services Fund of the Tel Aviv Souraski Medical Center., dated December
1, 2011, as amended on May 9, 2013 (incorporated by reference to Exhibit 10.8 of the Company’s Amendment No. 1 to its Registration
Statement on Form S-4 filed with the Securities and Exchange Commission on February 10, 2021).
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CMC Collaboration Agreement between Chemomab Ltd. and
CMC ICOS Biologics, Inc., dated June 7, 2015 (incorporated by reference to Exhibit 10.9 of the Company’s Amendment No. 1 to its
Registration Statement on Form S-4 filed with the Securities and Exchange Commission on February 10, 2021).
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Securities Purchase Agreement by and between Chemomab Ltd. and the Purchasers listed
therein, dated July 25, 2024 (as filed with the SEC on July 25, 2024 as Exhibit 99.1 to our Report of Foreign Private Issuer on Form 6-K
and incorporated by reference herein). |
There are currently no Israeli currency
control restrictions on remittances of dividends on our ordinary shares, proceeds from the sale of the ordinary shares or interest or
other payments to non-residents of Israel, except for shareholders who are subjects of countries that are, have been, or will be, in a
state of war with Israel.
Israeli Tax Considerations
General corporate tax structure
in Israel
Israeli companies are generally subject
to corporate tax. The standard corporate tax rate in 2024 was 23%. However, the effective tax rate payable by a company that derives income
from a “Preferred Enterprise”, a “Special Preferred Enterprise”, a “Preferred Technological Enterprise”,
or a “Special Preferred Technological Enterprise” (as discussed below) may be considerably less. Capital gains derived by
an Israeli company are generally subject to the prevailing corporate tax rate.
Law for the Encouragement of Capital
Investments, 5719-1959
The Law for the Encouragement of
Capital Investments, 5719-1959, generally referred to as the Investment Law, provides certain incentives for capital investments in production
facilities (or other eligible assets).
The Investment Law was significantly
amended effective as of April 1, 2005 (the “2005 Amendment”), as of January 1, 2011 (the “2011 Amendment”) and
as of January 1, 2017 (the “2017 Amendment”). Pursuant to the 2005 Amendment, tax benefits granted in accordance with the
provisions of the Investment Law prior to its revision by the 2005 Amendment remain in force but any benefits granted subsequently are
subject to the provisions of the amended Investment Law. Similarly, the 2011 Amendment introduced new benefits to replace those granted
in accordance with the provisions of the Investment Law in effect prior to the 2011 Amendment. However, companies entitled to benefits
under the Investment Law as in effect prior to January 1, 2011, were entitled to choose to continue to enjoy such benefits, provided that
certain conditions are met, or elect instead, irrevocably, to forego such benefits and have the benefits of the 2011 Amendment apply.
The 2017 Amendment introduced new benefits for Preferred Technological Enterprises, alongside the existing tax benefits.
Tax benefits under the 2011 Amendment
The 2011 Amendment introduced new
benefits for income generated by a “Preferred Company” through its “Preferred Enterprise” (as such terms are defined
in the Investment Law) as of January 1, 2011. The definition of a Preferred Company includes a company incorporated in Israel that is
not fully owned by a governmental entity, and that has, among other things, Preferred Enterprise status and is controlled and managed
from Israel.
Pursuant to the 2011 Amendment, a
Preferred Company was entitled to a reduced corporate tax rate of 15% with respect to its income derived from its Preferred Enterprise
in 2011 and 2012, unless the Preferred Enterprise is located in a certain development zone, in which case the rate was 10%. Under the
2011 Amendment, together with amendments to the Investment Law from 2014 and 2017, such corporate tax rate was reduced from 15% and 10%,
respectively, to 12.5% and 7%, respectively, in 2013, 16% and 9% respectively, in 2014, 2015 and 2016, and 16% and 7.5%, respectively,
in 2017 and thereafter. Income derived by a Preferred Company from a “Special Preferred Enterprise” (as such term is defined
in the Investment Law) would be entitled, during a benefits period of 10 years, to further reduced tax rates of 8%, or 5% if the Special
Preferred Enterprise is located in a certain development zone. Since January 1, 2017, the definition for “Special Preferred Enterprise”
includes less stringent conditions.
Dividends distributed from preferred
income which is attributed to a “Preferred Enterprise” or to a “Special Preferred Enterprise” should generally
be subject to withholding tax at source at the following rates: (i) Israeli resident corporations - 0%, (although, if such dividends are
subsequently distributed to individuals or a non-Israeli company the below rates detailed in sub sections (ii) and (iii) shall apply),
(ii) Israeli resident individuals - 20% and (iii) non-Israeli residents (individuals and corporations)- subject to the receipt in advance
of a valid certificate from the Israel Tax Authority (“ITA”) allowing for a reduced tax rate, 20% or such lower rate as may
be provided under the provisions of any applicable double tax treaty.
The 2011 Amendment also provided
transitional provisions to address companies already enjoying existing tax benefits under the Investment Law. These transitional provisions
provide, among other things, that unless an irrevocable request is made to apply the provisions of the Investment Law as amended in 2011
with respect to income to be derived as of January 1, 2011, a “Benefited Enterprise” (as such term is defined under the Investment
Law) can elect to continue to benefit from the benefits provided to it before the 2011 Amendment came into effect, provided that certain
conditions are met.
We currently do not intend to implement
the 2011 Amendment.
Tax benefits under the 2017 Amendment
The 2017 Amendment was enacted as
part of the Economic Efficiency Law that was published on December 29, 2016, and is effective as of January 1, 2017. The 2017 Amendment
provided new tax benefits for two types of “Preferred Technological Enterprises,” as described below, and is in addition to
the other existing tax beneficial programs under the Investment Law.
The 2017 Amendment provides that
a technology company satisfying certain conditions should qualify as a Preferred Technological Enterprise (“PTE”) and thereby
enjoy a reduced corporate tax rate of 12% on income that qualifies as “Preferred Technological Income,” as defined in the
Investment Law. The tax rate is further reduced to 7.5% for a PTE located in development zone “A”. In addition, a PTE will
enjoy a reduced corporate tax rate of 12% on capital gain derived from the sale of certain “Benefited Intangible Assets” (as
defined in the Investment Law) to a related foreign company if the Benefited Intangible Assets were acquired from a foreign company on
or after January 1, 2017 for at least NIS 200 million, and the sale received prior approval from the National Authority for Technological
Innovation (previously known as the Israeli Office of the Chief Scientist), to which we refer as IIA.
The 2017 Amendment further provides
that a technology company satisfying certain conditions (group turnover of at least NIS 10 billion) should qualify as a “Special
Preferred Technological Enterprise” and will thereby enjoy a reduced corporate tax rate of 6% on “Preferred Technological
Income” regardless of the company’s geographic location within Israel. In addition, a Special Preferred Technological Enterprise
should enjoy a reduced corporate tax rate of 6% on capital gain derived from the sale of certain “Benefited Intangible Assets”
to a related foreign company if the Benefited Intangible Assets were either developed by the Special Preferred Technological Enterprise
or acquired from a foreign company on or after January 1, 2017, and the sale received prior approval from IIA. A Special Preferred Technological
Enterprise that acquires Benefited Intangible Assets from a foreign company for more than NIS 500 million should be eligible for these
benefits for at least ten years, subject to certain approvals as specified in the Investment Law.
Dividends distributed to Israeli
shareholders by a PTE or a Special Preferred Technological Enterprise, paid out of Preferred Technological Income, should generally subject
to withholding tax at source at the rate of 20% (in the case of non-Israeli shareholders subject to the receipt in advance of a valid
certificate from the ITA allowing for a reduced tax rate, 20%, or such a lower rate as may be provided in an applicable tax treaty). However,
if such dividends are paid to an Israeli company, no tax is generally required to be withheld (although, if such dividends are subsequently
distributed to individuals or a non-Israeli company, the aforesaid should apply). If such dividends are distributed to a foreign company
that holds solely or together with other foreign companies 90% or more in the Israeli company and other conditions are met, the withholding
tax rate should be 4% (or such lower rate as may be provided in an applicable tax treaty, in either case, subject to the receipt in advance
of a valid certificate from the ITA allowing for such reduced tax rate).
Currently we have not exhausted the
benefits we believe we may qualify for as a PTE and continue to examine the degree to which we may qualify as a PTE, the amount of Preferred
Technological Income that we may have and other benefits that we may receive from the 2017 Amendment in the future.
Tax benefits and grants for research
and development
Israeli tax law allows, under certain
conditions, a tax deduction for expenditures, including capital expenditures, in scientific research in the fields of industry, agriculture,
transportation or energy, for the year in which they are incurred. Expenditures are deemed related to scientific research and development
projects, if:
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The expenditures are approved by the relevant Israeli government ministry, determined
by the field of research; |
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The research and development must be for the promotion of the company; and |
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The research and development is carried out by or on behalf of the company seeking
such tax deduction. |
The amount of such deductible expenses is reduced by the
sum of any funds received through government grants for the finance of such scientific research and development projects. No deduction
under these research and development deduction rules is allowed if such deduction is related to an expense invested in an asset depreciable
under the general depreciation rules of the Ordinance. Expenditures that are unqualified under the conditions above are deductible in
equal amounts over three years.
From time to time we may apply to
the Israel Innovation Authority for approval to allow a tax deduction for all or most of research and development expenses during the
year incurred. There can be no assurance that such application will be accepted.
Taxation of our
shareholders
Capital
gains taxes applicable to non-Israeli resident shareholders. Capital gain tax is imposed on the disposition of capital assets by
an Israeli resident for tax purposes, and on the disposition of such assets by a non-Israeli resident for tax purposes if those assets
are (i) located in Israel; (ii) are shares or a right to a share in an Israeli resident corporation, or (iii) represent, directly or indirectly,
rights to assets the majority of which are located in Israel, unless a specific exemption is available or unless a tax treaty between
Israel and the shareholder’s country of residence provides otherwise. The Ordinance distinguishes between “Real Capital Gain”
and the “Inflationary Surplus.” Real Capital Gain is the excess of the total capital gain over Inflationary Surplus.
Inflationary Surplus is a portion
of the total capital gain which is equivalent to the increase in the relevant asset’s cost base that is attributable to the increase
in the Israeli consumer price index or, in certain circumstances, a foreign currency exchange rate, between the date of purchase and the
date of disposition. Inflationary Surplus attributed to the period after December 31, 1993, is not currently subject to tax in Israel.
Real Capital Gain accrued by individuals
from the sale of our shares should generally be taxed at the rate of 25%. However, if the individual shareholder is a “substantial
shareholder” (as defined below) at the time of sale or at any time during the preceding 12-month period, such capital gain should
be taxed at the rate of 30%. Furthermore, where an individual claimed real interest expenses and linkage differentials on securities,
the capital gain on the sale of the securities should be taxed at a rate of 30%. Real Capital Gain derived by corporations should generally
be subject to the corporate tax rate (23% in 2024).
Individual and corporate shareholders
dealing in securities in Israel are taxed at the tax rates applicable to business income (a corporate tax rate for a corporation and a
marginal tax rate of up to 47% for an individual in 2024, excluding surtax as discussed below) unless contrary provisions in a relevant
tax treaty apply.
A non-Israeli resident who derives
capital gains from the sale of shares in an Israeli resident company that were purchased upon or after the company was listed for trading
on a stock exchange outside of Israel, should be exempt from Israeli capital gains tax so long as the capital gain derived from the sale
of shares was not attributed to a permanent establishment that the non-Israeli resident maintains in Israel. However, non-Israeli entities
(including corporations) should not be entitled to the foregoing exemption if Israeli residents: (i) have a controlling interest of more
than 25% in such non-Israeli entity or (ii) are the beneficiaries of, or are entitled to, 25% or more of the revenues or profits of such
non-Israeli corporation, whether directly or indirectly. In addition, such exemption is not applicable to a person whose gains from selling
or otherwise disposing of the shares are deemed to be business income.
Additionally, a sale of securities
by a non-Israeli resident may be exempt from Israeli capital gains tax under the provisions of an applicable tax treaty, subject to the
eligibility of such person to the treaty benefits. For example, under the Convention Between the Government of the United States of America
and the Government of the State of Israel with respect to Taxes on Income, as amended (the “U.S. Israel Tax Treaty”), the
sale, exchange or other disposition of shares by a shareholder who is a United States resident (for purposes of the U.S. Israel Tax Treaty)
holding the shares as a capital asset and is entitled to claim the benefits afforded to such a resident by the U.S. Israel Tax Treaty
(a “Treaty U.S. Resident”) is generally exempt from Israeli capital gains tax unless: (i) the capital gain arising from such
sale, exchange or disposition is attributed to real estate located in Israel; (ii) the capital gain arising from such sale, exchange or
disposition is attributed to royalties; (iii) the capital gain arising from the such sale, exchange or disposition is attributed to a
permanent establishment in Israel, under certain terms; (iv) such Treaty U.S. Resident holds, directly or indirectly, shares representing
10% or more of the voting capital during any part of the 12 month period preceding the disposition, subject to certain conditions; or
(v) such Treaty U.S. Resident, being an individual, was present in Israel for 183 days or more during the relevant taxable year. In such
case, the sale, exchange or disposition of our shares would be subject to Israeli tax, to the extent applicable; however, under the U.S.
Israel Tax Treaty, a Treaty U.S. resident would be permitted to claim a credit for such taxes against the U.S. federal income tax imposed
with respect to such sale, exchange or disposition, subject to the limitations under U.S. law applicable to foreign tax credits. The U.S.
Israel Tax Treaty does not relate to tax credits against U.S. state or local taxes.
Shareholders may be required to demonstrate
that they are exempt from tax on their capital gains in order to avoid withholding at source at the time of sale, by presenting a valid
withholding exemption certificate issued by the ITA prior to the applicable payment. In addition, in transactions involving a sale of
all of the shares of an Israeli resident company, in the form of a merger or otherwise, the ITA may require from shareholders who are
not liable for Israeli tax to sign declarations in forms specified by this authority or obtain a specific exemption from the ITA to confirm
their status as a non-Israeli resident for tax purposes, and, in the absence of such declarations or exemptions, may require the purchaser
of the shares to withhold taxes.
Taxation
of non-Israeli shareholders on receipt of dividends. Non-Israeli residents (either individuals or corporations) are generally subject
to Israeli income tax on the receipt of dividends paid on our ordinary shares at the rate of 25%, which tax will be withheld at source,
unless relief is provided in a treaty between Israel and the shareholder’s country of residence (subject to the receipt in advance
of a valid certificate from the ITA allowing for a reduced tax rate). With respect to a person who is a “substantial shareholder”
at the time of receiving the dividend or on any time during the preceding twelve months, the applicable tax rate is 30%. A “substantial
shareholder” is generally a person who alone or together with such person’s relative or another person who collaborates with
such person on a permanent basis, holds, directly or indirectly, 10% or more of any of the “means of control” of the corporation.
“Means of control” generally include the right to vote, receive profits, nominate a director or an executive officer, receive
assets upon liquidation, or order someone who holds any of the aforesaid rights how to act, regardless of the source of such right. Such
dividends are generally subject to Israeli withholding tax at a rate of 25% so long as the shares are registered with a nominee company
(whether the recipient is a substantial shareholder or not), or 20% if the dividend is distributed from income attributed to a Preferred
Enterprise or PTE, subject to the receipt in advance of a valid certificate from the ITA allowing for a reduced tax rate, 20% or such
lower rate as may be provided in an applicable tax treaty. For example, under the U.S. Israel Tax Treaty, and subject to the eligibility
to the benefits under this treaty, the maximum rate of tax withheld at source in Israel on dividends paid to a holder of our ordinary
shares who is a Treaty U.S. Resident is 25%. However, generally, the maximum rate of withholding tax on dividends, not generated by a
Preferred Enterprise, that are paid to a United States corporation holding 10% or more of the outstanding voting capital throughout the
tax year in which the dividend is distributed as well as during the previous tax year, is 12.5%, provided that not more than 25% of the
gross income for such preceding year consists of certain types of dividends and interest. Notwithstanding the foregoing, dividends distributed
from income attributed to a Preferred Enterprise are not entitled to such reduction under the tax treaty but are subject to a withholding
tax rate of 15% for a shareholder that is a U.S. corporation, provided that the conditions related to 10% or more holding and to our gross
income for the previous year (as set forth in the previous sentence) are met. If the dividend is attributable partly to income derived
from a Preferred Enterprise, and partly to other sources of income, the withholding rate will be a blended rate reflecting the relative
portions of the two types of income. We cannot assure you that we will designate the profits that we may distribute in a way that will
reduce shareholders’ tax liability. The aforementioned rates under the U.S. Israel Tax Treaty would not apply if the dividend income
is derived through a permanent establishment of the Treaty U.S. Resident in Israel. U.S. residents who are subject to Israeli withholding
tax on a dividend may be entitled to a credit or deduction for United States federal income tax purposes in the amount of the taxes withheld,
subject to detailed rules contained in U.S. tax legislation.
A non-Israeli resident who receives
dividends from which full tax was withheld is generally exempt from the obligation to file tax returns in Israel with respect to such
income, provided that (i) such income was not generated from business conducted in Israel by the taxpayer, (ii) the taxpayer has no other
taxable sources of income in Israel with respect to which a tax return is required to be filed, and (iii) the taxpayer is not obligated
to pay surtax (as further explained below).
Surtax.
Subject to the provisions of an applicable tax treaty, individuals who are subject to tax in Israel (whether any such individual is an
Israeli resident or non-Israeli resident) are also subject to an additional tax at a rate of 3% on annual taxable income (including, but
not limited to, dividends, interest and capital gain) exceeding NIS 721,560 for 2024, which amount is generally linked to the annual change
in the Israeli consumer price index (with the exception that based on Israeli new legislation such amount, and certain other statutory
amounts will not be linked to the Israeli consumer price index for the years 2025-2027). According to new legislation, in effect as of
January 1, 2025, an additional 2% surtax is imposed on Capital-Sourced Income (defined as income from any source other than employment
income, business income or income from “personal effort”), to the extent that the Individual’s Capital Sourced Income
exceeds the specified threshold of NIS 721,560 (and regardless of the employment/business income amount of such individual). This new
surtax applies, among other things, to income from capital gains, dividends, interest, rental income, or the sale of real property.
Estate
and Gift Tax. Israeli law presently does not impose estate or gift taxes.
Material U.S. Federal Income Tax
Considerations for U.S. Holders
The following is a description of
certain material United States federal income tax considerations of the ownership and disposition of our ordinary shares. This description
addresses only the United States federal income tax consequences to U.S. Holders (as defined below) that hold our ordinary shares as capital
assets within the meaning of Section 1221 of the Internal Revenue Code of 1986, as amended (the “Code”), and that have the
U.S. dollar as their functional currency. This discussion is based upon the Code, applicable U.S. Treasury regulations, administrative
pronouncements and judicial decisions, in each case as in effect on the date hereof, all of which are subject to change (possibly with
retroactive effect). No ruling will be requested from the Internal Revenue Service (the “IRS”) regarding the tax consequences
of the ownership or disposition of the ordinary shares, and there can be no assurance that the IRS will agree with the discussion set
out below. This summary does not address any U.S. tax consequences other than U.S. federal income tax consequences (e.g., the estate and
gift tax or the Medicare tax on net investment income) and does not address any state, local or non-U.S. tax consequences.
This description does not address
tax considerations applicable to holders that may be subject to special tax rules, including, without limitation:
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banks, financial institutions or insurance companies; |
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real estate investment trusts or regulated investment companies; |
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dealers or brokers; |
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traders that elect to mark to market; |
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tax-exempt entities or organizations; |
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“individual retirement accounts” and other tax-deferred accounts;
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certain former citizens or long-term residents of the United States; |
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persons that are resident or ordinarily resident in or have a permanent establishment
in a jurisdiction outside the United States; |
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persons that acquired our ordinary shares pursuant to the exercise of any employee
share option or otherwise as compensation for the performance of services; |
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persons holding our ordinary shares as part of a “hedging,” “integrated”
or “conversion” transaction or as a position in a “straddle” for United States federal income tax purposes;
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persons subject to special tax accounting as a result of any item of gross income
with respect to the ordinary shares being taken into account in an applicable financial statement; |
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partnerships or other pass-through entities and persons holding the ordinary shares
through partnerships or other pass-through entities; or |
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holders that own directly, indirectly or through attribution 10% or more of the total
voting power or value of all of our outstanding shares. |
For purposes of this description,
a “U.S. Holder” is a beneficial owner of our ordinary shares that, for United States federal income tax purposes, is:
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an individual who is a citizen or resident of the United States; |
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a corporation (or other entity treated as a corporation for United States federal
income tax purposes) created or organized in or under the laws of the United States or any state thereof, including the District of Columbia;
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an estate the income of which is subject to United States federal income taxation
regardless of its source; or |
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a trust if such trust has validly elected to be treated as a United States person
for United States federal income tax purposes or if (1) a court within the United States is able to exercise primary supervision over
its administration and (2) one or more United States persons have the authority to control all of the substantial decisions of such trust.
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If an entity or arrangement treated
as a partnership for United States federal income tax purposes holds our ordinary shares, the tax treatment of a partner in such partnership
will generally depend on the status of the partner and the activities of the partnership. Such a partner or partnership should consult
its tax advisor as to the particular United States federal income tax consequences of owning and disposing of our ordinary shares in its
particular circumstance.
You should consult
your tax advisor with respect to the United States federal, state, local and non-U.S. consequences of owning and disposing of our ordinary
shares.
Distributions
Subject to the discussion under “-Passive
Foreign Investment Company Considerations” below, the gross amount of any distribution made to you with respect to our ordinary
shares, before reduction for any Israeli taxes withheld therefrom, generally will be includible in your income as dividend income on the
date on which the dividends are actually or constructively received, to the extent such distribution is paid out of our current or accumulated
earnings and profits as determined under United States federal income tax principles. To the extent that the amount of any distribution
by us exceeds our current and accumulated earnings and profits as determined under United States federal income tax principles, it will
be treated first as a tax-free return of your adjusted tax basis in our ordinary shares and thereafter as capital gain. However, we do
not expect to maintain calculations of our earnings and profits under United States federal income tax principles and, therefore, you
should expect that the entire amount of any distribution generally will be taxable as dividend income to you. Non-corporate U.S. Holders
may qualify for the lower rates of taxation with respect to dividends on ordinary shares applicable to long-term capital gains (i.e.,
gains from the sale of capital assets held for more than one year), provided that we are
not a PFIC (as discussed below under “-Passive Foreign Investment Company Considerations”) with respect to you in our taxable
year in which the dividend was paid or in the prior taxable year and certain other conditions are met, including certain holding period
requirements and the absence of certain risk reduction transactions. However, such dividends will not be eligible for the dividends received
deduction generally allowed to corporate U.S. Holders. You should consult your tax advisor regarding the availability of the lower rate
for dividends paid with respect to our shares.
The amount of any distribution paid
in foreign currency will be equal to the U.S. dollar value of such currency, translated at the spot rate of exchange on the date such
distribution is received, regardless of whether the payment is in fact converted into U.S. dollars at that time.
Dividends paid to you with respect
to our ordinary shares generally will be treated as foreign source income, which may be relevant in calculating your foreign tax credit
limitation. Subject to certain conditions and limitations, Israeli tax withheld on dividends may be credited against your United States
federal income tax liability or, at your election, be deducted from your U.S. federal taxable income. Dividends that we distribute generally
should constitute “passive category income” for purposes of the foreign tax credit. However, if we are a “United States-owned
foreign corporation,” solely for foreign tax credit purposes, a portion of the dividends allocable to our U.S. source earnings and
profits may be recharacterized as U.S. source. A “United States-owned foreign corporation” is any foreign corporation in which
United States persons own, directly or indirectly, 50% or more (by vote or by value) of the stock. In general, United States-owned foreign
corporations with less than 10% of earnings and profits attributable to sources within the United States are excepted from these rules.
In the event we are treated as a “United States-owned foreign corporation,” if 10% or more of our earnings and profits are
attributable to sources within the United States, a portion of the dividends paid on our ordinary shares allocable to our U.S. source
earnings and profits will be treated as U.S. source, and, as such, a U.S. Holder may not offset any foreign tax withheld as a credit against
U.S. federal income tax imposed on that portion of dividends. A foreign tax credit for foreign taxes imposed on distributions may be denied
if you do not satisfy certain minimum holding period requirements. The rules relating to the determination of the foreign tax credit are
complex, and you should consult your tax advisor regarding the availability of a U.S. foreign tax credit in your particular circumstances
and the possibility of claiming a deduction (in lieu of the U.S. foreign tax credit) for any foreign taxes paid or withheld.
Sale, Exchange
or Other Disposition of Ordinary Shares
Subject to the discussion under “-Passive
Foreign Investment Company Considerations” below, you generally will recognize gain or loss on the sale, exchange or other disposition
of our ordinary shares equal to the difference between the amount realized on such sale, exchange or other disposition and your adjusted
tax basis in our ordinary shares, and such gain or loss will be capital gain or loss. If you are a non-corporate U.S. Holder, capital
gain from the sale, exchange or other disposition of ordinary shares is generally eligible for a preferential rate of taxation applicable
to capital gains, if your holding period for such ordinary shares exceeds one year (i.e., such gain is long-term capital gain). The deductibility
of capital losses for United States federal income tax purposes is subject to limitations under the Code. Any such gain or loss that a
U.S. Holder recognizes generally will be treated as U.S. source income or loss for foreign tax credit limitation purposes.
If the consideration received upon the sale or other disposition of our ordinary shares
is paid in foreign currency, the amount realized will be the U.S. dollar value of the payment received, translated at the spot rate of
exchange on the date of the sale or other disposition. If the ordinary shares are treated as traded on an established securities market
and you are either a cash basis taxpayer or an accrual basis taxpayer who has made a special election (which must be applied consistently
from year to year and cannot be changed without the consent of the IRS), the U.S. dollar value of the amount realized in foreign currency
will be determined by translating the amount received at the spot rate of exchange on the settlement date of the sale. If our ordinary
shares are not treated as traded on an established securities market, or you are an accrual basis taxpayer that does not elect to determine
the amount realized using the spot rate of exchange on the settlement date, you will recognize foreign currency gain or loss to the extent
of any difference between the U.S. dollar amount realized on the date of sale or disposition (as determined above) and the U.S. dollar
value of the currency received translated at the spot rate of exchange on the settlement date, and such gain or loss generally will constitute
U.S. source ordinary income or loss.
The adjusted tax basis in an ordinary
share generally will be equal to the cost of such ordinary share. If you used foreign currency to purchase the ordinary shares, the cost
of the ordinary shares will be the U.S. dollar value of the foreign currency purchase price on the date of purchase, translated at the
spot rate of exchange on that date. If our ordinary shares are treated as traded on an established securities market and you are either
a cash basis taxpayer or an accrual basis taxpayer who has made the special election described above, the U.S. dollar value of the cost
of such ordinary shares will be determined by translating the amount paid at the spot rate of exchange on the settlement date of the purchase.
Passive Foreign
Investment Company Considerations
If a non-U.S. company is classified
as a PFIC in any taxable year, a U.S. Holder of such PFIC’s shares will be subject to special rules generally intended to reduce
or eliminate any benefits from the deferral of U.S. federal income tax that such U.S. Holder could derive from investing in a non-U.S.
company that does not distribute all of its earnings on a current basis.
In general, a non-U.S. corporation
will be classified as a PFIC for any taxable year if at least (i) 75% of its gross income is classified as “passive income”
or (ii) 50% of its gross assets (determined on the basis of a quarterly average) produce or are held for the production of passive income
(the “asset test”). Passive income for this purpose generally includes dividends, interest, royalties, rents, gains from commodities
and securities transactions and the excess of gains over losses from the disposition of assets which produce passive income. For these
purposes, cash and other assets readily convertible into cash are considered passive assets, and the company’s goodwill and other
unbooked intangibles are generally taken into account. In making this determination, the non-U.S. corporation is treated as earning its
proportionate share of any income and owning its proportionate share of any assets of any corporation in which it directly or indirectly
holds 25% or more (by value) of the stock.
We have not yet determined
whether we were a PFIC for the taxable year ended December 31, 2024, and the determination of our status as a PFIC for our 2025
taxable year is made at the end of the year, accordingly, no assurances can be made in this regard. Our status as a PFIC requires
a factual determination that depends on, among other things, our income, assets and operations in each year. Fluctuations in the market
price of our ordinary shares may cause our classification as a PFIC for the current or future taxable years to change because the value
of our assets for purposes of the asset test, including the value of our goodwill and unbooked intangibles, may be determined by reference
to the market price of our shares from time to time (which may be volatile). Among other matters, if our market capitalization subsequently
declines, it may make our classification as a PFIC more likely for the current or future taxable years. The composition of our income
and assets may also be affected by how, and how quickly, we use our liquid assets. Therefore, there can be no assurance that we will not
be treated as a PFIC for our current taxable year or any future taxable year.
Under the PFIC rules, if we were
considered a PFIC at any time that you hold our ordinary shares, we would continue to be treated as a PFIC with respect to your investment
in all succeeding years during which you own our ordinary shares (regardless of whether we continue to meet the tests described above)
unless (i) we have ceased to be a PFIC and (ii) you have made a “deemed sale” election under the PFIC rules. If such election
is made, you will be deemed to have sold your ordinary shares at their fair market value on the last day of the last taxable year in which
we were a PFIC, and any gain from the deemed sale would be subject to the rules described in the following paragraph. After the deemed
sale election, so long as we do not become a PFIC in a subsequent taxable year, the ordinary shares with respect to which such election
was made will not be treated as shares in a PFIC. You should consult your tax advisor as to the possibility and consequences of making
a deemed sale election if we are (or were to become) and then cease to be a PFIC, and such election becomes available.
If we are considered a PFIC at any
time that you hold ordinary shares, unless you make one of the elections described below, any gain recognized by you on a sale or other
disposition of the ordinary shares, as well as the amount of any “excess distribution” (defined below) received by you, would
be allocated ratably over your holding period for the ordinary shares. The amounts allocated to the taxable year of the sale or other
disposition (or the taxable year of receipt, in the case of an excess distribution) and to any year before we became a PFIC would be taxed
as ordinary income. The amount allocated to each other taxable year would be subject to tax at the highest rate in effect for individuals
or corporations, as appropriate, for that taxable year, and an interest charge would be imposed. For purposes of these rules, an excess
distribution is the amount by which any distribution received by you on your ordinary shares in a taxable year exceeds 125% of the average
of the annual distributions on the ordinary shares during the preceding three taxable years or your holding period, whichever is shorter.
Distributions below the 125% threshold are treated as dividends taxable in the year of receipt and are not subject to the highest tax
rates or the interest charge described above.
If we are treated as a PFIC with
respect to you for any taxable year, you will be deemed to own shares in any entities in which we directly or indirectly own equity that
are also PFICs, and you may be subject to the tax consequences described above with respect to the shares of such lower-tier PFIC you
would be deemed to own.
Mark-to-market elections
If we are a PFIC for any taxable
year during which you hold ordinary shares, then in lieu of being subject to the tax and interest charge rules discussed above, you may
make an election to include gain on the ordinary shares as ordinary income under a mark-to-market method, provided that such ordinary
shares are “marketable.” The ordinary shares will be marketable if they are “regularly traded” on a qualified
exchange or other market, as defined in applicable U.S. Treasury regulations, such as the Nasdaq Global Select Market. For these purposes,
the ordinary shares will be considered regularly traded during any calendar year during which they are traded, other than in de
minimis quantities, on at least 15 days during each calendar quarter. Any trades that have as their principal purpose meeting this
requirement will be disregarded. However, because a mark-to-market election cannot be made for any lower-tier PFICs that we may own, you
will generally continue to be subject to the PFIC rules discussed above with respect to your indirect interest in any investments we hold
that are treated as an equity interest in a PFIC for United States federal income tax purposes. As a result, it is possible that any mark-to-market
election will be of limited benefit. If you make an effective mark-to-market election, in each year that we are a PFIC, you will include
in ordinary income the excess of the fair market value of your ordinary shares at the end of the year over your adjusted tax basis in
the ordinary shares. You will be entitled to deduct as an ordinary loss in each such year the excess of your adjusted tax basis in the
ordinary shares over their fair market value at the end of the year, but only to the extent of the net amount previously included in income
as a result of the mark-to-market election. If you make an effective mark-to-market election, in each year that we are a PFIC, any gain
that you recognize upon the sale or other disposition of your ordinary shares will be treated as ordinary income and any loss will be
treated as ordinary loss, but only to the extent of the net amount of previously included income as a result of the mark-to-market election.
Your adjusted tax basis in the ordinary
shares will be increased by the amount of any income inclusion and decreased by the amount of any deductions under the mark-to-market
rules discussed above. If you make an effective mark-to-market election, it will be effective for the taxable year for which the election
is made and all subsequent taxable years unless the ordinary shares are no longer regularly traded on a qualified exchange or the IRS
consents to the revocation of the election. You should consult your tax advisor about the availability of the mark-to-market election,
and whether making the election would be advisable in your particular circumstances.
Qualified electing fund elections
In certain circumstances, a U.S.
equity holder in a PFIC may avoid the adverse tax and interest-charge regime described above by making a “qualified electing fund”
or QEF election to include in income its share of the corporation’s income on a current basis. However, you may make a qualified
electing fund election with respect to the ordinary shares only if we agree to furnish you annually with a PFIC annual information statement
as specified in the applicable U.S. Treasury regulations. There is no assurance that we will be able to timely provide the information
necessary for you to make a qualified electing fund election if we are classified as a PFIC. U.S. Holders should consult with their
U.S. tax advisors concerning the availability of a QEF election, if we are classified as a PFIC for any taxable year.
Tax reporting
If you own ordinary shares during
any year in which we are a PFIC and you recognize gain on a disposition of such ordinary shares or receive distributions with respect
to such ordinary shares, you generally will be required to file an IRS Form 8621 with respect to us, generally with your federal income
tax return for that year. If we are a PFIC for a given taxable year, then you should consult your tax advisor concerning your annual filing
requirements.
You should consult
your tax advisor regarding whether we are a PFIC as well as the potential U.S. federal income tax consequences of holding and disposing
of our ordinary shares if we are or become classified as a PFIC, including the possibility of making a mark-to-market or QEF election
in your particular circumstances.
Backup Withholding
Tax and Information Reporting Requirements
Dividend payments on and proceeds
paid from the sale or other taxable disposition of the ordinary shares may be subject to information reporting to the IRS. In addition,
a U.S. Holder may be subject to backup withholding on cash payments received in connection with dividend payments and proceeds from the
sale or other taxable disposition of ordinary shares made within the United States or through certain U.S. related financial intermediaries.
Backup withholding will not apply,
however, to a U.S. Holder who furnishes a correct taxpayer identification number, provides other required certification and otherwise
complies with the applicable requirements of the backup withholding rules or who is otherwise exempt from backup withholding (and, when
required, demonstrates such exemption). Backup withholding is not an additional tax. Rather, any amount withheld under the backup withholding
rules will be creditable or refundable against the U.S. Holder’s U.S. federal income tax liability, provided the required information
is timely furnished to the IRS.
Foreign Asset
Reporting
Certain U.S. Holders are required
to report their holdings of certain foreign financial assets, including equity of foreign entities, if the aggregate value of all of these
assets exceeds certain threshold amounts by filing an IRS Form 8938 with their federal income tax return. Our ordinary shares are expected
to constitute foreign financial assets subject to these requirements unless the ordinary shares are held in an account at certain financial
institutions. U.S. Holders are urged to consult their tax advisors regarding their information reporting obligations, if any, with respect
to their ownership and disposition of our ordinary shares and the significant penalties for non-compliance.
The above description
is not intended to constitute a complete analysis of all tax consequences relating to the ownership and disposition of our ordinary shares.
You should consult your tax advisor concerning the tax consequences of your particular situation.
F. |
Dividends and Paying Agents
|
We are subject to the informational
requirements of the Exchange Act. Accordingly, we are required to file reports and other information with the SEC, including annual reports
on Form 20-F and reports on Form 6-K. The SEC maintains an internet website that contains reports and other information about issuers,
like us, that file electronically with the SEC. The address of that website is www.sec.gov.
We maintain a corporate website at
http://www.chemomab.com. Information contained on, or that can be accessed through our website
does not constitute a part of this Annual Report on Form 20-F. We also make available on our website’s investor relations page at
http://investors.chemomab.com, free of charge, our Annual Report and the text of our reports on
Form 6-K and 8-K, including any amendments to these reports, as well as certain other SEC filings, as soon as reasonably practicable after
they are electronically filed with or furnished to the SEC. The information contained on our website is not incorporated by reference
in this Annual Report.
As a foreign private issuer, we are
exempt under the Exchange Act from, among other things, the rules prescribing the furnishing and content of proxy statements, and our
officers, directors and principal shareholders are exempt from the reporting and short-swing profit recovery provisions contained in Section
16 of the Exchange Act. In addition, we are not required under the Exchange Act to file periodic reports and financial statements with
the SEC as frequently or as promptly as U.S. companies whose securities are registered under the Exchange Act. However, we will file with
the SEC, within four months after the end of each subsequent fiscal year, or such applicable time as required by the SEC, an annual report
on Form 20-F containing financial statements audited by an independent registered public accounting firm. We also intend to furnish certain
other material information to the SEC under cover of Form 6-K.
We will send our transfer agent a
copy of all notices of shareholders’ meetings and other reports, communications and information that are made generally available
to shareholders. The transfer agent has agreed to mail to all shareholders a notice containing the information (or a summary of the information)
contained in any notice of a meeting of our shareholders received by the transfer agent and will make available to all shareholders such
notices and all such other reports and communications received by the transfer agent.
I. |
Subsidiary Information
|
J. |
Annual Report to Security Holders
|
Item 11.
Quantitative and Qualitative Disclosures about Market Risk
We are exposed to market risk from
changes in exchange rates, interest rates and inflation. All of these market risks arise in the ordinary course of business, as we do
not engage in speculative trading activities. The following analysis provides additional information regarding these risks.
Interest rate
risk
Our investments are subject to market
risk due to changes in interest rates, which may affect our interest income and fair market value of our investments. To minimize this
risk, we maintain our portfolio in a variety of high-grade securities, including U.S. treasury bonds and government agencies. The primary
objectives of our investment activities are to support liquidity, preserve principal and to maximize income without significantly increasing
risk.
As of December 31, 2024, we had $14.3
million of cash and cash equivalent, bank deposits and marketable securities. Interest-earning instruments carry a degree of interest
rate risk. However, our historical interest income has not fluctuated significantly. A hypothetical 10% change in interest rates would
not have had a material impact on our financial results for the years ended December 31, 2023 and 2024. We do not enter into investments
for trading or speculative purposes and have not used any derivative financial instruments to manage our interest rate risk exposure.
Foreign Currency
Exchange Risk
Our functional currency is the U.S. Dollar.
We are exposed to foreign exchange rate risk. We are located in Israel, where part of our general and administrative expenses costs is
incurred in New Israeli Shekels. During each of the years ended December 31, 2024, and 2023, we recognized foreign currency transaction
gain of $9 thousand and $14 thousand, respectively, respectively. These foreign currency transaction gains were recorded in financial
expenses. We believe that a 10% change in the exchange rate between the U.S. Dollar and New Israeli Shekel would not have a material impact
on our financial position or results of operations.
As we continue to grow our business,
our results of operations and cash flows will be subject to fluctuations due to changes in foreign currency exchange rates, which could
adversely impact our results of operations. To date, we have not entered into any foreign currency hedging contracts to mitigate our exposure
to foreign currency exchange risk.
Item 12.
Description of Securities Other than Equity Securities
D. |
American Depositary Shares |
The Bank of New York Mellon, as depositary,
registers and delivers our ADSs. Each ADS will represent ordinary shares (or a right to receive twenty (20) ordinary shares). Each ADS
will also represent any other securities, cash or other property which may be held by the depositary. The depositary’s office at
which our ADSs will be administered and its principal executive office are located at 240 Greenwich Street, New York, New York 10286.
You may hold ADSs either (A) directly
(i) by having an ADR, which is a certificate evidencing a specific number of ADSs, registered in your name or (ii) by having
uncertificated ADSs registered in your name or (B) indirectly by holding a security entitlement in ADSs through your broker or other
financial institution that is a direct or indirect participant in DTC. If you hold ADSs directly, you are a registered ADS holder, also
referred to as an ADS holder. This description assumes you are an ADS holder. If you hold our ADSs indirectly, you must rely on the procedures
of your broker or other financial institution to assert the rights of ADS holders described in this section. You should consult with your
broker or financial institution to find out what those procedures are.
Registered holders of uncertificated
ADSs will receive statements from the depositary confirming their holdings.
As an ADS holder, we will not treat
you as one of our shareholders and you will not have shareholder rights. Israeli law governs shareholder rights. The depositary will be
the holder of the ordinary shares underlying your ADSs. As a registered holder of ADSs, you will have ADS holder rights. A deposit agreement
among us, the depositary, ADS holders and all other persons indirectly or beneficially holding ADSs sets out ADS holder rights as well
as the rights and obligations of the depositary. New York law governs the deposit agreement and our ADSs.
The following is a summary of the
material provisions of the deposit agreement. For more complete information, you should read the entire deposit agreement and the form
of ADR. For directions on how to obtain copies of those documents see “Where You Can Find More
Information.”
Dividends and Other Distributions
How will you receive dividends and
other distributions on the shares?
The depositary has agreed to pay
or distribute to ADS holders the cash dividends or other distributions it or the custodian receives on ordinary shares or other deposited
securities, upon payment or deduction of its fees and expenses. You will receive these distributions in proportion to the number of ordinary
shares your ADSs represent.
Cash. The
depositary will convert any cash dividend or other cash distribution we pay on the ordinary shares into U.S. dollars, if it can do so
on a reasonable basis and can transfer the U.S. dollars to the United States. If that is not possible or if any government approval is
needed and cannot be obtained, the deposit agreement allows the depositary to distribute the foreign currency only to those ADS holders
to whom it is possible to do so. It will hold the foreign currency it cannot convert for the account of our ADS holders who have not been
paid. It will not invest the foreign currency and it will not be liable for any interest.
Before making a distribution, any
withholding taxes or other governmental charges that must be paid will be deducted. See “Taxation and Government Programs.”
It will distribute only whole U.S. dollars and cents and will round fractional cents to the nearest whole cent. If the exchange rates
fluctuate during a time when the depositary cannot convert the foreign currency, you may lose some or all of the value of the distribution.
Shares. The
depositary may distribute additional ADSs representing any ordinary shares we distribute as a dividend or free distribution. The depositary
will only distribute whole ADSs. It will sell ordinary shares which would require it to deliver a fraction of an ADS (or ADSs representing
those ordinary shares) and distribute the net proceeds in the same way as it does with cash. If the depositary does not distribute additional
ADSs, the outstanding ADSs will also represent the new shares. The depositary may sell a portion of the distributed ordinary shares (or
ADSs representing those ordinary shares) sufficient to pay its fees and expenses in connection with that distribution.
Rights
to purchase additional shares. If we offer holders of our securities any rights to subscribe for additional ordinary
shares or any other rights, the depositary may (i) exercise those rights on behalf of ADS holders, (ii) distribute those rights
to ADS holders or (iii) sell those rights and distribute the net proceeds to ADS holders, in each case after deduction or upon payment
of its fees and expenses. To the extent the depositary does not do any of those things, it will allow the rights to lapse. In
that case, you will receive no value for them. The depositary will exercise or distribute rights only if we ask it to and
provide satisfactory assurances to the depositary that it is legal to do so. If the depositary will exercise rights, it will purchase
the securities to which the rights relate and distribute those securities or, in the case of ordinary shares, new ADSs representing the
new ordinary shares, to subscribing ADS holders, but only if ADS holders have paid the exercise price to the depositary. U.S. securities
laws may restrict the ability of the depositary to distribute rights or ADSs or other securities issued on exercise of rights to all or
certain ADS holders, and the securities distributed may be subject to restrictions on transfer.
Other
Distributions. The depositary will send to ADS holders anything else we distribute on deposited securities by
any means it thinks is legal, fair and practical. If it cannot make the distribution in that way, the depositary will have a choice. It
may decide to sell what we distributed and distribute the net proceeds, in the same way as it does with cash. Or, it may decide to hold
what we distributed, in which case ADSs will also represent the newly distributed property. However, the depositary is not required to
distribute any securities (other than ADSs) to ADS holders unless it receives satisfactory evidence from us that it is legal to make that
distribution. The depositary may sell a portion of the distributed securities or property sufficient to pay its fees and expenses in connection
with that distribution. U.S. securities laws may restrict the ability of the depositary to distribute securities to all or certain ADS
holders, and the securities distributed may be subject to restrictions on transfer.
The depositary is not responsible
if it decides that it is unlawful or impractical to make a distribution available to any ADS holders. We have no obligation to register
ADSs, ordinary shares, rights or other securities under the Securities Act. We also have no obligation to take any other action to permit
the distribution of ADSs, shares, rights or anything else to ADS holders. This means that you may not receive the distributions we make
on our ordinary shares or any value for them if it is illegal or impractical for us to make them available to you.
Deposit, Withdrawal and Cancellation
How are ADSs issued?
The depositary will deliver ADSs
if you or your broker deposits ordinary shares or evidence of rights to receive ordinary shares with the custodian. Upon payment of its
fees and expenses and of any taxes or charges, such as stamp taxes or stock transfer taxes or fees, the depositary will register the appropriate
number of ADSs in the names you request and will deliver our ADSs to or upon the order of the person or persons that made the deposit.
How can ADS holders withdraw the
deposited securities?
You may surrender your ADSs for the
purpose of withdrawal at the depositary’s office. Upon payment of its fees and expenses and of any taxes or charges, such as stamp
taxes or stock transfer taxes or fees, the depositary will deliver the ordinary shares and any other deposited securities underlying our
ADSs to the ADS holder or a person the ADS holder designates at the office of the custodian. Or, at your request, risk and expense, the
depositary will deliver the deposited securities at its office, if feasible. However, the depositary is not required to accept surrender
of ADSs to the extent it would require delivery of a fraction of a deposited share or other securities. The depositary may charge you
a fee and its expenses for instructing the custodian regarding delivery of deposited securities.
How do ADS holders interchange between
certificated ADSs and uncertificated ADSs?
You may surrender your ADR to the
depositary for the purpose of exchanging your ADR for uncertificated ADSs. The depositary will cancel that ADR and will send to the ADS
holder a statement confirming that the ADS holder is the registered holder of uncertificated ADSs. Alternatively, upon receipt by the
depositary of a proper instruction from a registered holder of uncertificated ADSs requesting the exchange of uncertificated ADSs for
certificated ADSs, the depositary will execute and deliver to the ADS holder an ADR evidencing those ADSs.
Voting Rights
How do you vote?
ADS holders may instruct the depositary
how to vote the number of deposited ordinary shares their ADSs represent. If we request the depositary to solicit your voting instructions
(and we are not required to do so), the depositary will notify you of a shareholders’ meeting and send or make voting materials
available to you. Those materials will describe the matters to be voted on and explain how ADS holders may instruct the depositary how
to vote. For instructions to be valid, they must reach the depositary by a date set by the depositary. The depositary will try, as far
as practical, subject to the laws of Israel and the provisions of our articles of association or similar documents, to vote or to have
its agents vote the ordinary shares or other deposited securities as instructed by ADS holders. If we do not request the depositary to
solicit your voting instructions, you can still send voting instructions, and, in that case, the depositary may try to vote as you instruct,
but it is not required to do so.
Except
by instructing the depositary as described above, you won’t be able to exercise voting rights unless you surrender your ADSs and
withdraw the ordinary shares. However, you may not know about the meeting enough in advance to withdraw the ordinary shares. In
any event, the depositary will not exercise any discretion in voting deposited securities and it will only vote or attempt to vote as
instructed.
We cannot assure you that you will
receive the voting materials in time to ensure that you can instruct the depositary to vote your shares. In addition, the depositary and
its agents are not responsible for failing to carry out voting instructions or for the manner of carrying out voting instructions. This
means that you may not be able to exercise your right to vote and there may be nothing you can do if your ordinary shares are not voted
as you requested.
In order to give you a reasonable
opportunity to instruct the Depositary as to the exercise of voting rights relating to Deposited Securities, if we request the Depositary
to act, we agree to give the Depositary notice of any such meeting and details concerning the matters to be voted upon at least 45 days
in advance of the meeting date.
Fees and Expenses
Persons depositing or withdrawing ordinary shares or ADS holders must pay
|
|
For |
$5.00 (or less) per 100 ADSs (or portion of 100 ADSs) |
|
Issuance of ADSs, including issuances resulting from a distribution of ordinary shares or rights or other
property Cancellation of ADSs for the purpose of withdrawal, including if the deposit agreement terminates |
|
|
|
$.05 (or less) per ADS |
|
Any cash distribution to ADS holders |
|
|
|
A fee equivalent to the fee that would be payable if securities distributed to you had been ordinary shares
and the ordinary shares had been deposited for issuance of ADSs |
|
Distribution of securities distributed to holders of deposited securities (including rights) that are distributed
by the depositary to ADS holders |
|
|
|
$.05 (or less) per ADS per calendar year |
|
Depositary services |
Persons depositing or withdrawing ordinary shares or ADS holders must pay
|
|
For |
Registration or transfer fees |
|
Transfer and registration of ordinary shares on our share register to or from the name of the depositary
or its agent when you deposit or withdraw ordinary shares |
|
|
|
Expenses of the depositary |
|
Cable, telex and facsimile transmissions (when expressly provided in the
deposit agreement)
Converting foreign currency to U.S. dollars |
|
|
|
Taxes and other governmental charges the depositary or the custodian have to pay on any ADSs or ordinary
shares underlying ADSs, such as stock transfer taxes, stamp duty or withholding taxes |
|
As necessary |
|
|
|
Any charges incurred by the depositary or its agents for servicing the deposited securities |
|
As necessary |
The depositary collects its fees
for delivery and surrender of ADSs directly from investors depositing ordinary shares or surrendering ADSs for the purpose of withdrawal
or from intermediaries acting for them. The depositary collects fees for making distributions to investors by deducting those fees from
the amounts distributed or by selling a portion of distributable property to pay the fees. The depositary may collect its annual fee for
depositary services by deduction from cash distributions or by directly billing investors or by charging the book-entry system accounts
of participants acting for them. The depositary may collect any of its fees by deduction from any cash distribution payable (or by selling
a portion of securities or other property distributable) to ADS holders that are obligated to pay those fees. The depositary may generally
refuse to provide fee-attracting services until its fees for those services are paid.
From time to time, the depositary
may make payments to us to reimburse us for costs and expenses generally arising out of establishment and maintenance of our ADS program,
waive fees and expenses for services provided to us by the depositary or share revenue from the fees collected from ADS holders. In performing
its duties under the deposit agreement, the depositary may use brokers, dealers, foreign currency or other service providers that are
owned by or affiliated with the depositary and that may earn or share fees, spreads or commissions.
The depositary may convert foreign
currency itself or through any of its affiliates and, in those cases, acts as principal for its own account and not as an agent, fiduciary
or broker on behalf of any other person and earns revenue, including, without limitation, fees and spreads that it will retain for its
own account. The revenue is based on, among other things, the difference between the exchange rate assigned to the currency conversion
made under the deposit agreement and the rate that the depositary or its affiliate receives when buying or selling foreign currency for
its own account. The depositary makes no representation that the exchange rate used or obtained in any currency conversion under the deposit
agreement will be the most favorable rate that could be obtained at the time or that the method by which that rate will be determined
will be most favorable to ADS holders, subject to its obligations under the deposit agreement. The methodology used to determine exchange
rates used in currency conversions is available upon request.
Payment of Taxes
You will be responsible for any taxes
or other governmental charges payable on your ADSs or on the deposited securities represented by any of your ADSs. The depositary may
refuse to register any transfer of your ADSs or allow you to withdraw the deposited securities represented by your ADSs until such taxes
or other charges are paid. It may apply payments owed to you or sell deposited securities represented by your ADSs to pay any taxes owed
and you will remain liable for any deficiency. If the depositary sells deposited securities, it will, if appropriate, reduce the number
of ADSs to reflect the sale and pay to ADS holders any proceeds, or send to ADS holders any property, remaining after it has paid the
taxes.
Tender and Exchange Offers; Redemption,
Replacement or Cancellation of Deposited Securities
The depositary will not tender deposited
securities in any voluntary tender or exchange offer unless instructed to do by an ADS holder surrendering ADSs and subject to any conditions
or procedures the depositary may establish.
If deposited securities are redeemed
for cash in a transaction that is mandatory for the depositary as a holder of deposited securities, the depositary will call for surrender
of a corresponding number of ADSs and distribute the net redemption money to the holders of called ADSs upon surrender of those ADSs.
If there is any change in the deposited
securities such as a subdivision, combination or other reclassification, or any merger, consolidation, recapitalization or reorganization
affecting the issuer of deposited securities in which the depositary receives new securities in exchange for or in lieu of the old deposited
securities, the depositary will hold those replacement securities as deposited securities under the deposit agreement. However, if the
depositary decides it would not be lawful and practical to hold the replacement securities because those securities could not be distributed
to ADS holders or for any other reason, the depositary may instead sell the replacement securities and distribute the net proceeds upon
surrender of our ADSs.
If there is a replacement of the
deposited securities and the depositary will continue to hold the replacement securities, the depositary may distribute new ADSs representing
the new deposited securities or ask you to surrender your outstanding ADRs in exchange for new ADRs identifying the new deposited securities.
If there are no deposited securities
underlying ADSs, including if the deposited securities are cancelled, or if the deposited securities underlying ADSs have become apparently
worthless, the depositary may call for surrender or of those ADSs or cancel those ADSs upon notice to the ADS holders.
Amendment and Termination
How may the deposit agreement be
amended?
We may agree with the depositary
to amend the deposit agreement and the ADRs without your consent for any reason. If an amendment adds or increases fees or charges, except
for taxes and other governmental charges or expenses of the depositary for registration fees, facsimile costs, delivery charges or similar
items, or prejudices a substantial right of ADS holders, it will not become effective for outstanding ADSs until 30 days after the
depositary notifies ADS holders of the amendment. At the time an amendment becomes effective, you are considered, by continuing to hold
your ADSs, to agree to the amendment and to be bound by the ADRs and the deposit agreement as amended.
How may the deposit agreement be
terminated?
The depositary will initiate termination
of the deposit agreement if we instruct it to do so. The depositary may initiate termination of the deposit agreement if:
• |
90 days have passed since the depositary told us it wants to resign but a successor
depositary has not been appointed and accepted its appointment; |
• |
we delist our ADSs from an exchange on which they were listed and do not list our
ADSs on another exchange within a reasonable time; |
• |
we appear to be insolvent or enter insolvency proceedings; |
• |
all or substantially all the value of the deposited securities has been distributed
either in cash or in the form of securities; |
• |
there are no deposited securities underlying our ADSs or the underlying deposited
securities have become apparently worthless; or |
• |
there has been a replacement of deposited securities. |
If the deposit agreement is terminated,
the depositary will notify ADS holders at least 90 days before the termination date. At any time after the termination date, the
depositary may sell the deposited securities. After that, the depositary will hold the money it received on the sale, as well as any other
cash it is holding under the deposit agreement, unsegregated and without liability for interest, for the pro rata benefit of the
ADS holders that have not surrendered their ADSs. Normally, the depositary will sell as soon as practicable after the termination date.
After the termination date and before
the depositary sells, ADS holders can still surrender their ADSs and receive delivery of deposited securities, except that the depositary
may refuse to accept a surrender for the purpose of withdrawing deposited securities or reverse previously accepted surrenders of that
kind if it would interfere with the selling process. The depositary may refuse to accept a surrender for the purpose of withdrawing sale
proceeds until all the deposited securities have been sold. The depositary will continue to collect distributions on deposited securities,
but, after the termination date, the depositary is not required to register any transfer of ADSs or distribute any dividends or other
distributions on deposited securities to the ADSs holder (until they surrender their ADSs) or give any notices or perform any other duties
under the deposit agreement except as described in this paragraph.
Limitations on Obligations and Liability
Limits on our obligations and the
obligations of the depositary; Limits on liability to holders of ADSs
The deposit agreement expressly limits
our obligations and the obligations of the depositary. It also limits our liability and the liability of the depositary. We and the depositary:
• |
are only obligated to take the actions specifically set forth in the deposit agreement
without negligence or bad faith and the depositary will not be a fiduciary or have any fiduciary duty to holders of ADSs; |
• |
are not liable if we are or it is prevented or delayed by law or circumstances beyond
our or its control from performing our or its obligations under the deposit agreement; |
• |
are not liable if we exercise or it exercises discretion permitted under the deposit
agreement; |
• |
are not liable for the inability of any holder of ADSs to benefit from any distribution
on deposited securities that is not made available to holders of ADSs under the terms of the deposit agreement, or for any special, consequential
or punitive damages for any breach of the terms of the deposit agreement; |
• |
have no obligation to become involved in a lawsuit or other proceeding related to
our ADSs or the deposit agreement on your behalf or on behalf of any other person; |
• |
are not liable for the acts or omissions of any securities depository, clearing agency
or settlement system; |
• |
may rely upon any documents we believe or it believes in good faith to be genuine
and to have been signed or presented by the proper person; and |
• |
the depositary has no duty to make any determinations or provide any information as
to our status, or any liability for any tax consequences that may be incurred by ADS holders as a result of owning or holding ADSs or
liable for the inability or failure of an ADS holder to obtain the benefit of a foreign tax credit reduced rate of withholdings or refund
of amounts withheld in respect of tax or any other tax benefit. |
In the deposit agreement, we and
the depositary agree to indemnify each other under certain circumstances.
Requirements for Depositary Actions
Before the depositary will deliver
or register a transfer of ADSs, make a distribution on ADSs, or permit withdrawal of shares, the depositary may require:
• |
payment of stock transfer or other taxes or other governmental charges and transfer
or registration fees charged by third parties for the transfer of any ordinary shares or other deposited securities; |
• |
satisfactory proof of the identity and genuineness of any signature or other information
it deems necessary; and |
• |
compliance with regulations it may establish, from time to time, consistent with the
deposit agreement, including presentation of transfer documents. |
The depositary may refuse to deliver
ADSs or register transfers of ADSs when the transfer books of the depositary or our transfer books are closed or at any time if the depositary
or we think it advisable to do so.
Your Right to Receive the Ordinary
Shares Underlying your ADSs
ADS holders have the right to cancel
their ADSs and withdraw the underlying ordinary shares at any time except:
• |
when temporary delays arise because: (i) the depositary has closed its transfer
books or we have closed our transfer books; (ii) the transfer of ordinary shares is blocked to permit voting at a shareholders’
meeting; or (iii) we are paying a dividend on our shares; |
• |
when you owe money to pay fees, taxes and similar charges; or |
• |
when it is necessary to prohibit withdrawals in order to comply with any laws or governmental
regulations that apply to ADSs or to the withdrawal of ordinary shares or other deposited securities. |
This right of withdrawal may not be limited by any other
provision of the deposit agreement.
Direct Registration System
In the deposit agreement, all parties
to the deposit agreement acknowledge that the Direct Registration System, or DRS, and Profile Modification System, or Profile, will apply
to our ADSs. DRS is a system administered by DTC that facilitates interchange between registered holding of uncertificated ADSs and holding
of security entitlements in ADSs through DTC and a DTC participant. Profile is a feature of DRS that allows a DTC participant, claiming
to act on behalf of a registered holder of uncertificated ADSs, to direct the depositary to register a transfer of those ADSs to DTC or
its nominee and to deliver those ADSs to the DTC account of that DTC participant without receipt by the depositary of prior authorization
from the ADS holder to register that transfer.
In connection with and in accordance
with the arrangements and procedures relating to DRS/Profile, the parties to the deposit agreement understand that the depositary will
not determine whether the DTC participant that is claiming to be acting on behalf of an ADS holder in requesting registration of transfer
and delivery as described in the paragraph above has the actual authority to act on behalf of the ADS holder (notwithstanding any requirements
under the Uniform Commercial Code). In the deposit agreement, the parties agree that the depositary’s reliance on and compliance
with instructions received by the depositary through the DRS/Profile system and in accordance with the deposit agreement will not constitute
negligence or bad faith on the part of the depositary.
Shareholder Communications; Inspection
of Register of Holders of ADSs
The depositary will make available
for your inspection at its office all communications that it receives from us as a holder of deposited securities that we make generally
available to holders of deposited securities. The depositary will send you copies of those communications or otherwise make those communications
available to you if we ask it to. You have a right to inspect the register of holders of ADSs, but not for the purpose of contacting those
holders about a matter unrelated to our business or our ADSs.
Jury Trial Waiver
The deposit agreement provides that,
to the extent permitted by law, ADS holders waive the right to a jury trial of any claim they may have against us or the depositary arising
out of or relating to our shares, our ADSs or the deposit agreement, including any claim under the U.S. federal securities laws. If we
or the depositary opposed a jury trial demand based on the waiver, the court would determine whether the waiver was enforceable in the
facts and circumstances of that case in accordance with applicable case law.
PART II
Item 13.
Defaults, Dividend Arrearages and Delinquencies
None.
Item 14.
Material Modifications to the Rights of Security Holders and Use of Proceeds
None.
Item 15.
Controls and Procedures
Disclosure Controls
and Procedures
We have evaluated, with the participation
of our chief executive officer and chief financial officer, the effectiveness of our disclosure controls and procedures (as that term
is defined in Rule 13a-15(e) and 15d-15(e) under the Exchange Act) as of December 31, 2024. There are inherent limitations to the effectiveness
of any system of disclosure controls and procedures, including the possibility of human error and the circumvention or overriding of the
controls and procedures. Accordingly, even effective disclosure controls and procedures can only provide reasonable assurance of achieving
their control objectives. Based upon our evaluation, our chief executive officer and chief financial officer concluded that our disclosure
controls and procedures were effective as of December 31, 2024 to provide reasonable assurance that information required to be disclosed
by us in the reports that we file or submit under the Exchange Act is recorded, processed, summarized and reported, within the time periods
specified in the applicable rules and forms, and that it is accumulated and communicated to our management, including our chief executive
officer and chief financial officer, as appropriate to allow timely decisions regarding required disclosure.
Management’s
Annual Report on Internal Control over Financial Reporting
Our management is responsible for
establishing and maintaining adequate internal control over our financial reporting. Internal control over financial reporting is defined
in Rules 13a-15(f) and 15d-15(f) promulgated under the Exchange Act as a process designed by, or under the supervision
of, our principal executive and principal financial officers and effected by our board of directors, management and other personnel to
provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external
purposes in accordance with GAAP and includes those policies and procedures that:
• |
pertain to the maintenance of records that in reasonable detail accurately and fairly reflect the transactions
and dispositions of our assets; |
• |
provide reasonable assurance that transactions are recorded as necessary to permit preparation
of financial statements in accordance with GAAP, and that our receipts and expenditures are being made only in accordance with authorizations
of our management; and |
• |
provide reasonable assurance regarding prevention or timely detection of unauthorized
acquisition, use or disposition of our assets that could have a material effect on the financial statements. |
Because of its inherent limitations,
internal control over financial reporting may not prevent or detect misstatements. Projections of any evaluation of effectiveness to future
periods are subject to the risks that controls may become inadequate because of changes in conditions or that the degree of compliance
with the policies or procedures may deteriorate.
Our management, including our Chief
Executive Officer and Chief Financial Officer, assessed the effectiveness of our internal control over financial reporting at December 31,
2024. In making this assessment, management used the criteria set forth by the Committee of Sponsoring Organizations of the Treadway Commission
(COSO) in Internal Control—Integrated Framework (2013). Based on that assessment under those criteria, management determined that,
as of December 31, 2024, our internal control over financial reporting was effective.
Attestation Report
of the Registered Public Accounting Firm
Our independent registered public
accounting firm, Somekh Chaikin, a member firm of KPMG International, has audited the consolidated financial statements included in this
annual report on Form 20-F, This Annual Report on Form 20-F does not include an attestation report of our registered public accounting
firm regarding internal control over financial reporting. Management’s report was not subject to attestation by the Company’s
registered public accounting firm pursuant to the exemption provided to issuers that are not “large accelerated filers” or
“accelerated filers” under the Dodd-Frank Wall Street Reform and Consumer Protection Act.
Changes in Internal
Control over Financial Reporting
There were no changes in our internal
control over financial reporting (as such term is defined in Rules 13a-15(f) and 15d-15(f) under the Exchange Act) that occurred
during the period covered by this annual report that have materially affected, or that are reasonably likely to materially affect, our
internal control over financial reporting.
Item 16.
[Reserved]
Item 16A.
Audit Committee Financial Expert
The members of the audit committee
are Jill Quigley, Alan Moses and Claude Nicaise. Claude Nicaise is the chairperson of the audit committee and is a financial expert under
the rules of the SEC. Our board of directors has concluded that the composition of the audit committee meets the requirements for independence
under the rules and regulations of Nasdaq and the SEC.
Item 16B.
Code of Ethics
We have adopted a Code of Business
Conduct and Ethics that includes provisions ranging from restrictions on gifts to conflicts of interest. All of our employees and directors
are bound by this Code of Business Conduct and Ethics. Violations of our Code of Business Conduct and Ethics may be reported to the audit
committee. The Code of Business Conduct and Ethics includes provisions applicable to all of our employees, including senior financial
officers and members of our board of directors and is posted on our website. We intend to post amendments to or waivers from any such
Code of Business Conduct and Ethics.
We granted no waivers under our Code
of Ethics and Conduct in 2024.
Item 16C.
Principal Accountant Fees and Services
Somekh Chaikin, a member firm of
KPMG International, located in Tel Aviv, Israel, PCAOB ID 1057, has served as our independent registered public accounting firm for the
years 2024, 2023 and 2022. The following table sets forth fees billed to us by our independent registered public accounting firm during
the fiscal years ended December 31, 2024, 2023 and 2022 for (i) services rendered for the audit of our annual financial statements and
the review of our quarterly financial statements; (ii) services by our independent registered public accounting firm that are reasonably
related to the performance of the audit or review of our financial statements and that are not reported as audit fees; (iii) services
rendered during the period in connection with tax compliance, tax advice and tax planning; and (iv) all other fees for services rendered.
|
|
Year ended December 31, |
|
|
|
2024 |
|
|
2023 |
|
|
2022 |
|
|
|
(in thousands) |
|
Audit Fees |
|
$ |
180 |
|
|
$ |
233 |
|
|
$ |
223 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Audit-Related Fees |
|
|
- |
|
|
|
- |
|
|
|
- |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Tax Fees |
|
|
5 |
|
|
|
4 |
|
|
|
30 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
All Other Fees |
|
|
|
- |
|
|
- |
|
|
|
- |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Total |
|
$ |
185 |
|
|
$ |
237 |
|
|
$ |
253 |
|
Audit Fees
Audit fees for the years ended December
31, 2024, 2023 and 2022 consisted of fees for professional services provided in connection with the audit of our annual consolidated financial
statements and audit services that are normally provided by an independent registered public accounting firm in connection with statutory
and regulatory filings or engagements for those years.
Tax Fees
Tax fees for the years ended December
31, 2024, and 2023 refer to professional services rendered by our auditors, which include ongoing tax advisory, tax compliance and tax
consulting associated with transfer pricing.
Pre-Approval Policies and Procedures
Our audit committee has the sole
authority to approve the scope of the audit and any audit-related services, as well as all audit fees and terms. The audit committee must
pre-approve any audit and non-audit services provided by our independent registered public accounting firm. The audit committee will not
approve the engagement of the independent registered public accounting firm to perform any services that the independent registered public
accounting firm would be prohibited from providing under applicable laws, rules and regulations, including those of self-regulating organizations.
The audit committee will approve permitted non-audit services by our independent registered public accounting firm only if it determines
that using a different firm to perform such services will be less efficient or cost-effective. The audit committee reviews and pre-approves
the statutory audit fees that can be provided by the independent registered public accounting firm on an annual basis.
Item 16D.
Exemptions from the Listing Standards for Audit Committees
Not applicable.
Item 16E.
Purchases of Equity Securities by the Issuer and Affiliated Purchasers
None.
Item 16F.
Change in Registrant’s Certifying Accountant
None.
Item 16G.
Corporate Governance
As an Israeli company, we are subject
to various corporate governance requirements under the Companies Law, relating to matters such as external directors, the audit committee,
the compensation committee and an internal auditor.
We are a “foreign private issuer”,
as such term is defined in Rule 405 under the Securities Act. As a foreign private issuer we will be permitted to comply with Israeli
corporate governance practices instead of the certain listing rules of Nasdaq, provided that we disclose which requirements we are not
following and the equivalent Israeli requirements.
We rely on this “foreign private issuer exemption”
with respect to the following:
(i) Quorum
for Shareholder Meetings. Whereas under the corporate governance rules of Nasdaq, a quorum requires the presence, in person or by proxy,
of holders of at least 33 1/3% of the total issued and outstanding voting power of our shares at each general meeting of shareholders,
pursuant to the Articles, and as permitted under the Companies Law, the quorum required for a general meeting of shareholders will consist
of at least two shareholders present in person or by proxy in accordance with the Companies Law who hold or represent at least 33 1/3%
of the total outstanding voting power of our shares, except if (i) any such general meeting of shareholders was initiated by and convened
pursuant to a resolution adopted by the board of directors and (ii) at the time of such general meeting, we qualify as a “foreign
private issuer,” then in such case, the requisite quorum will consist of two or more shareholders present in person or by proxy
who hold or represent at least 25% of the total outstanding voting power of our shares (and if the meeting is adjourned for a lack of
quorum, the quorum for such adjourned meeting will be, subject to certain exceptions, any number of shareholders).
(ii)
Shareholder approval. We do not intend to follow Nasdaq Stock Market rules which require shareholder approval in order to enter into any
transaction, other than a public offering, involving the sale, issuance or potential issuance by the Company of ordinary shares (or securities
convertible into or exercisable for ordinary shares) equal to 20% or more of the outstanding share capital of the Company or 20% or more
of the voting power outstanding before the issuance for less than the greater of book or market value of the ordinary shares. We will
follow Israeli law with respect to any requirement to obtain shareholder approval in connection with any private placements of equity
securities.
(iii)
Adoption or Amendment of Equity-Based Compensation Plans. We have elected to follow Israeli corporate governance practice instead of the
Nasdaq Listing Rule 5635(c), which requires listed issuers to obtain shareholder approval for the establishment or material amendment
of certain equity-based compensation plans and arrangements. Under Israeli law and practice, in general, the approval of the board of
directors is required for the establishment or amendment of equity-based compensation plans and arrangements.
We otherwise comply with and intend
to continue to comply with the rules generally applicable to U.S. domestic companies listed on the Nasdaq Capital Market. We may in the
future, however, decide to use other foreign private issuer exemptions with respect to some or all of the Listing Rules of the Nasdaq
Stock Market. Following our home country governance practices may provide less protection than is accorded to investors under the Listing
Rules of the Nasdaq Stock Market applicable to domestic issuers.
Item 16H.
Mine Safety Disclosure
Not applicable.
Item 16I.
Disclosure Regarding Foreign Jurisdictions that Prevent Inspections
Not applicable.