This prospectus supplement updates, amends and
supplements the prospectus dated December 8, 2021 (as supplemented or amended from time to time, the “Prospectus”), which
forms a part of our Registration Statement on Form F-1 (Registration No. 333-260338). Capitalized terms used in this prospectus supplement
and not otherwise defined herein have the meanings specified in the Prospectus.
This prospectus supplement is being filed to
update, amend and supplement the information included in the Prospectus with the information contained in our Annual Report on Form 20-F
filed with the Securities and Exchange Commission (the “SEC”) on April 14, 2022, which is set forth below.
This prospectus supplement is not complete without
the Prospectus. This prospectus supplement should be read in conjunction with the Prospectus, which is to be delivered with this prospectus
supplement, and is qualified by reference thereto, except to the extent that the information in this prospectus supplement updates or
supersedes the information contained in the Prospectus. Please keep this prospectus supplement with your Prospectus for future reference.
Our ordinary shares and warrants are listed on
the Nasdaq Stock Market LLC under the trading symbols “NRSN” and “NRSNW,” respectively. On April 13, 2022, the
closing prices for our ordinary shares and warrants on the Nasdaq Stock Market LLC were $2.185 per ordinary share and $0.51 per warrant.
The date of this prospectus supplement is April 14, 2022.
Securities registered or to be registered pursuant
to Section 12(g) of the Act.
Securities for which there
is a reporting obligation pursuant to Section 15(d) of the Act.
Indicate
the number of outstanding shares of each of the issuer’s classes of capital or common stock as of the close of the period covered
by the annual report: 10,943,534 ordinary shares, no par value
Indicate
by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.
If
this report is an annual or transition report, indicate by check mark if the registrant is not required to file reports pursuant to Section
13 or 15(d) of the Securities Exchange Act of 1934.
Note
— Checking the box above will not relieve any registrant required to file reports pursuant to Section 13 or 15(d) of the Securities
Exchange Act of 1934 from their obligations under those Sections.
Indicate
by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange
Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2)
has been subject to such filing requirements for the past 90 days.
Indicate
by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data
File required to be submitted and posted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding
12 months (or for such shorter period that the registrant was required to submit and post such files).
Indicate by check mark whether
the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or an emerging growth company. See the definitions
of “large accelerated filer,” “accelerated filer,” and “emerging growth company” in Rule 12b-2 of
the Exchange Act.
If an emerging growth company
that prepares its financial statements in accordance with U.S. GAAP, indicate by check mark if the registrant has elected not to use the
extended transition period for complying with any new or revised financial accounting standards† provided pursuant to Section 13(a)
of the Exchange Act. ☐
† The term “new
or revised financial accounting standard” refers to any update issued by the Financial Accounting Standards Board to its Accounting
Standards Codification after April 5, 2012.
Indicate by check mark
whether the registrant has filed a report on and attestation to its management's assessment of the effectiveness of its internal control
over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that
prepared or issued its audit report. ☐
Indicate
by check mark which basis of accounting the registrant has used to prepare the financial statements included in this filing:
If
“Other” has been checked in response to the previous question, indicate by check mark which financial statement item the registrant
has elected to follow. N/A
If
this is an annual report, indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act).
(APPLICABLE ONLY TO ISSUERS
INVOLVED IN BANKRUPTCY PROCEEDINGS DURING THE PAST FIVE YEARS)
Indicate
by check mark whether the registrant has filed all documents and reports required to be filed by Sections 12, 13 or 15(d) of the Securities
Exchange Act of 1934 subsequent to the distribution of securities under a plan confirmed by a court. N/A
Summary of Risk Factors
The following is a summary of certain important factors that may make
an investment in our Company speculative or risky. You should carefully consider the full risk factor disclosure set forth below, in addition
to the other information herein, including the section of this report titled “Operating and Financial Review and Prospects”
and our financial statements and related notes.
| ● | We have a limited operating history and have incurred significant
losses and negative cash flows since our inception, and we anticipate that we will continue to incur significant losses and negative
cash flows for the foreseeable future, which makes it difficult to assess our future viability. |
| ● | We will require substantial additional financing to achieve our
goals, and a failure to obtain this capital when needed and on acceptable terms, or at all, could force us to delay, limit, reduce or
terminate our product development, commercialization efforts or other operations. |
| ● | Raising additional capital may cause dilution to our shareholders,
restrict our operations or require us to relinquish rights to our technologies or product candidates. |
| ● | We are dependent on the success of our lead product candidate, PrimeC, including obtaining regulatory approval to market PrimeC in
the United States. |
| ● | We may be unable to obtain regulatory approval for our product
candidates. |
| ● | To date, we have only generated limited clinical data for our
product candidates. |
| ● | We have limited experience in conducting clinical trials and
have never obtained approval for any product candidates, and may be unable to do so successfully. |
| ● | We have not applied for regulatory approvals to market any of
our other product candidates, and we may be delayed in obtaining or failing to obtain such regulatory approvals and to commercialize
our product candidates. |
| ● | We may not be able to advance our preclinical product candidates
into clinical development and through regulatory approval and commercialization. |
| ● | Clinical drug development involves a lengthy and expensive process
with an uncertain outcome, results of earlier studies and trials may not be predictive of future trial results, and our clinical trials
may fail to adequately demonstrate the safety and efficacy of our product candidates. |
| ● | PrimeC or any of our other product candidates may produce undesirable
side effects that we may not have detected in our previous preclinical studies and clinical trials. This could prevent us from gaining
marketing approval or market acceptance for these product candidates, or from maintaining such approval and acceptance, and could substantially
increase commercialization costs and even force us to cease operations. |
| ● | Our product candidates, if approved, will face significant competition
with competing technologies and our failure to compete effectively may prevent us from achieving significant market penetration. |
| ● | We may enter into collaborations with third parties for the development
or commercialization of our product candidates. If our collaborations are not successful, we may not be able to capitalize on the market
potential of these product candidates. |
| ● | If we fail to manage our growth effectively, our business could
be disrupted. |
| ● | If we fail to attract and keep senior management and key scientific
personnel, we may be unable to successfully develop our product candidates, conduct our clinical trials and commercialize any of the
products we develop. |
| ● | If our efforts to obtain, protect or enforce our patents and
other intellectual property rights related to our product candidates and technologies are not adequate, we may not be able to compete
effectively in our market and we otherwise may be harmed. |
| ● | We may be subject to claims that we infringe, misappropriate
or otherwise violate the intellectual property rights of third parties. |
| ● | We may receive only limited protection, or no protection, from
our issued patents and patent applications. |
| ● | If we are unable to protect the confidentiality of our trade
secrets, our business and competitive position would be harmed. |
| ● | We may not be able to protect our intellectual property rights
throughout the world. |
| ● | We may become involved in lawsuits to protect or enforce our
patents or other intellectual property, which could be expensive and time consuming, delay or prevent the development and commercialization
of our products and product candidates or put our patents and other proprietary rights at risk. |
| ● | An active, liquid and orderly trading market for our ordinary
shares or Warrants may not develop, which may inhibit the ability of our shareholders to sell ordinary shares and Warrants. |
| ● | The market price of our ordinary shares and Warrants may be subject
to fluctuation and you could lose all or part of your investment. |
| ● | If equity research analysts do not publish research or reports
about our business or if they issue unfavorable commentary or downgrade our ordinary shares and Warrants, the price of our ordinary shares
and Warrants could decline. |
| ● | Future sales of our ordinary shares could reduce the market price
of our ordinary shares and Warrants. |
| ● | The significant share ownership position of our officers, directors
and entities affiliated with certain of our directors may limit your ability to influence corporate matters. |
| ● | We have never paid cash dividends on our share capital, and we do not anticipate paying any cash dividends in the foreseeable future. |
| ● | Provisions of Israeli law and our amended and restated articles
of association may delay, prevent or otherwise impede a merger with, or an acquisition of, us, even when the terms of such a transaction
are favorable to us and our shareholders. |
| ● | Your rights and responsibilities as a shareholder will be governed
by Israeli law, which differs in some material respects from the rights and responsibilities of shareholders of U.S. companies. |
Risks Related to Our Limited Operating History, Financial Condition
and Capital Requirements
We have a limited operating history and have incurred significant
losses and negative cash flows since our inception, and we anticipate that we will continue to incur significant losses and negative cash
flows for the foreseeable future, which makes it difficult to assess our future viability.
We are a clinical-stage drug development company
with a limited operating history upon which you can evaluate our business and prospects. We are not profitable and have incurred net losses
in each period since we commenced operations in February 2017, including net losses of $4.04 million and $2.83 million for the
years ended December 31, 2021 and 2020, respectively. We expect to continue to incur significant expenses and increasing operating
losses for the foreseeable future. Our ability to ultimately achieve recurring revenues and profitability is dependent upon our ability
to successfully complete the development of our product candidates, obtain necessary regulatory approvals for and successfully manufacture,
market and commercialize our products.
We believe that we will continue to expend substantial
resources in the foreseeable future for the clinical development of our current product candidates or any additional product candidates
and indications that we may choose to pursue in the future. These expenditures will include costs associated with research and development,
conducting preclinical studies and clinical trials, and payments for third-party manufacturing and supply, as well as sales and marketing
of any of our product candidates that are approved for sale by regulatory agencies. Because the outcome of any clinical trial is highly
uncertain, we cannot reasonably estimate the actual amounts necessary to successfully complete the development and commercialization of
our clinical stage and preclinical drug candidates and any other drug candidates that we may develop in the future. Other unanticipated
costs may also arise.
Our future capital requirements depend on many factors,
including:
| ● | the timing of, and the costs involved in, clinical development
and obtaining regulatory approvals for our product candidates; |
| ● | changes in regulatory requirements during the development
phase that can delay or force us to stop our activities related to any of our product candidates; |
| ● | the cost of commercialization activities if our products
are approved for sale, including marketing, sales and distribution costs; |
| ● | the cost of third-party manufacturing of our products; |
| ● | the number and characteristics of any other product candidates
we develop or acquire; |
| ● | our ability to establish and maintain strategic collaborations,
licensing or other commercialization arrangements, and the terms and timing of such arrangements; |
| ● | the extent and rate of market acceptance of any approved
products; |
| ● | the expenses needed to attract and retain skilled personnel; |
| ● | the costs associated with being a public company; |
| ● | the costs involved in preparing, filing, prosecuting, maintaining,
defending and enforcing patent claims, including potential litigation costs and the outcome of such litigation; |
| ● | the timing, receipt and amount of sales of, or royalties
on, future approved products, if any; |
| ● | any product liability or other lawsuits related to our products; |
| ● | scientific breakthroughs in the field of treatment for neurodegenerative
diseases that could significantly diminish the need for our product candidates or make them obsolete; and |
| ● | changes in reimbursement policies that could have a negative
impact on our future revenue stream. |
In addition, we have limited experience and have
not yet demonstrated an ability to successfully overcome many of the risks and uncertainties frequently encountered by companies in new
and rapidly evolving fields, particularly in the biopharmaceutical industry. Drug development is a highly speculative undertaking and
involves a substantial degree of risk. To date, we have not obtained any regulatory approvals for any of our product candidates, commercialized
any of our product candidates or generated any material revenue.
We will require substantial additional financing to achieve our
goals, and a failure to obtain this capital when needed and on acceptable terms, or at all, could force us to delay, limit, reduce or
terminate our product development, commercialization efforts or other operations.
Since our inception, almost all of our resources
have been dedicated to the preclinical and clinical development of our lead product candidate, PrimeC. As of December 31, 2021, we
had cash and cash equivalents of $11.06 million.
We believe that our existing cash and cash equivalents
will be sufficient to fund our operations for a period of at least 12 months from the date of approval of our financial statements.
We expect that we will require additional capital to complete clinical trials, obtain regulatory approval for and commercialize our product
candidates. In addition, our operating plan may change as a result of many factors currently unknown to us, and we may need to seek additional
funds sooner than planned, through public or private equity, convertible debt or debt financings, third-party funding, marketing
and distribution arrangements, as well as other collaborations, strategic alliances and licensing arrangements, or a combination of these
approaches. In any event, we will require additional capital to pursue preclinical and clinical activities, and pursue regulatory approval
for, and to commercialize, our pipeline product candidates. Even if we believe that we have sufficient funds for our current or future
operating plans, we may seek additional capital if market conditions are favorable or if we have specific strategic considerations.
Any additional fundraising efforts may divert the
attention of our management from day-to-day activities, which may adversely affect our ability to develop and commercialize our product
candidates. In addition, we cannot guarantee that future financing will be available in sufficient amounts or on terms acceptable to us,
if at all. Moreover, the terms of any financing may negatively impact the holdings or the rights of our shareholders, and the issuance
of additional securities, whether equity or debt, by us or the possibility of such issuance may cause the market price of our ordinary
shares and Warrants to decline. The incurrence of indebtedness could result in increased fixed payment obligations and we may be required
to agree to certain restrictive covenants, such as limitations on our ability to incur additional debt, limitations on our ability to
acquire, sell or license intellectual property rights and other operating restrictions that could adversely impact our ability to conduct
our business. We could also be required to seek funds through arrangements with collaborative partners or otherwise at an earlier stage
than would be desirable and we may be required to relinquish rights to some of our technologies, intellectual property or product candidates
or otherwise agree to terms unfavorable to us, any of which may harm our business, financial condition, operating results and prospects.
If adequate funds are not available to us on a timely
basis, we may be required or choose to:
| ● | delay, limit, reduce or terminate preclinical studies, clinical
trials or other development activities for our product candidates or any of our future product candidates; |
| ● | delay, limit, reduce or terminate our other research and
development activities; or |
| ● | delay, limit, reduce or terminate our establishment or expansion
of manufacturing, sales and marketing or distribution capabilities or other activities that may be necessary to commercialize PrimeC
or any of our other product candidates. |
We may also be unable to expand our operations or
otherwise capitalize on our business opportunities, as desired, which could harm our business, financial condition and results of operations.
Raising additional capital may cause dilution to our shareholders,
restrict our operations or require us to relinquish rights to our technologies or product candidates.
Until such time, if ever, as we can generate substantial
product revenues, we expect to finance our cash needs through equity, convertible debt or debt financings, as well as selectively continuing
to enter into collaborations, strategic alliances and licensing arrangements. We do not currently have any committed external source of
funds. To the extent that we raise additional capital through the sale of equity or convertible debt securities, your ownership interest
will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect your rights as an
ordinary shareholder. Debt 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 and distributing dividends, and
may be secured by all or a portion of our assets.
If we raise funds by entering into collaborations,
strategic alliances or licensing arrangements with third parties, we may have to relinquish additional valuable rights to our technologies,
future revenue streams, research programs or product candidates or to grant licenses on terms that may not be favorable to us. If we are
unable to raise additional funds through equity, convertible debt or debt financings when needed, we may be required to delay, limit,
reduce or terminate our product development or future commercialization efforts or grant rights to develop and market product candidates
that we would otherwise prefer to develop and market ourselves. If we are unable to raise additional funds through collaborations, strategic
alliances or licensing arrangements, we may be required to terminate product development or future commercialization efforts or to cease
operations altogether.
Risks Related to Our Business and Strategy
We are dependent on the success of our lead product candidate,
PrimeC, including obtaining regulatory approval to market PrimeC in the United States.
We have invested almost all of our efforts and financial
resources in the research and development of our lead product candidate, PrimeC. Our future success depends on our ability to develop,
commercialize, market and sell PrimeC and our other product candidates. However, our product candidates are in various stages of preclinical
and clinical development and each of them has yet to receive marketing approval from the U.S. Food and Drug Administration, or the FDA,
or any other regulatory agency. Our product candidate’s marketability is subject to significant risks associated with successfully
completing current and future clinical trials, including:
| ● | the FDA’s timely acceptance of our IND filing for PrimeC
and our other product candidates for which we plan to file an IND. Without such IND acceptances, we will be unable to commence clinical
trials in the United States; |
| ● | the FDA’s acceptance of our parameters for regulatory
approval relating to PrimeC and our other product candidates, including our proposed indications, primary and secondary endpoint assessments
and measurements, safety evaluations, CMC activities and regulatory pathways; |
| ● | the FDA’s acceptance of the number, design, size, conduct
and implementation of our clinical trials, our trial protocols and the interpretation of data from preclinical studies or clinical trials; |
| ● | our ability to successfully complete the clinical trials
of our product candidates, including timely patient enrollment and acceptable safety and efficacy data and our ability to demonstrate
the safety and efficacy of the product candidates undergoing such clinical trials; |
| ● | our ability to complete in a timely fashion the PrimeC pivotal
trial, and that the single pivotal trial, even if successfully completed, will be sufficient to support a New Drug Application, or NDA,
submission; |
| ● | the FDA’s acceptance of the sufficiency of the data
we collected from our preclinical studies and Phase IIa NST002 clinical trial and will collect ahead of initiating a pivotal Phase III
trial, and our ability to commence a pivotal Phase III clinical trial in the United States for PrimeC following an IND submission, if
accepted; |
| ● | the FDA’s willingness to schedule an advisory committee
meeting in a timely manner to evaluate and decide on the approval of our potential future NDA for PrimeC; |
| ● | the recommendation of the FDA’s advisory committee
to approve our applications to market PrimeC and our other product candidates in the United States, without limiting the approved labeling,
specifications, distribution or use of the products, or imposing other restrictions; |
| ● | the FDA’s satisfaction with the safety, quality and
efficacy of our product candidates; |
| ● | the prevalence and severity of adverse events associated
with our product candidates; |
| ● | the timely and satisfactory performance by third-party contractors
of their obligations in relation to our clinical trials; |
| ● | our success in educating physicians and patients about the
benefits, administration and use of our product candidates, if approved, particularly in light of the fact that there is a limited number
of currently available and approved treatment options for Amyotrophic Lateral Sclerosis, or ALS; |
| ● | the availability, perceived advantages, relative cost, safety
and efficacy of alternative and competing treatments for the indications addressed by our product candidates; |
| ● | the effectiveness of our marketing, sales and distribution
strategy, and operations, as well as that of any current and future licensees; and |
| ● | our ability to obtain, protect and enforce our intellectual
property rights with respect to our product candidates. |
Many of these clinical, regulatory and commercial
risks are beyond our control. Accordingly, we cannot assure you that we will be able to advance any of our product candidates through
clinical development, or to obtain regulatory approval of or commercialize any of our product candidates. If we fail to achieve these
objectives or overcome the challenges presented above, we could experience significant delays or an inability to successfully commercialize
our product candidates. Accordingly, we may not be able to generate sufficient revenues through the sale of our product candidates to
enable us to continue our business.
We may be unable to obtain regulatory approval for our product
candidates.
The research, development, testing, manufacturing,
labeling, packaging, approval, promotion, advertising, storage, recordkeeping, marketing, distribution, post-approval monitoring
and reporting, and export and import of drug products are subject to extensive regulation by the FDA, and by foreign regulatory authorities
in other countries. These regulations differ from country to country. To gain approval to market our product candidates, we must provide
clinical data that adequately demonstrate the safety and efficacy of the product for the intended indication. We have not yet obtained
regulatory approval to market any of our product candidates in the United States or any other country.
Our business depends upon obtaining these regulatory approvals. There
are currently a limited number of alternative drugs approved by the FDA for the treatment of ALS. The FDA can delay, limit or deny approval
of our product candidates for many reasons, including:
| ● | our inability to satisfactorily demonstrate that the product
candidates are safe and effective for the target indication; |
| ● | the FDA’s disagreement with our trial protocol, the
interpretation of data from preclinical studies or clinical trials, or adequate conduct and control of clinical trials; |
| ● | the population studied in the clinical trial may not be sufficiently
broad or representative to assess safety in the patient population for which we seek approval; |
| ● | our inability to demonstrate that clinical or other benefits
of our product candidates outweigh any safety or other perceived risks; |
| ● | the FDA’s determination that the 505(b)(2) regulatory
pathway is not available for our product candidates; |
| ● | the FDA’s determination that additional preclinical
studies or clinical trials are required; |
| ● | the FDA’s non-approval of the formulation, labeling
or the specifications of our product candidates; |
| ● | the FDA’s failure to accept the manufacturing processes
or facilities of third-party manufacturers with which we contract; |
| ● | the potential for approval policies or regulations of the
FDA to significantly change in a manner rendering our clinical data insufficient for approval; or |
| ● | resistance to approval from the FDA’s advisory committee
for any reason including safety or efficacy concerns. |
Even if we eventually complete clinical testing
and receive approval of any regulatory filing for our product candidates, the FDA may grant approval contingent on the performance of
costly and potentially time-consuming additional post-approval clinical trials or subject to restrictive Risk Evaluation and
Mitigation Strategies. The FDA may also approve our product candidates for a more limited indication or a narrower patient population
than we originally requested, and the FDA may not approve the labeling that we believe is necessary or desirable for the successful commercialization
of our product candidates. To the extent we seek regulatory approval in foreign countries, we may face challenges similar to those described
above with regulatory authorities in applicable jurisdictions. Any delay in obtaining, or inability to obtain, applicable regulatory approval
for any of our product candidates would delay or prevent commercialization of our product candidates and would thus negatively impact
our business, results of operations and prospects.
To date, we have only generated limited clinical data for our
product candidates.
Positive results in preclinical testing and early
clinical trials do not ensure that later clinical trials will be successful. A number of pharmaceutical companies have suffered significant
setbacks in clinical trials, including in Phase III clinical trials, after promising results in preclinical testing and early clinical
trials. These setbacks have included negative safety and efficacy observations in later clinical trials, including previously unreported
adverse effects. For example, our completed Phase IIa NST002 trial of PrimeC involved a limited number of 15 patients. If our clinical
trials do not ultimately indicate that our product candidates are safe or efficacious for their intended application, the FDA may not
approve any NDA that we may file to market such product candidates, and our business would not be able to generate revenue from the sale
of any such product candidates.
We have limited experience in conducting clinical trials and
have never obtained approval for any product candidates, and may be unable to do so successfully.
As a company, we have limited experience in conducting clinical trials
and have never progressed a product candidate through to regulatory approval. In part because of this lack of experience, our clinical
trials may require more time and incur greater costs than we anticipate. We cannot be certain that our planned clinical trials will begin
or conclude on time, if at all. Large-scale trials will require significant additional financial and management resources. Third-party clinical
investigators do not operate under our control. Any performance failure on the part of such third parties could delay the clinical development
of our product candidates or delay or prevent us from obtaining regulatory approval or commercializing our current or future product candidates,
depriving us of potential product revenue and resulting in additional losses.
We have not applied for regulatory approvals to market any of
our other product candidates, and we may be delayed in obtaining or failing to obtain such regulatory approvals and to commercialize our
product candidates.
The process of developing, obtaining regulatory
approval for and commercializing our product candidates is long, complex, costly and uncertain, and delays or failure can occur at any
stage. The research, testing, manufacturing, labeling, marketing, sale and distribution of drugs are subject to extensive and rigorous
regulation by the FDA and foreign regulatory agencies, as applicable. These regulations are agency-specific and differ by jurisdiction.
We are not permitted to market any product candidate in the United States until we receive approval of an NDA from the FDA, or in any
foreign countries until we receive the requisite approval from the respective regulatory agencies in such countries. To gain approval
of an NDA or other equivalent regulatory approval, we must provide the FDA or relevant foreign regulatory authority with preclinical and
clinical data that demonstrates the safety and efficacy of the product for the intended indication.
Before we can submit an NDA to the FDA or comparable
applications to foreign regulatory authorities, we must conduct Phase III clinical trials, or a pivotal/registrational trial equivalent,
for each product candidate. Based on the results of our Phase IIa NST002 trial and our discussions with the FDA on potential trial design,
we intend to initiate a pivotal Phase III trial to further evaluate PrimeC in the second half of 2023. Prior to commencing the pivotal
Phase III trial, we expect to initiate three additional studies to further support our future regulatory submissions. First, we plan to
initiate a three-month toxicity study in rats to confirm the safety of PrimeC in high doses, in accordance with the FDA’s expectations.
We also plan to evaluate PrimeC’s extended release, or ER, formulation in a pharmacokinetic, or PK, study to assess the exposure
levels and to ensure the desired PK profile with the potential to demonstrate maximum efficacy in our planned Phase III trial. We have
already initiated the toxicity study and PK study. In addition, we intend execute a Phase IIb trial with PrimeC’s ER formulation
in the first half of 2022 that will evaluate several biomarkers, which we expect will increase our understanding of the changes in the
pathological pathways of ALS and inform the final trial design for our pivotal Phase III trial. We currently expect top-line results
from our Phase IIb trial in the first half of 2023.
Before commencing a clinical trial for PrimeC in
the United States, we must first file an IND, which must be accepted by the FDA. We cannot assure you that the FDA will not decide to
materially alter certain parameters, including potentially requiring a pivotal study with several control arms, during the trial or require
us to conduct more than one pivotal trial before submitting an NDA.
Phase III clinical trials often produce unsatisfactory
results even though prior clinical trials were successful. Moreover, the results of clinical trials may be unsatisfactory to the FDA or
foreign regulatory authorities even if we believe those clinical trials to be successful. The FDA or applicable foreign regulatory agencies
may suspend one or all of our clinical trials or require that we conduct additional clinical, preclinical, manufacturing, validation or
drug product quality studies and submit that data before considering or reconsidering any NDA or comparable foreign regulatory application
that we may submit. Depending on the extent of these additional studies, approval of any applications that we submit may be significantly
delayed or may cause the termination of such programs, or may require us to expend more resources than we have available.
Apart from our clinical development of PrimeC, at
the request of two respected U.S.-based ALS clinicians treating ALS patients (six in total), we have financed the pharmaceutical
compounding for an off-label use of the two FDA-approved drugs that comprise PrimeC for use by these clinicians for their patients.
We provided this funding and the relevant information to the clinicians under a CDA. Since it was prescribed by the clinicians as an off-label use
of two FDA-approved drugs and upon their discretion, it was not discussed with the FDA. The patients have been using these drugs
for periods ranging from 18 to 24 months to date without any reports of drug related significant adverse events. We cannot guarantee
that FDA will agree with our involvement in this compassionate use matter. Information from all clinical use of a drug is required to
be reported to the FDA in connection with an IND. We intend to report this use to the FDA as part of our annual report to the IND. Nevertheless
the FDA could view this use as a deviation from our IND.
If any of these outcomes occur, we may not receive
regulatory approval for the corresponding product candidates, and our business would not be able to generate revenue from the sale of
any such product candidates.
We may not be able to advance our preclinical product candidates
into clinical development and through regulatory approval and commercialization.
Certain of our product candidates are currently
in preclinical development and are therefore currently subject to the risks associated with preclinical development, including the risks
associated with:
| ● | generating adequate and sufficient preclinical safety and
efficacy data in a timely fashion to support the initiation of clinical trials; |
| ● | obtaining regulatory approval to commence clinical trials
in any jurisdiction, including the filing and acceptance of INDs; |
| ● | contracting with the necessary parties to conduct a clinical
trial; |
| ● | enrolling sufficient numbers of patients in clinical trials;
and |
| ● | timely manufacture of sufficient quantities of the product
candidate for use in clinical trials. |
If we are unsuccessful in advancing our preclinical
product candidates into clinical trials in a timely fashion, our business may be harmed. Even if we are successful in advancing our preclinical
product candidates into clinical development, their success will be subject to all of the clinical, regulatory and commercial risks described
elsewhere in “Risk Factors.” Accordingly, we cannot assure you that we will be able to develop, obtain regulatory approval
for, commercialize or generate significant revenue from our product candidates.
Clinical drug development involves a lengthy and expensive process
with an uncertain outcome, results of earlier studies and trials may not be predictive of future trial results, and our clinical trials
may fail to adequately demonstrate the safety and efficacy of our product candidates.
Clinical testing is expensive and can take many
years to complete, and its outcome is inherently uncertain. A failure of one or more of our clinical trials can occur at any time
during the clinical trial process. We do not know whether future clinical trials, if any, will begin on time, need to be redesigned, enroll
an adequate number of patients on time or be completed on schedule, if at all. Clinical trials can be delayed, suspended or terminated
for a variety of reasons, including failure to:
| ● | generate sufficient preclinical, toxicology, or other in
vivo or in vitro data to support the initiation or continuation of clinical trials; |
| ● | obtain regulatory approval, or feedback on trial design,
in order to commence a trial; |
| ● | identify, recruit and train suitable clinical investigators; |
| ● | reach agreement on acceptable terms with prospective contract
research organizations, or CROs, and clinical trial sites, and have such CROs and sites effect the proper and timely conduct of our clinical
trials; |
| ● | obtain and maintain institutional review board, or IRB, approval
at each clinical trial site; |
| ● | identify, recruit and enroll suitable patients to participate
in a trial; |
| ● | have a sufficient number of patients complete a trial or
return for post-treatment follow-up; |
| ● | ensure clinical investigators and clinical trial sites observe
trial protocol or continue to participate in a trial; |
| ● | address any patient safety concerns that arise during the
course of a trial; |
| ● | address any conflicts with new or existing laws or regulations; |
| ● | add a sufficient number of clinical trial sites; |
| ● | manufacture sufficient quantities at the required quality
of product candidate for use in clinical trials; or |
| ● | raise sufficient capital to fund a trial. |
Patient enrollment is a significant factor in the
timing and success of clinical trials and is affected by many factors, including the size and nature of the patient population, the proximity
of patients to clinical sites, the eligibility criteria for the trial, the design of the clinical trial, competing clinical trials and
clinicians’ and patients’ or caregivers’ perceptions as to the potential advantages of the drug candidate being studied
in relation to other available therapies, including any new drugs or treatments that may be developed or approved for the indications
we are investigating.
We may also encounter delays if a clinical trial
is suspended or terminated by us, by the IRBs of the institutions in which such trials are being conducted, by the trial’s data
safety monitoring board, by the FDA or by the applicable foreign regulatory authorities. Such authorities may suspend or terminate one
or more of our clinical trials due to a number of factors, including our failure to conduct the clinical trial in accordance with relevant
regulatory requirements or clinical protocols, inspection of the clinical trial operations or trial site by the FDA or foreign regulatory
authorities resulting in the imposition of a clinical hold, unforeseen safety issues or adverse side effects, failure to demonstrate a
benefit from using a drug, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical
trial.
In addition, disruptions caused by the COVID-19 pandemic
may increase the likelihood that we encounter such difficulties or delays in initiating, enrolling, conducting or completing our planned
and ongoing preclinical studies and clinical trials, as applicable. For example, on March 18, 2020, the FDA announced its intention
to temporarily postpone routine surveillance inspections of domestic manufacturing facilities in response to the COVID-19 pandemic.
If global health concerns continue to prevent the FDA or other regulatory authorities from conducting their regular inspections, reviews
or other regulatory activities, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions.
If we experience delays in the initiation, enrollment or completion of any preclinical study or clinical trial of our product candidates,
or if any preclinical studies or clinical trials of our product candidates are cancelled, the commercial prospects of our product candidates
may be materially adversely affected, and our ability to generate product revenues from any of these product candidates will be delayed
or not realized at all. In addition, any delays in completing our clinical trials may increase our costs and slow down our product candidate
development and approval process.
If we experience delays in carrying out or completing
any clinical trial of our product candidates, the commercial prospects of our product candidates may be harmed, and our ability to generate
product revenues from any of these product candidates will be delayed. In addition, any delays in completing our clinical trials will
increase our costs, slow down our product candidate development and approval process and jeopardize our ability to commence product sales
and generate revenues. Any of these occurrences may significantly harm our business and financial condition. In addition, many of the
factors that cause, or lead to, a delay in the commencement or completion of clinical trials may also ultimately lead to the denial of
regulatory approval of our product candidates.
The continuing outbreak of COVID-19 around the world may adversely
affect our business and that of our suppliers, CROs or other third parties relevant to our business.
The COVID-19 pandemic is impacting worldwide
economic activity, particularly economic activity in the United States, and poses the risk that we or our employees, contractors, suppliers,
or other partners may be prevented or delayed from conducting business activities for an indefinite period of time, including due to shutdowns
that may be requested or mandated by governmental authorities. The continued prevalence of COVID-19 and the measures taken by the
governments of countries affected could disrupt our supply chain and manufacturing, cause diversion of healthcare resources away from
the conduct of preclinical and clinical trial matters to focus on pandemic concerns, limit travel in a manner that interrupts key trial
activities, such as trial site initiations and monitoring, delay regulatory filings with regulatory agencies in affected areas or adversely
affect our ability to obtain regulatory approvals. These disruptions could also affect other facets of our business, including but not
limited to:
| ● | our ability to recruit employees from outside of Israel; |
| ● | the ability of our employees to travel; |
| ● | the ability of our CROs to conduct preclinical studies in
foreign countries; |
| ● | our ability to import materials from outside of Israel; and |
| ● | our ability to export materials to our CROs and other third-parties located
outside of Israel. |
The COVID-19 pandemic and mitigation measures
also may have an adverse impact on global economic conditions, which could adversely impact our business, financial condition or results
of operations. Additionally, the COVID-19 pandemic has resulted in significant financial market volatility and uncertainty. A continuation
or worsening of the levels of market disruption and volatility seen in the recent past as a result of the COVID-19 outbreak could
have an adverse effect on our ability to access capital and on the market price of our ordinary shares and Warrants. In March 2020, we
put in place a number of protective measures in response to the COVID-19 pandemic. These measures included cancelling all commercial
business travel, requesting employees to limit non-essential personal travel, asking some employees to self-quarantine at home
and encouraging employees to work from home to the extent their job function enables them to do so. We have revisited these measures on
a regular basis throughout the pandemic and we will continue to do so. Although restrictions imposed by governmental authorities have
begun to ease, if conditions worsen, we may need to implement new restrictive measures that could adversely affect our business.
PrimeC or any of our other product candidates may produce undesirable
side effects that we may not have detected in our previous preclinical studies and clinical trials. This could prevent us from gaining
marketing approval or market acceptance for these product candidates, or from maintaining such approval and acceptance, and could substantially
increase commercialization costs and even force us to cease operations.
As with most pharmaceutical products, use of PrimeC
or our other product candidates may be associated with side effects or adverse events that can vary in severity and frequency. Side effects
or adverse events associated with the use of PrimeC may be observed at any time, including in clinical trials or once a product is commercialized,
and any such side effects or adverse events may negatively affect our ability to obtain regulatory approval or market our product candidates.
We cannot assure you that we will not observe drug-related serious adverse events in the future or that the FDA will not determine
them as such. Side effects such as toxicity or other safety issues associated with the use of our product candidates could require us
to perform additional studies or halt development or sale of these product candidates or expose us to product liability lawsuits, which
will harm our business.
Furthermore, commencing the planned pivotal Phase
III clinical trial for PrimeC will involve a larger patient base than that previously studied, and the commercial marketing of PrimeC,
if approved, will further expand the clinical exposure of the drug to a wider and more diverse group of patients than those participating
in the clinical trials, which may identify undesirable side effects caused by these products that were not previously observed or reported.
The FDA and foreign regulatory agency regulations
require that we report certain information about adverse medical events if our products may have caused or contributed to those adverse
events. The timing of our obligation to report would be triggered by the date upon which we become aware of the adverse event as well
as the nature and severity of the event. We may fail to report adverse events of which we become aware within the prescribed timeframe.
We may also fail to appreciate that we have become aware of a reportable adverse event, especially if it is not reported to us as an adverse
event or if it is an adverse event that is unexpected or removed in time from the use of our products. If we fail to comply with our reporting
obligations, the FDA or a foreign regulatory agency could take action including enforcing a hold on or cessation of clinical trials, withdrawal
of approved drugs from the market, criminal prosecution, the imposition of civil monetary penalties or seizure of our products.
Additionally, in the event we discover the existence
of adverse medical events or side effects caused by one of our product candidates, a number of other potentially significant negative
consequences could result, including:
| ● | our inability to file an NDA or similar application for our
product candidates because of insufficient risk-reward, or the denial of such application by the FDA or foreign regulatory authorities; |
| ● | the FDA or foreign regulatory authorities suspending or withdrawing
their approval of the product; |
| ● | the FDA or foreign regulatory authorities requiring the addition
of labeling statements, such as warnings or contraindications or distribution and use restrictions; |
| ● | the FDA or foreign regulatory authorities requiring us to
issue specific communications to healthcare professionals, such as letters alerting them to new safety information about our product,
changes in dosage or other important information; |
| ● | the FDA or foreign regulatory authorities issuing negative
publicity regarding the affected product, including safety communications; |
| ● | our being limited with respect to the safety-related claims
that we can make in our marketing or promotional materials; |
| ● | our being required to change the way the product is administered,
conduct additional preclinical studies or clinical trials or restrict or cease the distribution or use of the product; and |
| ● | our being sued and held liable for harm caused to patients. |
Any of these events could prevent us from achieving
approval or market acceptance of the affected product candidate and could substantially increase commercialization costs or even force
us to cease operations. We cannot assure you that we will resolve any issues related to any product-related adverse events to the
satisfaction of the FDA or any regulatory agency in a timely manner or ever, which could harm our business, prospects and financial condition.
Even if our product candidates receive marketing approval, we
may continue to face future developmental and regulatory difficulties. In addition, we are subject to government regulations and we may
experience delays in obtaining required regulatory approvals to market our proposed product candidates.
Even if we complete clinical testing and receive
approval of any regulatory filing for our product candidates, the FDA or applicable foreign regulatory agency may grant approval contingent
on the performance of additional costly post-approval clinical trials, risk mitigation requirements and surveillance requirements
to monitor the safety or efficacy of the product, which could negatively impact us by reducing revenues or increasing expenses, and cause
the approved product candidate not to be commercially viable. Absence of long-term safety data may further limit the approved uses
of our products, if any.
The FDA or applicable foreign regulatory agency
also may approve our product candidates for a more limited indication or a narrower patient population than we originally requested, or
may not approve the labeling that we believe is necessary or desirable for the successful commercialization of our product candidates.
Furthermore, any such approved product will remain subject to extensive regulatory requirements, including requirements relating to manufacturing,
labeling, packaging, adverse event reporting, storage, advertising, promotion, distribution and recordkeeping.
If we fail to comply with the regulatory requirements
of the FDA or other applicable foreign regulatory authorities, or previously unknown problems with any approved commercial products, manufacturers
or manufacturing processes are discovered, we could be subject to administrative or judicially imposed sanctions or other setbacks, including
the following:
| ● | suspension or imposition of restrictions on operations, including
costly new manufacturing requirements; |
| ● | regulatory agency refusal to approve pending applications
or supplements to applications; |
| ● | suspension of any ongoing clinical trials; |
| ● | suspension or withdrawal of marketing approval; |
| ● | an injunction or imposition of civil or criminal penalties
or monetary fines; |
| ● | seizure or detention of products; |
| ● | bans or restrictions on imports and exports; |
| ● | issuance of warning letters or untitled letters; |
| ● | suspension or imposition of restrictions on operations, including
costly new manufacturing requirements; or |
| ● | refusal of regulatory authorities to approve pending applications
or supplements to applications. |
In addition, various aspects of our operations are
subject to federal, state or local laws, rules and regulations, any of which may change from time to time. Costs arising out of any regulatory
developments could be time-consuming and expensive and could divert management resources and attention and, consequently, could adversely
affect our business, financial condition and results of operations.
Even if our product candidates receive regulatory approval, they
may fail to achieve the broad degree of physician adoption and use and market acceptance necessary for commercial success.
Even if we obtain FDA or foreign regulatory approvals
for our product candidates, the commercial success of such products will depend significantly on their broad adoption and use by physicians,
for approved indications. The degree and rate of physician and patient adoption of our product candidates, if approved, will depend on
a number of factors, including:
| ● | the clinical indications for which the product is approved; |
| ● | the prevalence and severity of adverse side effects; |
| ● | physicians’ satisfaction with the results shown in
clinical trials |
| ● | patient satisfaction with the results and administration
of our product and overall treatment experience, including relative convenience, ease of use and avoidance of, or reduction in, adverse
side effects; |
| ● | the extent to which physicians recommend our products to
patients; |
| ● | physicians’ and patients’ willingness to adopt
new therapies in lieu of other products or treatments; |
| ● | the cost of treatment, safety and efficacy in relation to
alternative treatments; |
| ● | the extent to which the costs of our product candidates are
reimbursed by third-party payors, and patients’ willingness to pay for our products; |
| ● | the extent to which physicians adopt and prescribe PrimeC,
rather than the two alternative FDA-approved drugs, ciprofloxacin and celecoxib, that we synthesized to create PrimeC; |
| ● | the revenues and profitability that our products will offer
physicians as compared to alternative therapies; and |
| ● | the effectiveness of our sales and marketing efforts. |
If PrimeC or any of our other product candidates
is approved for use, but fails to achieve the broad degree of physician adoption and market acceptance necessary for commercial success,
our operating results and financial condition would be adversely affected.
Our product candidates, if approved, will face significant competition
with competing technologies and our failure to compete effectively may prevent us from achieving significant market penetration.
The biopharmaceutical industry is intensely competitive
and subject to rapid and significant technological change. Our potential competitors include large and experienced companies that enjoy
significant competitive advantages over us, such as greater financial, research and development, manufacturing, personnel and marketing
resources, greater brand recognition and more experience and expertise in obtaining marketing approvals from the FDA and foreign regulatory
authorities. These companies may develop new drugs to treat the indications that we target, or seek to have existing drugs approved for
use for the treatment of the indications that we target.
We are aware that potentially disease modifying
therapeutics for ALS are being developed by several large and specialty pharmaceutical and biotechnology companies and academic institutions,
including Biogen Inc., Amylyx Pharmaceuticals Inc., AB Science SA, Prilenia Therapeutics B.V, and Apellis Pharmaceuticals, in various
stages of clinical trials. In addition, we are aware of several large and specialty pharmaceutical companies, such as Eli Lilly and Company
and Roche (including Genentech Inc., its wholly owned subsidiary), that are developing potentially disease modifying therapeutics for
Alzheimer’s Disease and Parkinson’s Disease. We do not know whether these potential competitors are already developing, or
plan to develop, the same treatments or treatments for other indications that we are pursuing, and we may be unable to ascertain whether
such activities are underway in the future.
Competition may increase further as a result of
advances in the commercial applicability of technologies and greater availability of capital for investment in this industry. Our competitors
may succeed in developing, acquiring or licensing on an exclusive basis products that are more effective or less costly than our product
candidates.
We have no experience in marketing or distributing products and
no internal capability to do so, and are therefore subject to certain risks in relation to the commercialization of our product candidates
once approved.
We have not yet established a commercial organization
for the marketing, sale and distribution of our product candidates. Therefore, even if we receive approval to market our product candidates
in the United States or other markets, in order to successfully commercialize our product candidates, we will need to either build marketing,
sales, distribution, managerial and other non-technical capabilities or contract with third parties to obtain these capabilities.
This involves many challenges, such as recruiting and retaining talented personnel, training employees, setting the appropriate system
of incentives, managing additional headcount and integrating new business units into an existing corporate infrastructure. The development
of our own sales infrastructure or contracting with third parties will involve substantial expense, much of which we will incur well in
advance of any marketing or sales. Moreover, we do not have experience as a company in establishing a significant sales infrastructure,
and we cannot be certain that we will successfully develop this capability or contract successfully with third parties for the necessary
services. We will have to compete with other pharmaceutical and biotechnology companies to recruit, hire, train and retain personnel for
medical affairs, marketing and sales. If we fail to establish an effective sales and marketing infrastructure or contract with third parties
to do so, we will be unable to successfully commercialize our product candidates, which in turn would have an adverse effect on our business,
financial condition and results of operations.
We may enter into collaborations with third parties for the development
or commercialization of our product candidates. If our collaborations are not successful, we may not be able to capitalize on the market
potential of these product candidates.
We may utilize a variety of types of collaboration,
distribution and other marketing arrangements with third parties to develop our product candidates and commercialize our approved product
candidates, if any. We are not currently party to any such arrangement. Our ability to generate revenues from these arrangements will
depend on our collaborators’ abilities and efforts to successfully perform the functions assigned to them in these arrangements.
Any future collaborations that we enter into may
pose a number of risks, including the following:
| ● | collaborators have significant discretion in determining
the amount and timing of efforts and resources that they will apply to these collaborations; |
| ● | collaborators may not perform their obligations as expected; |
| ● | product candidates developed by collaborators may not perform
sufficiently in clinical trials to be determined to be safe and effective, thereby delaying or terminating the drug approval process
and reducing or eliminating milestone payments to which we would otherwise be entitled if the product candidates had successfully met
their endpoints and/or received FDA approval; |
| ● | collaborators may not pursue development and commercialization
of our product candidates that receive marketing approval or may elect not to continue or renew development or commercialization programs
based on clinical trial results, changes in the collaborators’ strategic focus or available funding, or external factors, such
as an acquisition, that divert resources or create competing priorities; |
| ● | collaborators may delay clinical trials, provide insufficient
funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or
require a new formulation of a product candidate for clinical testing; |
| ● | collaborators could independently develop, or develop with
third parties, products that compete directly or indirectly with our products or product candidates if the collaborators believe that
competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive
than ours; |
| ● | product candidates discovered in collaboration with us may
be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to cease to
devote resources to the commercialization of our product candidates; |
| ● | a collaborator with marketing and distribution rights to
one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution
of such product or products; |
| ● | disagreements with collaborators, including disagreements
over proprietary rights, contract interpretation or the preferred course of development, might cause delays or termination of the research,
development or commercialization of product candidates, might lead to additional responsibilities for us with respect to product candidates,
or might result in litigation or arbitration, any of which would divert management attention and resources, be time-consuming and
expensive; |
| ● | collaborators may not properly maintain or defend our intellectual
property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our
intellectual property or proprietary information or expose us to potential litigation; |
| ● | collaborators may infringe the intellectual property rights
of third parties, which may expose us to litigation and potential liability; and |
| ● | collaborations may be terminated for the convenience of the
collaborator and, if terminated, we could be required to raise additional capital to pursue further development or commercialization
of the applicable product candidates. |
Collaboration agreements may not lead to the development
or commercialization of product candidates in the most efficient manner, or at all. If any future collaborations that we enter into do
not result in the successful development and commercialization of products or if one of our collaborators terminates its agreement with
us, we may not receive any future research funding or milestone or royalty payments under the collaboration. If we do not receive the
funding we expect under these agreements, our development of our product candidates could be delayed and we may need additional resources
to develop our product candidates. All of the risks relating to product development, regulatory approval and commercialization described
in this Annual Report on Form 20-F also apply to the activities of our collaborators.
Additionally, subject to its contractual obligations
to us, if a collaborator of ours were to be involved in a business combination, it might deemphasize or terminate the development or commercialization
of any product candidate licensed to it by us. If one of our collaborators terminates its agreement with us, we may find it more difficult
to attract new collaborators and our perception in the business and financial communities could be harmed.
If in the future we acquire or in-license technologies or product
candidates, we may incur various costs, may have integration difficulties and may experience other risks that could harm our business
and results of operations.
In the future, we may acquire or in-license additional
product candidates and technologies. Any product candidate or technologies we in-license or acquire will likely require additional
development efforts prior to commercial sale, including extensive preclinical or clinical testing, or both, and approval by the FDA and
applicable foreign regulatory authorities, if any. All product candidates are prone to risks of failure inherent in pharmaceutical product
development, including the possibility that the product candidate, or product developed based on in-licensed technology, will not
be shown to be sufficiently safe and effective for approval by regulatory authorities. If intellectual property related to product candidates
or technologies we in-license is not adequate, we may not be able to commercialize the affected products even after expending resources
on their development. In addition, we may not be able to manufacture economically or successfully commercialize any product candidate
that we develop based on acquired or in-licensed technology that is granted regulatory approval, and such products may not gain wide
acceptance or be competitive in the marketplace. Moreover, integrating any newly acquired or in-licensed product candidates could
be expensive and time-consuming. If we cannot effectively manage these aspects of our business strategy, our business may be materially
harmed.
We currently contract with third-party contractors for certain
raw materials, compounds and components necessary to produce PrimeC for clinical trials, and expect to continue to do so to support commercial
scale production of PrimeC, if approved. There are significant risks associated with contracting with third-party suppliers. Furthermore,
our existing suppliers may not be able to meet the increased need for certain raw materials, compounds and components that may result
from our potential commercialization efforts. This increases the risk that we will not have sufficient quantities of PrimeC or be able
to obtain such quantities at an acceptable cost, which could delay, prevent or impair our development or commercialization efforts.
We currently rely on third-party contract manufacturers
and suppliers for all of our required raw materials, active ingredients and finished products for our preclinical studies and clinical
trials. Because there are a limited number of suppliers for the raw materials that we use to manufacture our product candidates, we may
need to engage alternate suppliers to prevent a possible disruption of the manufacture of the materials necessary to produce our product
candidates for our clinical trials, and if approved, ultimately for commercial sale. We do not have any control over the availability
of raw materials. If we or our manufacturers are unable to purchase these raw materials on acceptable terms, at sufficient quality levels,
or in adequate quantities, if at all, the development and commercialization of our product candidates or any future product candidates,
would be delayed or there would be a shortage in supply, which would impair our ability to meet our development objectives for our product
candidates or generate revenues from the sale of any approved products.
We expect to continue to rely on these or other
subcontractors and suppliers to support our commercial requirements if PrimeC or any of our other product candidates is approved for marketing
by the FDA or foreign regulatory authorities. We plan to continue to rely on third parties for the raw materials, compounds and components
necessary to produce our product candidates and for preclinical studies and clinical trials.
Our continuing reliance on third-party contract
manufacturers and suppliers entails a number of risks, including reliance on the third party for regulatory compliance and quality assurance,
the possible breach of the manufacturing or supply agreement by the third party, and the possible termination or nonrenewal of the agreement
by the third party at a time that is costly or inconvenient for us. In addition, third-party contract manufacturers and suppliers
may not be able to comply with cGMP or quality system regulation, or similar regulatory requirements outside the United States. If any
of these risks transpire, we may be unable to timely retain alternate subcontractors or suppliers on acceptable terms and with sufficient
quality standards and production capacity, which may disrupt and delay our clinical trials or the manufacture and commercial sale of our
product candidates, if approved.
Our failure or the failure of our third-party contract
manufacturers and suppliers to comply with applicable regulations could result in sanctions being imposed on us, including fines, injunctions,
civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of products, operating restrictions
and criminal prosecutions, any of which could significantly and adversely affect supplies of PrimeC or any of our other product candidates
that we may develop. Any failure or refusal to supply or any interruption in supply of the components for PrimeC or any other product
candidates or products that we may develop could delay, prevent or impair our clinical development or commercialization efforts.
The manufacture of pharmaceutical products is complex and manufacturers
often encounter difficulties in production. If we or any of our third-party manufacturers encounter any difficulties, our ability to provide
product candidates for clinical trials or our product candidates to patients, if approved, and the development or commercialization of
our product candidates could be delayed or stopped.
The manufacture of pharmaceutical products is complex
and requires significant expertise and capital investment, including the development of advanced manufacturing techniques and process
controls. We and our contract manufacturers must comply with cGMP requirements. Manufacturers of pharmaceutical products often encounter
difficulties in production, particularly in scaling up and validating initial production and contamination controls. These problems include
difficulties with production costs and yields, quality control, including stability of the product, quality assurance testing, operator
error, shortages of qualified personnel, as well as compliance with strictly enforced federal, state and foreign regulations. Furthermore,
if microbial, viral or other contaminations are discovered in our product candidates or in the manufacturing facilities in which our product
candidates are made, such manufacturing facilities may need to be closed for an extended period of time to investigate and remedy the
contamination.
We cannot assure you that any stability or
other issues relating to the manufacture of any of our product candidates will not occur in the future. Additionally, we and our
third-party manufacturers may experience manufacturing difficulties due to resource constraints or as a result of labor
disputes or unstable political environments. If we or our third-party manufacturers were to encounter any of these
difficulties, our ability to provide any product candidates to patients in clinical trials and products to patients, once approved,
would be jeopardized. Any delay or interruption in the supply of clinical trial supplies could delay the initiation or completion of
clinical trials, increase the costs associated with maintaining clinical trial programs and, depending upon the period of delay,
require us to commence new clinical trials at additional expense or terminate clinical trials completely. Any adverse developments
affecting clinical or commercial manufacturing of our product candidates may result in shipment delays, inventory shortages, lot
failures, product withdrawals or recalls, or other interruptions in the supply of our product candidates. We may also have to take
inventory write-offs and incur other charges and expenses for products that fail to meet specifications, undertake costly
remediation efforts or seek more costly manufacturing alternatives. Accordingly, failures or difficulties faced at any level of our
supply chain could materially adversely affect our business and delay or impede the development and commercialization of any of our
product candidates and could have a material adverse effect on our business, prospects, financial condition and results of
operations.
Failure to obtain marketing approval in international jurisdictions
would prevent our product candidates from being marketed abroad.
In order to market and sell our products in the
European Union and other jurisdictions, we or our third-party collaborators must obtain separate marketing approvals and comply with
numerous and varying regulatory requirements. The approval procedure varies among countries and can involve additional testing. The time
required to obtain approval may differ substantially from that required to obtain FDA approval. Regulatory approval processes outside
the United States generally include all of the risks associated with obtaining FDA approval. In addition, in many countries outside the
United States, it is required that the product be approved for reimbursement before the product can be approved for sale in that country.
We may not obtain approvals from regulatory authorities outside the United States on a timely basis, if at all. Approval by the FDA does
not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside the
United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA. We may not be able
to file for marketing approvals and may not receive the necessary approvals to commercialize our product candidates in any particular
market.
We intend to rely on third parties and consultants to assist
us in conducting our single pivotal Phase III trial for PrimeC and certain preclinical and clinical trials for our other product candidates.
If these third parties or consultants do not successfully carry out their contractual duties or meet expected deadlines, we may be unable
to obtain regulatory approval for or commercialize PrimeC or any of our other product candidates.
We do not have the ability to independently conduct
many of our preclinical studies or our clinical trials. We rely on medical institutions, clinical investigators, contract laboratories,
and other third parties, such as CROs to conduct clinical trials on our product candidates. Third parties play a significant role in the
conduct of our clinical trials and the subsequent collection and analysis of data. These third parties are not our employees, and except
for remedies available to us under our agreements, we have limited ability to control the amount or timing of resources that any such
third party will devote to our clinical trials. If our CROs or any other third parties upon which we rely for administration and conduct
of our clinical trials do not successfully carry out their contractual duties or obligations or meet expected deadlines, if they need
to be replaced or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our clinical
protocols, regulatory requirements, or for other reasons, or if they otherwise perform in a substandard manner, our clinical trials may
be extended, delayed, suspended or terminated, and we may not be able to complete development of, obtain regulatory approval for, or successfully
commercialize our product candidates.
We and the third parties upon whom we rely are required to comply with
Good Clinical Practice, or GCP, regulations, which are regulations and guidelines enforced by regulatory authorities around the world
for products in clinical development. Regulatory authorities enforce these GCP regulations through periodic inspections of clinical trial
sponsors, principal investigators and clinical trial sites. If we or our third parties fail to comply with applicable GCP regulations,
the clinical data generated in our clinical trials may be deemed unreliable and our submission of marketing applications may be delayed
or the regulatory authorities may require us to perform additional clinical trials before approving our marketing applications. We cannot
assure you that, upon inspection, a regulatory authority will determine that any of our clinical trials comply or complied with applicable
GCP regulations. In addition, our clinical trials must be conducted with material produced under current cGMP regulations, which are enforced
by regulatory authorities. Our failure to comply with these regulations may require us to repeat clinical trials, which would delay the
regulatory approval process. Moreover, our business may be impacted if our CROs, clinical investigators or other third parties violate
federal or state fraud and abuse or false claims laws and regulations or healthcare privacy and security laws.
In order for our clinical trials to be carried out
effectively and efficiently, it is imperative that our CROs and other third parties communicate and coordinate with one another. Moreover,
our CROs and other third parties may also have relationships with other commercial entities, some of which may compete with us. Our CROs
and other third parties may terminate their agreements with us upon as few as 30 days’ notice under certain circumstances. If our
CROs or other third parties conducting our clinical trials do not perform their contractual duties or obligations, experience work stoppages,
do not meet expected deadlines, terminate their agreements with us or need to be replaced, or if the quality or accuracy of the clinical
data they obtain is compromised due to the failure to adhere to our clinical trial protocols or GCPs, or for any other reason, we may
need to conduct additional clinical trials or enter into new arrangements with alternative CROs, clinical investigators or other third
parties. We may be unable to enter into arrangements with alternative CROs on commercially reasonable terms, or at all. Switching or adding
CROs, clinical investigators or other third parties can involve substantial cost and require extensive management time and focus. In addition,
there is a natural transition period when a new CRO commences work. As a result, delays may occur, which can impact our ability to meet
our desired clinical development timelines. Although we carefully manage our relationship with our CROs, clinical investigators and other
third parties, there can be no assurance that we will not encounter such challenges or delays in the future or that these delays or challenges
will not have a negative impact on our business, prospects, financial condition or results of operations.
If our product candidates are approved for marketing, and we
are found to have improperly promoted off-label uses, or if physicians misuse our products, we may become subject to prohibitions on the
sale or marketing of our products, significant sanctions, and product liability claims, and our image and reputation within the industry
and marketplace could be harmed.
The FDA and other regulatory agencies strictly regulate
the marketing and promotional claims that are made about drug products. In particular, a product may not be promoted for uses or indications
that are not approved by the FDA or such other regulatory agencies as reflected in the product’s approved labeling. For example,
if we receive marketing approval for PrimeC for treatment of ALS, the first indication we are pursuing, we cannot promote the use of our
product in a manner that is inconsistent with the approved label. If we are found to have promoted such off-label uses, we may receive
warning letters and become subject to significant liability, which would harm our business. The federal government has levied large administrative,
civil and criminal fines against companies for alleged improper promotion and has enjoined several companies from engaging in off-label promotion.
If we become the target of such an investigation or prosecution based on our marketing and promotional practices, we could face similar
sanctions, which would harm our business. In addition, management’s attention could be diverted from our business operations, significant
legal expenses could be incurred, and our reputation could be damaged. The FDA has also requested that companies enter into consent decrees
or permanent injunctions under which specified promotional conduct is changed or curtailed. If we are deemed by the FDA to have engaged
in the promotion of our products for off-label use, we could be subject to prohibitions on the sale or marketing of our products
or significant fines and penalties, and the imposition of these sanctions could also affect our reputation with physicians, patients and
caregivers, and our position within the industry.
Physicians may also misuse our products or use improper
techniques, potentially leading to adverse results, side effects or injury, which may lead to product liability claims. If our products
are misused or used with improper technique, we may become subject to costly litigation. Product liability claims could divert management’s
attention from our core business, be expensive to defend, and result in sizable damage awards against us that may not be covered by insurance.
We currently carry product liability insurance covering our clinical trials with policy limits that we believe are customary for similarly
situated companies and adequate to provide us with coverage for foreseeable risks. Although we maintain such insurance, any claim that
may be brought against us could result in a court judgment or settlement in an amount that is not covered, in whole or in part, by our
insurance or that is in excess of the limits of our insurance coverage. Furthermore, the use of our products for conditions other than
those approved by the FDA may not effectively treat such conditions, which could harm our reputation in the marketplace among physicians
and patients.
If we fail to manage our growth effectively, our business could
be disrupted.
As of March 31, 2022, we had eleven full and part time employees
and several part-time consultants, most of whom are based at our headquarters in Herzliya, Israel and the rest of whom work in office
space in Cambridge, Massachusetts or Zurich, Switzerland. We will need to continue to expand our development, quality, sales, managerial,
operational, finance, marketing and other resources to manage our operations and clinical trials, continue our development activities
and commercialize our product candidates, if approved. Our management, personnel, systems and facilities currently in place may not be
adequate to support this future growth. Our need to effectively execute our expansion strategy requires that we:
| ● | manage our clinical trials effectively; |
| ● | identify, recruit, retain, incentivize and integrate additional
employees; |
| ● | manage our internal development efforts effectively while
carrying out our contractual obligations to third parties; and |
| ● | continue to improve our operational, financial and management
controls, reporting systems and procedures. |
Due to our limited financial resources and our limited
experience in managing a larger company, we may not be able to effectively manage the expansion of our operations or recruit and train
additional qualified personnel. The physical expansion of our operations may lead to significant costs and may divert our management and
business development resources. Any inability to manage expansion could delay the execution of our development and strategic objectives,
or disrupt our operations; and if we are not successful in commercializing our product candidates, either on our own or through collaborations
with one or more third parties, our revenues will suffer and we would incur significant additional losses.
If product liability lawsuits are brought against us, we may
incur substantial liabilities and may be required to limit commercialization of any of our other products we develop.
We face an inherent risk of product liability as
a result of the clinical testing of our product candidates and will face an even greater risk if we commercialize any products. For example,
we may be sued if any product we develop allegedly causes injury or is found to be otherwise unsuitable during product testing, 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 and a breach of warranties. Claims could also be asserted under
state consumer protection acts. If we cannot successfully defend ourselves against product liability claims, we may incur substantial
liabilities or be required to limit commercialization of our products. Even a successful defense would require significant financial and
management resources. Regardless of the merits or eventual outcome, liability claims may result in:
| ● | decreased demand for our product candidates or products we
develop; |
| ● | injury to our reputation and significant negative media attention; |
| ● | withdrawal of clinical trial participants or cancellation
of clinical trials; |
| ● | costs to defend the related litigation, which may be only
partially recoverable even in the event of successful defenses; |
| ● | a diversion of management’s time and our resources; |
| ● | substantial monetary awards to trial participants or patients; |
| ● | regulatory investigations, product recalls, withdrawals or
labeling, marketing or promotional restrictions; |
| ● | exhaustion of any available insurance and our capital resources;
and |
| ● | the inability to commercialize any product we develop. |
Our inability to obtain and maintain sufficient
product liability insurance at an acceptable cost and scope of coverage to protect against potential product liability claims could prevent
or inhibit the commercialization of products we may develop. We currently carry general clinical trial product liability insurance in
an amount that we believe is adequate to cover the scope of our ongoing clinical programs. Although we maintain such insurance, any claim
that may be brought against us could result in a court judgment or settlement in an amount that is not covered, in whole or in part, by
our insurance or that is in excess of the limits of our insurance coverage. Our insurance policies also have various exclusions and deductibles,
and we may be subject to a product liability claim for which we have no coverage. We will have to pay any amounts awarded by a court or
negotiated in a settlement that exceed our coverage limitations or that are not covered by our insurance, and we may not have, or be able
to obtain, sufficient capital to pay such amounts. Moreover, in the future, we may not be able to maintain insurance coverage at a reasonable
cost or in sufficient amounts to protect us against losses. If and when we obtain approval for marketing PrimeC or any other product candidate,
we intend to expand our insurance coverage to include the commercialization of PrimeC or any other approved product that we may have;
however, we may be unable to obtain this liability insurance on commercially reasonable terms.
If we fail to attract and keep senior management and key scientific
personnel, we may be unable to successfully develop our product candidates, conduct our clinical trials and commercialize any of the products
we develop.
Our success depends in part on our continued ability
to attract, retain and motivate highly qualified management, clinical and scientific personnel. We believe that our future success is
highly dependent upon the contributions of members of our senior management, as well as our senior scientists and other members of our
management team. The loss of services of any of these individuals could delay or prevent the successful development of our product pipeline,
completion of our planned clinical trials or the commercialization of our product candidates. Although we have employment agreements with
some of our employees, these agreements do not prevent them from terminating their employment with us after providing the appropriate
notice as described in the agreements.
Although we have not historically experienced unique
difficulties in attracting and retaining qualified employees, we could experience such problems in the future. For example, competition
for qualified personnel in the pharmaceutical field is intense due to the limited number of individuals who possess the skills and experience
required by our industry. We will need to hire additional personnel as we expand our clinical development and commercial activities. We
may not be able to attract and retain quality personnel on acceptable terms, or at all. In addition, to the extent we hire personnel from
competitors, we may be subject to allegations that they have been improperly solicited or that they have divulged proprietary or other
confidential information, or that their former employers own their research output. Moreover, we are domiciled in Israel and are predominantly
based in Israel, which may make it difficult to hire necessary U.S.-based personnel.
Our internal computer systems, or those of our CROs or other
contractors or consultants, may fail or suffer security breaches, which could result in a disruption of our drug development programs.
Despite the implementation of security measures,
our internal computer systems and those of our CROs and other contractors and consultants are vulnerable to damage from cyber-security threats,
including computer viruses, harmful code and unauthorized access, natural disasters, fire, terrorism, war and telecommunication and electrical
failures. If a disruption event were to occur and cause interruptions in our operations, it could result in a material disruption of our
drug development programs. For example, the loss of clinical trial data from completed, ongoing or planned clinical trials could result
in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. To the extent that
any disruption or security breach results in a loss of or damage to our data or applications, or inappropriate disclosure of confidential
or proprietary information, we could incur liability and the further development of our product candidates could be delayed.
Under applicable employment laws, we may not be able to enforce
covenants not to compete.
We generally enter into non-competition agreements
as part of our employment agreements with our employees. These agreements generally prohibit our employees, if they cease working for
us, from competing directly with us or working for our competitors for a limited period. We may be unable to enforce these agreements
under the laws of the jurisdictions in which our employees work and it may be difficult for us to restrict our competitors from benefitting
from the expertise our former employees or consultants developed while working for us.
For example, Israeli labor courts have required
employers seeking to enforce non-compete undertakings of a former employee to demonstrate that the competitive activities of the
former employee will harm one of a limited number of material interests of the employer which have been recognized by the courts as justification
for the enforcement of non-compete undertakings, such as the protection of a company’s trade secrets or other intellectual
property.
Our employees, independent contractors, clinical investigators,
CROs, consultants and vendors may engage in misconduct or other improper activities, including noncompliance with regulatory standards
and requirements and insider trading.
We are exposed to the risk that our employees, independent
contractors, clinical investigators, CROs, consultants and vendors may engage in fraudulent conduct or other illegal activity. Misconduct
by these parties could include intentional, reckless and/or negligent conduct, breach of contract or disclosure of unauthorized activities
to us that violates: FDA regulations, including those laws requiring the reporting of true, complete and accurate information to the FDA;
manufacturing standards; federal, state and foreign healthcare fraud and abuse laws; or laws that require the reporting of financial information
or data accurately.
Specifically, research, sales, marketing, education
and other business arrangements in the healthcare industry are subject to extensive laws intended to prevent fraud, misconduct, kickbacks,
self-dealing and other abusive practices. These laws may restrict or prohibit a wide range of pricing, discounting, education, marketing
and promotion, sales commission, customer incentive programs and other business arrangements. Activities subject to these laws also involve
the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm
to our reputation. We have adopted a code of business conduct and ethics, but it is not always possible to identify and deter misconduct
by employees and other third parties, and the precautions we take to detect and prevent this activity may not be effective in controlling
unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a
failure to be in compliance with such laws. If any such actions are instituted against us, even if we are successful in defending ourselves
or asserting our rights, those actions could have a significant impact on our business. Violations of such laws subject us to numerous
penalties, including, but not limited to, the imposition of civil, criminal and administrative penalties, damages, monetary fines, disgorgement,
individual imprisonment, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar
agreement to resolve allegations of non-compliance with these laws, possible exclusion from participation in Medicare, Medicaid and
other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, and curtailment of
our operations, any of which could adversely affect our ability to operate our business and our results of operations.
Exchange rate fluctuations between the U.S. Dollar and the NIS
may negatively affect our earnings.
The U.S. dollar is our functional and reporting
currency. However, a significant portion of our operating expenses are incurred in NIS, which is the lawful currency of the State of Israel.
As a result, we are exposed to the risks that the NIS may appreciate relative to the dollar, or, if the NIS instead devalues relative
to the dollar, that the inflation rate in Israel may exceed such rate of devaluation of the NIS, or that the timing of such devaluation
may lag behind inflation in Israel. In any such event, the dollar cost of our operations in Israel would increase and our dollar-denominated results
of operations would be adversely affected. We cannot predict any future trends in the rate of inflation in Israel or the rate of devaluation
(if any) of the NIS against the dollar. For example, the dollar depreciated against the NIS in 2020 by 6.97% and the dollar depreciated
against the NIS in 2021 by 3.27%. If the dollar cost of our operations in Israel increases, our dollar-measured results of operations
will be adversely affected.
Risks Related to Our Intellectual Property
If our efforts to obtain, protect or enforce our patents and
other intellectual property rights related to our product candidates and technologies are not adequate, we may not be able to compete
effectively in our market and we otherwise may be harmed.
Our commercial success depends in significant part upon our ability
to obtain, maintain, enforce and defend patent protection and utilize trade secret protection with respect to our proprietary technologies,
our products and their uses, and to operate our business without infringing, misappropriating, or otherwise violating the intellectual
property rights of others. We rely upon a combination of patents, trade secret protection, confidentiality agreements, assignment of invention
agreements and other contractual arrangements to protect the intellectual property related to PrimeC’s fixed dose combination of
ciprofloxacin and celecoxib and our other product candidates. If we are unable to obtain and maintain sufficient intellectual property
protection for our technologies and product candidates, or if the scope of the intellectual property protection obtained is not sufficiently
broad, our competitors and other third parties could develop and commercialize technologies and product candidates similar or identical
to ours, and our ability to successfully commercialize the technologies and product candidates that we may pursue may be impaired.
Although we enter into confidentiality agreements
with parties who have access to confidential or patentable aspects of our research and development output, such as our employees, collaborators,
CROs, contract manufacturers, consultants, advisors and other third parties, any of these parties may breach the agreements and disclose
such output before a patent application is filed, thereby jeopardizing our ability to seek patent protection. Further, we may not be aware
of all third-party intellectual property rights potentially relating to our product candidates. Publications of discoveries in the
scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are
typically not published until 18 months after filing or, in some cases, not at all. Therefore, we cannot know with certainty whether
we were the first to make the inventions claimed in our patents or pending patent applications, or that we were the first to file for
patent protection of such inventions.
While we seek patent protection for all of our product
candidates, our patent coverage is limited, and we can provide no assurance that any of our current or future patent applications will
result in issued patents or that any issued patents will provide us with any competitive advantage. As of August 2021, our patent portfolio
includes U.S. Patent 10,980,780, which relates to methods for treatment of ALS using ciprofloxacin and celecoxib, and which expires in
2038. In September 2021, we received notice that our pending patent application, related to our lead candidate, PrimeC, had been allowed
in Australia. Similar patent applications are pending in the European Patent Office, Japan, Canada and Israel. In addition, U.S. patent
application 16/623,467, which relates to methods of treatment of neurodegenerative disease using combinations of ciprofloxacin and celecoxib,
is currently pending. This patent application is expected to expire on June 20, 2038.
In addition, we have developed a pharmaceutical
composition comprising, as active ingredients, ciprofloxacin and celecoxib, and have filed a U.S. provisional application directed to
the compositions. Our U.S. provisional application 63/257,130 relates to pharmaceutical formulations. Applications claiming priority from
the U.S. provisional application are expected to expire on October 19, 2042.
Limitations on the scope of our intellectual property
rights may limit our ability to prevent third parties from designing around such rights and competing against us. For example, some of
our patent applications and patents do not claim a new compound. Rather, the active pharmaceutical ingredients of PrimeC are existing
compounds and some of our pending patent applications are directed to, among other things, novel formulations of these existing compounds.
Accordingly, other parties may compete with us, for example, by independently developing or obtaining competing formulations that design
around our patent claims, but which may contain the same active ingredients, or by seeking to invalidate our patents. Any disclosure to
or misappropriation by third parties of our confidential proprietary information could enable competitors to quickly duplicate or surpass
our technological achievements, eroding our competitive position in the market.
The patent applications that we own may fail to result in granted patents
in the United States or foreign jurisdictions, or if granted may fail to prevent a potential infringer from marketing its product or be
deemed invalid and unenforceable by a court. Our ability to obtain and maintain valid and enforceable patents depends on various factors,
including interpretation of our technology and the prior art and whether the differences between them allow our technology to be patentable.
Patent applications and patents granted from them are complex, lengthy and highly technical documents that are often prepared under very
limited time constraints and may not be free from errors that make their interpretation uncertain. The existence of errors in a patent
may have an adverse effect on the patent, its scope and its enforceability. Even if our pending and future patent applications issue as
patents in relevant jurisdictions, they may not issue in a form that will provide us with any meaningful protection for our technology
or product candidates, prevent competitors from competing with us or otherwise provide us with any competitive advantage. Additionally,
our competitors may be able to circumvent our patents by developing similar or alternative technologies or product candidates in a non-infringing manner.
Also, our granted patents may be subject to challenges.
We may be subject to a third-party preissuance submission of prior art to the United States Patent and Trademark Office, or the USPTO,
or become involved in opposition, derivation, revocation, ex parte reexamination, inter partes review, post grant review, derivation,
or interference proceedings challenging our patent rights or the patent rights of others, or other proceedings in the USPTO or applicable
foreign offices that challenge priority of invention or other features of patentability. For example, patents granted by the European
Patent Office may be opposed by any person within nine months from the publication of their grant.
An adverse determination in any such submission,
proceeding or litigation could result in loss of exclusivity, patent claims being narrowed, invalidated or held unenforceable, in whole
or in part, or limits of the scope or duration of the patent protection of our technologies or product candidates, all of which could
limit our ability to stop others from using or commercializing similar or identical product candidates or technology to compete directly
with us, without payment to us.
We may be subject to claims that we infringe, misappropriate
or otherwise violate the intellectual property rights of third parties.
Even if our patents do successfully issue, third
parties may own rights to third party patents which relate to various aspects of the PrimeC product and any of our other product candidates.
To meet such challenges, which are part of the risks and uncertainties of developing and marketing product candidates, we may need to
evaluate third party intellectual property rights and, if appropriate, to seek licenses for such third party intellectual property or
to challenge such third party intellectual property, which may be costly and may or may not be successful, which could also have an adverse
effect on the commercial potential for PrimeC and any of our other product candidates.
We may receive only limited protection, or no protection, from
our issued patents and patent applications.
If we encounter delays in our clinical trials or
regulatory approval of our product candidates, the period of time during which we could market any of our product candidates under patent
protection could be reduced. Since patent applications in the United States and most other countries are confidential for a period of
time after filing, we cannot be certain that we were the first to either (i) file any patent application related to the treatment of ALS
using ciprofloxacin and celecoxib or (ii) conceive and invent any of the compositions or methods claimed in our patents or patent applications,
including patents or patent applications related to PrimeC and our other product candidates.
The patent application process, also known as patent
prosecution, is expensive and time consuming, and we or any future licensors and licensees may not be able to prepare, file and prosecute
all necessary or desirable patent applications at a reasonable cost or in a timely manner. It is also possible that we or any future licensors
or licensees will fail to identify patentable aspects of inventions made in the course of development and commercialization activities
before it is too late to obtain patent protection on them. Therefore, these and any of our patents and applications may not be prosecuted
and enforced in a manner consistent with the best interests of our business. It is possible that defects of form in the preparation or
filing of our patents or patent applications may exist, or may arise in the future, for example with respect to proper priority claims,
inventorship, etc., although we are unaware of any such defects that we believe are of material import. If we or any future licensors
or licensees fail to establish, maintain or protect such patents and other intellectual property rights, such rights may be reduced or
eliminated. If any future licensors or licensees, are not fully cooperative or disagree with us as to the prosecution, maintenance or
enforcement of any patent rights, such patent rights could be compromised. If there are material defects in the form or preparation of
our patents or patent applications, such patents or applications may be invalid and unenforceable. Any of these outcomes could impair
our ability to prevent competition from third parties, which may have an adverse impact on our business.
The strength of patents in the pharmaceutical field
involves complex legal and scientific questions and can be uncertain. This uncertainty includes changes to the patent laws through either
legislative action to change statutory patent law or court action that may reinterpret existing law in ways affecting the scope or validity
of issued patents. The patent applications that we own or in-license may fail to result in issued patents in the United States or
foreign countries with claims that cover our product candidates. Even if patents do successfully issue from the patent applications that
we own or in-license, third parties may challenge the validity, enforceability or scope of such patents, which may result in such patents
being narrowed, invalidated or held unenforceable. For example, patents granted by the European Patent Office may be challenged, also
known as opposed, by any person within nine months from the publication of their grant. In addition, post grant review in the USPTO begins
with a third party filing a petition on or prior to the date that is 9 months after the grant of the patent or issuance of a reissue
patent. Third parties can also challenge a patent in the USPTO by way of inter partes review, ex parte reexamination, derivation, or interference
proceedings. Any successful challenge to our patents could deprive us of exclusive rights necessary for the successful commercialization
of our product candidates. Furthermore, even if they are unchallenged, our patents may not adequately protect our product candidates,
provide exclusivity for our product candidates, or prevent others from designing around our claims. If the breadth or strength of protection
provided by the patents we hold or pursue with respect to our product candidates is challenged, it could dissuade companies from collaborating
with us to develop, or threaten our ability to commercialize our product candidates.
Patents have a limited lifespan. In the United States,
the natural expiration of a patent is generally 20 years after it is filed. Various extensions may be available; however the life of a
patent, and the protection it affords, is limited. Without patent protection for our product candidates, we may be open to competition
from generic versions of our product candidates. Further, if we encounter delays in our development efforts, including our clinical trials,
the period of time during which we could market our product candidates under patent protection would be reduced.
If we are unable to protect the confidentiality of our trade
secrets, our business and competitive position would be harmed.
In addition to the protection afforded by patents,
we also rely on trade secret protection to protect proprietary know-how, technology and other proprietary information that may not be
patentable or that we elect not to patent, processes for which patents may be difficult to obtain or enforce, and any other elements of
our product candidates, and our product development processes (such as manufacturing and formulation technologies) that involve proprietary
know-how, information or technology that is not covered by patents.
Trade secrets and know-how can be difficult
to protect. We seek to protect these trade secrets and other proprietary technology, in part, by requiring all of our employees, consultants,
advisors, and any other third parties that have access to our proprietary know-how, information or technology to execute confidentiality
agreements upon the commencement of their relationships with us. We cannot be certain that we have or will obtain these
agreements in all circumstances and we cannot guarantee that we have entered into such agreements with each party that may have or have
had access to our trade secrets or proprietary information. If the steps taken to maintain our trade secrets are deemed inadequate, we
may have insufficient recourse against third parties for misappropriating any trade secrets.
Despite our efforts, any of these parties may breach
the agreements and disclose our proprietary information, including our trade secrets. Adequate remedies may not exist in the event of
unauthorized use or disclosure of our trade secrets. In addition, in some situations, these confidentiality agreements may conflict with,
or be subject to, the rights of third parties with whom our employees, consultants, or advisors have previous employment or consulting
relationships. To the extent that our employees, consultants or contractors use any intellectual property owned by third parties in their
work for us, disputes may arise as to the rights in any related or resulting know-how and inventions. Any misappropriation or unauthorized
disclosure of our trade secrets could have an adverse effect on our business, impact our ability to establish or maintain a competitive
advantage in our market, or otherwise harm our business, operating results and financial condition.
Furthermore, trade secret protection does not prevent competitors from
independently developing substantially equivalent information and techniques and we cannot guarantee that our competitors will not independently
develop substantially equivalent information and techniques. The FDA, as part of its Transparency Initiative, is currently considering
whether to make additional information publicly available on a routine basis, including information that we may consider to be trade secrets
or other proprietary information, and it is not clear at the present time how the FDA’s disclosure policies may change in the future,
if at all.
Changes in U.S. patent law could diminish the value of patents
in general, thereby impairing our ability to protect our products.
As is the case with other pharmaceutical companies,
our success is heavily dependent on intellectual property, particularly on obtaining and enforcing patents. Obtaining and enforcing patents
in the pharmaceutical industry involves both technological and legal complexity, and therefore, is costly, time-consuming and inherently
uncertain. In addition, the Leahy-Smith America Invents Act, or the AIA, which was passed on September 16, 2011, resulted in
significant changes to the U.S. patent system. Further, U.S. Supreme Court rulings in recent years have either narrowed the scope of patent
protection available in certain circumstances or weakened 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 value of patents, once obtained.
The significant changes to U.S. patent law under
the AIA include provisions that affect the way patent applications will be prosecuted and may also affect patent litigation. For our U.S.
patent applications that contain or contained at any time a claim not entitled to priority before March 16, 2013, there is a greater
level of uncertainty in the patent law. The USPTO has developed and continues to develop regulations and procedures to govern administration
of the AIA, and many of the substantive changes to patent law associated with the AIA. The AIA and its implementation could increase the
uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all
of which could harm our business and financial condition. It is not clear what other, if any, impact the AIA will have on the operation
of our business.
An important change introduced by the AIA is that,
as of March 16, 2013, the United States transitioned 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. A third party that files a patent
application in the USPTO after that date but before us could therefore be awarded a patent covering an invention of ours even if we had
made the invention before it was made by the third party. This will require us to be cognizant going forward of the time from invention
to filing of a patent application, but circumstances could prevent us from promptly filing patent applications on our inventions. Furthermore,
our ability to obtain and maintain valid and enforceable patents depends on whether the differences between our technology and the prior
art allow our technology to be patentable over the prior art. Since patent applications in the United States and most other countries
are confidential for a period of time after filing, we cannot be certain that we were the first to either (i) file any patent application
related to our product candidates or (ii) invent any of the inventions claimed in our patents or patent applications.
Among some of the other changes introduced by the
AIA are changes that limit where a patentee may file a patent infringement suit and provide opportunities for third parties to challenge
any issued patent in the USPTO. This applies to all of our U.S. 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 court 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.
Depending on decisions by the U.S. Congress, the
federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that would weaken our ability
to obtain new patents or to enforce our existing patents and patents that we might obtain in the future.
Obtaining and maintaining our patent protection depends on compliance
with various procedural, documentary, 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 various foreign governmental patent
agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent prosecution
process.
Periodic maintenance fees and various other governmental
fees on any issued patent and/or pending patent applications are due to be paid to the USPTO and foreign patent agencies in several stages
over the lifetime of a patent or patent application. We have systems in place to remind us to pay these fees, and we employ an outside
firm and rely on our outside counsel to pay these fees. While an inadvertent lapse may sometimes be cured by payment of a late fee or
by other means in accordance with the applicable rules, there are many situations in which noncompliance can result in abandonment or
lapse of the patent or patent application, resulting in 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. If we fail to maintain the patents
and patent applications directed to our product candidates, our competitors might be able to enter the market earlier than should otherwise
have been the case, which could harm our business, financial condition, results of operations, and prospects.
We may not be able to protect our intellectual property rights
throughout the world.
Filing, prosecuting and defending patents on our
product candidates in all countries throughout the world would be prohibitively expensive and our intellectual property rights in some
countries outside of the United States, Europe, and Israel. The requirements for patentability may differ in certain countries, particularly
developing countries. For example, unlike other countries, China has a heightened requirement for patentability, and specifically requires
a detailed description of medical uses of a claimed drug. In addition, the laws of some foreign countries do not protect intellectual
property rights to the same extent as laws in the United States. Consequently, we may not be able to prevent third parties from practicing
our inventions in all countries outside the United States. Competitors may use our technologies in jurisdictions where we have not obtained
patent protection to develop their own products and further, may export otherwise infringing products to territories where we have patent
protection, but enforcement on infringing activities is inadequate. These products may compete with our products, and our patents or other
intellectual property rights may not be effective or sufficient to prevent them from competing.
Many companies have encountered significant problems
in protecting and defending intellectual property rights in foreign jurisdictions. The legal systems of certain countries, particularly
certain developing countries, do not favor the enforcement of patents and other intellectual property protection, particularly those relating
to pharmaceuticals, which could make it difficult for us to stop the infringement of our patents or marketing of competing products in
violation of our proprietary rights generally.
Proceedings to enforce our patent rights in foreign
jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our
patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing, and could provoke third
parties to assert claims against us. We may not prevail in any lawsuits that we initiate and the damages or other remedies awarded, if
any, may not be commercially meaningful.
In addition, some countries have compulsory licensing
laws under which a patent owner may be compelled to grant licenses to third parties. In those countries, we may have limited remedies
if our patents are infringed or if we are compelled to grant a license to our patents to a third party, which could materially diminish
the value of those patents. This could limit our potential revenue opportunities. Accordingly, our efforts to enforce our intellectual
property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we
own or license. Finally, our ability to protect and enforce our intellectual property rights may be adversely affected by unforeseen changes
in foreign intellectual property laws.
If we are unable to protect our trademarks from infringement,
our business prospects may be harmed.
We plan to register trademarks that identify PrimeC in the United States
and Israel. Although we take steps to monitor the possible infringement or misuse of our trademarks, it is possible that third parties
may infringe, dilute or otherwise violate our trademark rights. Any unauthorized use of our trademarks could harm our reputation or commercial
interests. In addition, our enforcement against third-party infringers or violators may be unduly expensive and time-consuming, and
the outcome may be an inadequate remedy. Over the long term, if we are unable to successfully register our trademarks and trade names
and establish name recognition based on our trademarks and trade names, then we may not be able to compete effectively, and our business
may be adversely affected. Our efforts to enforce or protect our proprietary rights related to trademarks, trade secrets, domain names,
copyrights or other intellectual property may be ineffective and could result in substantial costs and diversion of resources and could
adversely impact our financial condition or results of operations.
We may become involved in lawsuits to protect or enforce our
patents or other intellectual property, which could be expensive and time consuming, delay or prevent the development and commercialization
of our products and product candidates or put our patents and other proprietary rights at risk.
Third parties may infringe or misappropriate our
intellectual property, including our existing patents, patents that may issue to us in the future. As a result, we may be required to
file infringement claims to stop third-party infringement or unauthorized use. Further, we may not be able to prevent misappropriation
of our intellectual property rights, particularly in countries where the laws may not protect those rights as fully as in the United States.
Generic drug manufacturers may develop, seek approval
for, and launch generic versions of our products. If we file an infringement action against such a generic drug manufacturer, that company
may challenge the scope, validity or enforceability of our patents, requiring us to engage in complex, lengthy and costly litigation or
other proceedings.
For example, if we initiated legal proceedings against
a third party to enforce a patent covering our product candidates, the defendant could counterclaim that the patent covering our product
candidates is invalid and/or unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity and/or
unenforceability are commonplace, and there are numerous grounds upon which a third party can assert invalidity or unenforceability of
a patent.
In addition, within and outside of the United States,
there has been a substantial amount of litigation and administrative proceedings, including inter partes review, post grant review, interference
or derivation proceedings, and ex parte reexamination proceedings before the USPTO or other comparable proceedings in various foreign
jurisdictions, regarding patent and other intellectual property rights in the pharmaceutical industry. These proceedings bring uncertainty
to the possibility of challenges to our patents in the future, including challenges by competitors who perceive our patents as blocking
entry into the market for their products, and the outcome of such challenges.
Such litigation and administrative proceedings could
result in revocation of our patents or amendment of our patents such that they do not cover our product candidates. They may also put
our pending patent applications at risk of not issuing, or issuing with limited and potentially inadequate scope to cover our product
candidates. The outcome following legal assertions of invalidity and unenforceability is unpredictable. With respect to the validity question,
for example, we cannot be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during prosecution.
Additionally, it is also possible that prior art of which we are aware, but which we do not believe affects the validity or enforceability
of a claim, may, nonetheless, ultimately be found by a court of law or an administration panel to affect the validity or enforceability
of a claim. If a defendant were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at least part, and
perhaps all, of the patent protection on our product candidates. Such a loss of patent protection could have a negative impact on our
business.
Enforcing our intellectual property rights through
litigation would be very expensive, particularly for a company of our size, time-consuming, and inherently uncertain. Some of our competitors
may be able to sustain the costs of litigation more effectively than we can because of greater financial resources. Patent litigation
and other proceedings may also divert technical and management personnel from their normal responsibilities.
Uncertainties resulting from the initiation and
continuation of patent litigation or other proceedings could impair our ability to compete in the marketplace. The occurrence of any of
the foregoing could harm our business, financial condition or results of operations.
Furthermore, because of the substantial amount of
discovery required in connection with intellectual property litigation or administrative proceedings, there is a risk that some of our
confidential information could be compromised by disclosure. In addition, during the course of litigation or administrative proceedings,
there could be public announcements of the results of hearings, motions or other interim proceedings or developments or public access
to related documents. If investors perceive these results to be negative, the market price for our ordinary shares and Warrants could
be significantly harmed.
We may become subject to claims for remuneration or royalties
for assigned service invention rights by our employees, which could result in litigation and adversely affect our business.
A significant portion of our intellectual property
has been developed by our employees in the course of their employment for us. Under the Israeli Patent Law, 5727-1967, or the Patent Law,
inventions conceived by an employee during the scope of his or her employment with a company are regarded as “service inventions,”
which belong to the employer, absent an agreement between the employee and employer providing otherwise. The Patents Law also provides
that if there is no agreement between an employer and an employee determining whether the employee is entitled to receive consideration
for service inventions and on what terms, this will be determined by the Israeli Compensation and Royalties Committee, or the Committee,
a body constituted under the Patents Law. Case law clarifies that the right to receive consideration for “service inventions”
can be waived by the employee and that in certain circumstances, such waiver does not necessarily have to be explicit. The Committee will
examine, on a case-by-case basis, the general contractual framework between the parties, using interpretation rules of the general
Israeli contract laws. Further, the Committee has not yet determined one specific formula for calculating this remuneration, but rather
uses the criteria specified in the Patents Law. Although we generally enter into agreements with our employees pursuant to which such
individuals assign to us all rights to any inventions created during and as a result of their employment with us, we may face claims demanding
remuneration in consideration for assigned inventions. As a consequence of such claims, we could be required to pay additional remuneration
or royalties to our current and/or former employees, or be forced to litigate such monetary claims (which will not affect our proprietary
rights), which could negatively affect our business.
Third party claims alleging intellectual property infringement
may adversely affect our business.
Our commercial success depends in part on our avoiding
infringement of the patents and proprietary rights of third parties, for example, the intellectual property rights of competitors. Our
research, development and commercialization activities may be subject to claims that we infringe or otherwise violate patents owned or
controlled by third parties. Numerous U.S. and foreign issued patents and pending patent applications, which are owned by third parties,
exist in the fields in which we are developing our product candidates. As the biotechnology and pharmaceutical industries expand and more
patents are issued, the risk increases that our activities related to our product candidates may give rise to claims of infringement of
the patent rights of others. We cannot assure you that our product candidates will not infringe existing or future patents. We may not
be aware of patents that have already issued that a third party might assert are infringed by our product candidates. It is also possible
that patents of which we are aware, but which we do not believe are relevant to our product candidates, could nevertheless be found to
be infringed by our product candidates. Nevertheless, we are not aware of any issued patents that we believe would prevent us from marketing
our product candidates, if approved. There may also be patent applications that have been filed but not published that, when issued as
patents, could be asserted against us. In addition, patent holding companies that focus solely on extracting royalties and settlements
by enforcing patent rights may target us. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk
increases that we may be subject to claims of infringement of the intellectual property rights of third parties.
Third parties making claims against us for infringement or misappropriation
of their intellectual property rights may seek and obtain injunctive or other equitable relief, which could effectively block our ability
to further develop and commercialize our product candidates. Further, if a patent infringement suit were brought against us, we could
be forced to stop or delay research, development, manufacturing or sales of the product or product candidate that is the subject of the
suit. Defense of these claims, regardless of their merit, would cause us to incur substantial expenses and, and would be a substantial
diversion of management time and employee resources from our business. In the event of a successful claim of infringement against us by
a third party, we may have to (i) pay substantial damages, including treble damages and attorneys’ fees if we are found to have
willfully infringed the third party’s patents; (ii) obtain one or more licenses from the third party; (iii) pay royalties to the
third party; and/or (iv) redesign any infringing products. Redesigning any infringing products may be impossible or require substantial
time and monetary expenditure. Further, we cannot predict whether any required license would be available at all or whether it would be
available on commercially reasonable terms. In the event that we could not obtain a license, we may be unable to further develop and commercialize
our product candidates, which could harm our business significantly. Even if we are able to obtain a license, the license would likely
obligate us to pay license fees or royalties or both, and the rights granted to us might be nonexclusive, which could result in our competitors
gaining access to the same intellectual property. Ultimately, we could be prevented from commercializing a product, or be forced to cease
some aspect of our business operations, if, as a result of actual or threatened patent infringement claims, we are unable to enter into
licenses on acceptable terms. Furthermore, even in the absence of litigation, we may need or may choose to obtain licenses from third
parties to advance our research or allow commercialization of our product candidates. We may fail to obtain any of these licenses at a
reasonable cost or on reasonable terms, if at all. In that event, we would be unable to further develop and commercialize our product
candidates, which could harm our business significantly.
Defending ourselves in litigation is very expensive,
particularly for a company of our size, and time-consuming. Some of our competitors may be able to sustain the costs of litigation or
administrative proceedings more effectively than we can because of greater financial resources. Patent litigation and other proceedings
may also absorb significant management time. Uncertainties resulting from the initiation and continuation of patent litigation or other
proceedings could impair our ability to compete in the marketplace. The occurrence of any of the foregoing could harm our business, financial
condition or results of operations.
We may be subject to claims that our employees, consultants or
independent contractors have wrongfully used or disclosed confidential information or alleged trade secrets of third parties or competitors
or are in breach of non-competition or non-solicitation agreements with our competitors.
We employ individuals who were previously employed
at other biotechnology or pharmaceutical companies. We may be subject to claims that we or our employees, consultants or independent contractors
have inadvertently or otherwise improperly used or disclosed confidential information or trade secrets of these third parties or our employees’
former employers. Further, we may be subject to ownership disputes in the future arising, for example, from conflicting obligations of
consultants or others who are involved in developing our product candidates. We may also be subject to claims that former employees, consultants,
independent contractors, collaborators or other third parties have an ownership interest in our patents or other intellectual property.
Litigation may be necessary to defend against these and other claims challenging our right to and use of confidential and proprietary
information. If we fail in defending any such claims, in addition to paying monetary damages, we may lose our rights therein. Such an
outcome could have a negative impact on our business. Even if we are successful in defending against these claims, litigation could result
in substantial cost and be a distraction to our management and employees. Any litigation or the threat thereof may adversely affect our
ability to hire employees. A loss of key personnel or their work product could hamper or prevent our ability to commercialize product
candidates, which could have an adverse effect on our business, results of operations and financial condition. We may not have sufficient
financial or other resources to adequately conduct such litigation or proceedings. Some of our competitors may be able to sustain the
costs of such litigation or proceedings more effectively than we can because of their substantially greater financial resources. Uncertainties
resulting from the initiation and continuation of litigation proceedings could adversely affect our ability to compete in the marketplace.
Risks Related to Government Regulation
If the FDA does not conclude that PrimeC, or our other product
candidates satisfy the requirements under Section 505(b)(2) of the Federal Food Drug and Cosmetic Act, or Section 505(b)(2), or if the
requirements for such product candidates are not as we expect, the approval pathway for these product candidates will likely take significantly
longer, cost significantly more and entail significantly greater complications and risks than anticipated, and in either case may not
be successful.
We intend to commence a pivotal Phase III clinical
trial for PrimeC under the FDA’s Section 505(b)(2) regulatory pathway. The Drug Price Competition and Patent Term Restoration Act
of 1984, also known as the Hatch-Waxman Act, added Section 505(b)(2) to the Federal Food, Drug and Cosmetic Act. Section 505(b)(2)
permits the filing of an NDA where at least some of the information required for approval comes from studies that were not conducted by
or for the applicant, and for which the applicant has not received a right of reference, which could expedite the development program
for PrimeC and our other product candidates by potentially decreasing the amount of preclinical and clinical data that we would need to
generate in order to obtain FDA approval. Although PrimeC is a formulation of two FDA-approved drugs, ciprofloxacin and celecoxib,
which will not be treated as new chemical entities, or NCEs, the submission of an NDA under the Section 505(b)(2) or similar regulatory
pathway does not preclude the FDA from determining that the product candidate that is the subject of such submission is an NCE and therefore
not eligible for review under such regulatory pathway.
Though we have received initial agreement from the
FDA for our development to continue under the 505(b)(2) pathway, the FDA may reverse that decision and not allow us to pursue the Section
505(b)(2) or similar regulatory pathway as anticipated. In that case, we may need to conduct additional preclinical experiments and clinical
trials, provide additional data and information, and meet additional standards for regulatory approval. If this were to occur, the time
and financial resources required to obtain FDA approval for these product candidates, and complications and risks associated with these
product candidates, would likely increase significantly. Moreover, inability to pursue the Section 505(b)(2) or similar regulatory pathway
could result in new competitive products reaching the market more quickly than our product candidates, which would likely harm our competitive
position and prospects. Even if we are allowed to pursue the Section 505(b)(2) or similar regulatory pathway, our product candidates may
not receive the requisite approvals for commercialization.
In addition, notwithstanding the approval of a number
of products by the FDA under Section 505(b)(2) over the last few years, certain competitors and others have objected to the FDA’s
interpretation of Section 505(b)(2). If the FDA’s interpretation of Section 505(b)(2) is successfully challenged, the FDA may be
required to change its 505(b)(2) policies and practices, which could delay or even prevent the FDA from approving any NDA that we submit
under Section 505(b)(2). In addition, the pharmaceutical industry is highly competitive, and Section 505(b)(2) NDAs are subject to special
requirements designed to protect the patent rights of sponsors of previously approved drugs that are referenced in a Section 505(b)(2)
NDA. These requirements may give rise to patent litigation and mandatory delays in approval of our potential future NDAs for up to 30 months
depending on the outcome of any litigation. It is not uncommon for a manufacturer of an approved product to file a citizen petition with
the FDA seeking to delay approval of, or impose additional approval requirements for, pending competing products. If successful, such
petitions can significantly delay, or even prevent, the approval of the new product. However, even if the FDA ultimately denies such a
petition, the FDA may substantially delay approval while it considers and responds to the petition. In addition, even if we are able to
utilize the Section 505(b)(2) regulatory pathway for our product candidates, there is no guarantee this would ultimately lead to faster
product development or earlier approval.
Moreover, even if these product candidates are approved
under the Section 505(b)(2) pathway, as the case may be, the approval may be subject to limitations on the indicated uses for which the
products may be marketed or to other conditions of approval, or may contain requirements for costly post-marketing testing and surveillance
to monitor the safety or efficacy of the products.
We expect current and future legislation affecting the healthcare
industry, including healthcare reform, to impact our business generally and to increase limitations on reimbursement, rebates and other
payments, which could adversely affect third-party coverage of our products, our operations, and/or how much or under what circumstances
healthcare providers will prescribe or administer our products, if approved.
The United States and some foreign jurisdictions
are considering or have enacted a number of legislative and regulatory proposals to change the healthcare system in ways that could affect
our ability to sell our products profitably. Among policy makers and payors in the United States and elsewhere, there is significant interest
in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality or expanding access.
In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by
major legislative initiatives.
For example, in March 2010, President Obama signed
into law the Patient Protection and Affordable Care Act and the Health Care and Education Affordability Reconciliation Act of 2010, or
collectively, the ACA, a law intended, among other things, to broaden access to health insurance, improve quality of care, and reduce
or constrain the growth of healthcare spending.
Provisions of the ACA relevant to the pharmaceutical
industry include the following:
| ● | an annual, nondeductible fee on any entity that manufactures
or imports certain branded prescription drugs and biologic agents, apportioned among these entities according to their market share in
certain government healthcare programs, not including orphan drug sales; |
| ● | an increase in the statutory minimum rebates a manufacturer
must pay under the Medicaid Drug Rebate Program to 23.1% and 13% of the average manufacturer price for most branded and generic drugs,
respectively; |
| ● | a new Medicare Part D coverage gap discount program, in which
manufacturers must agree to offer 50% point-of-sale discounts on negotiated prices of applicable brand drugs to eligible beneficiaries
during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D; |
| ● | extension of manufacturers’ Medicaid rebate liability
to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations; |
| ● | expansion of eligibility criteria for Medicaid programs by,
among other things, allowing states to offer Medicaid coverage to additional individuals and by adding new mandatory eligibility categories
for certain individuals with income at or below 133% of the Federal Poverty Level, thereby potentially increasing manufacturers’
Medicaid rebate liability; |
| ● | expansion of the entities eligible for discounts under the
Public Health Service pharmaceutical pricing program; |
| ● | new requirements to report annually certain financial arrangements
with physicians and teaching hospitals; as defined in the ACA and its implementing regulations, including reporting any payment or “transfer
of value” provided to physicians and teaching hospitals and any ownership and investment interests held by physicians and their
immediate family members during the preceding calendar year; |
| ● | expansion of healthcare fraud and abuse laws, including the
federal civil False Claims Act and the federal Anti-Kickback Statute, new government investigative powers and enhanced penalties
for noncompliance; and |
| ● | a new Patient-Centered Outcomes Research Institute to
oversee, identify priorities in and conduct comparative clinical effectiveness research, along with funding for such research. |
There have been judicial and Congressional challenges
to certain aspects of the ACA. As a result, there have been delays in the implementation of, and action taken to repeal or replace, certain
aspects of the ACA. In January 2017, President Trump signed an Executive Order directing federal agencies with authorities and responsibilities
under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal
or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices.
Further, in January 2017, Congress adopted a budget resolution for fiscal year 2017, or the Budget Resolution, that authorizes the implementation
of legislation that would repeal portions of the ACA. Following the passage of the Budget Resolution, in March 2017, the U.S. House of
Representatives introduced legislation known as the American Health Care Act, which, if enacted, would amend or repeal significant portions
of the ACA.
In addition, other legislative changes have been
proposed and adopted since the ACA was enacted. For example, in August 2011, President Obama signed into law the Budget Control Act of
2011, which, among other things, created the Joint Select Committee on Deficit Reduction to recommend to Congress proposals in spending
reductions. The Joint Select Committee did not achieve a targeted deficit reduction of an amount greater than $1.2 trillion for the
years 2013 through 2021, triggering the legislation’s automatic reduction to several government programs. This includes aggregate
reductions to Medicare payments to healthcare providers of up to 2.0% per fiscal year, which started in 2013 and, following passage of
the Bipartisan Budget Act of 2015, will stay in effect through 2025 unless additional Congressional action is taken. In January 2013,
President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, reduced Medicare payments to several
categories of healthcare providers and increased the statute of limitations period for the government to recover overpayments to providers
from three to five years. Additionally, there have been several recent U.S. Congressional inquiries and proposed bills designed to, among
other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce
the cost of drugs under Medicare, and reform government program reimbursement methodologies for drugs. Further, the U.S. House of Representatives
recently formed an Affordable Drug Pricing Task Force to advance legislation intended to control pharmaceutical drug costs and investigate
pharmaceutical drug pricing, and the U.S. Senate has requested information from certain pharmaceutical companies in connection with an
investigation into pharmaceutical drug pricing practices. If healthcare policies or reforms intended to curb healthcare costs are adopted,
or if we experience negative publicity with respect to the pricing of our products or the pricing of pharmaceutical drugs generally, the
prices that we charge for any approved products may be limited, our commercial opportunity may be limited and/or our revenues from sales
of our products may be negatively impacted.
If we obtain regulatory approval and commercialization
of PrimeC or any of our other product candidates, these laws may result in additional reductions in healthcare funding, which could have
an adverse effect on our customers and accordingly, our financial operations. Legislative and regulatory proposals have been made to expand
post-approval requirements and restrict sales and promotional activities for pharmaceutical products. We cannot be sure whether additional
legislative changes will be enacted, or whether the FDA regulations, guidance or interpretations will be changed, or what the impact of
such changes on the marketing approvals of PrimeC or our other product candidates may be.
Although we cannot predict the full effect on our
business of the implementation of existing legislation or the enactment of additional legislation pursuant to healthcare and other legislative
reform, we believe that legislation or regulations that would reduce reimbursement for, or restrict coverage of, our products could adversely
affect how much or under what circumstances healthcare providers will prescribe or administer our products. This could adversely affect
our business by reducing our ability to generate revenues, raise capital, obtain licensees and market our products. In addition, we believe
the increasing emphasis on managed care in the United States has and will continue to put pressure on the price and usage of pharmaceutical
products, which may adversely impact product sales.
Orphan Drug Designation may not ensure that we will enjoy market
exclusivity in a particular market, and if we fail to obtain or maintain orphan drug exclusivity for our product candidates, we may be
subject to earlier competition and our potential revenue will be reduced.
Orphan Drug Designation entitles a party to financial
incentives, such as opportunities for grant funding towards clinical trial costs, tax advantages, user-fee waivers and market exclusivity
for certain periods of time.
The FDA and the EMA have both granted PrimeC orphan
drug designation for the treatment of ALS. Even if we obtain Orphan Drug Designation for our other product candidates, we may not be the
first to obtain regulatory approval for any particular orphan indication due to the uncertainties associated with developing biopharmaceutical
products. Further, even if we obtain Orphan Drug Designation for a product candidate, that exclusivity may not effectively protect the
product from competition because different drugs with different active moieties can be approved for the same condition. In addition, if
a competitor obtains approval and marketing exclusivity for a drug product with an active moiety that is the same as that in a product
candidate we are pursuing for the same indication, approval of our product candidate would be blocked during the period of marketing exclusivity
unless we could demonstrate that our product candidate is clinically superior to the approved product. In addition, if a competitor obtains
approval and marketing exclusivity for a drug product with an active moiety that is the same as that in a product candidate we are pursuing
for a different orphan indication, this may negatively impact the market opportunity for our product candidate. There have been legal
challenges to aspects of the FDA’s regulations and policies concerning the exclusivity provisions of the Orphan Drug Act, and future
challenges could lead to changes that affect the protections afforded our product candidates in ways that are difficult to predict.
Even if we receive regulatory approval for our product candidates,
we will be subject to ongoing regulatory obligations and continued regulatory review, which may result in significant additional expenses,
limit or withdraw regulatory approval and subject us to penalties if we fail to comply with applicable regulatory requirements.
If and when regulatory approval has been granted,
our product candidates or any approved product will be subject to continual regulatory review by the FDA and/or non-U.S. regulatory authorities.
Additionally, any product candidates, if approved, will be subject to extensive and ongoing regulatory requirements, including labeling
and other restrictions and market withdrawal and we may be subject to penalties if we fail to comply with regulatory requirements or experience
unanticipated problems with our products.
Any regulatory approvals that we receive for our
product candidates may also be subject to limitations on the approved indications for which the product may be marketed or to the conditions
of approval, or contain requirements for potentially costly post-marketing testing, including Phase IV clinical trials, and surveillance
to monitor the safety and efficacy of the product. In addition, if the applicable regulatory agency approves our product candidates, the
manufacturing processes, labeling, packaging, distribution, adverse event reporting, storage, advertising, promotion and recordkeeping
for the product will be subject to extensive and ongoing regulatory requirements. These requirements include submissions of safety and
other post-marketing information and reports, registration, as well as continued compliance with cGMP and GCP for any clinical trials
that we conduct post-approval.
Later discovery of previously unknown problems with
our product candidates, including adverse events of unanticipated severity or frequency, or problems with our third-party manufacturers’
processes, or failure to comply with regulatory requirements, may result in, among other things:
| ● | restrictions on the marketing or manufacturing of the product,
withdrawal of the product from the market, or voluntary or mandatory product recalls; |
| ● | fines, warnings letters or holds on clinical trials; |
| ● | refusal by the FDA to approve pending applications or supplements
to approved applications filed by us, or suspension or revocation of product license approvals; and |
| ● | product seizure or detention, or refusal to permit the import
or export of products; and injunctions or the imposition of civil or criminal penalties. |
Our ongoing regulatory requirements may also change
from time to time, potentially harming or making costlier our commercialization efforts. We cannot predict the likelihood, nature or extent
of government regulation that may arise from future legislation or administrative action, either in the United States or other countries.
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 and we may not achieve or sustain
profitability, which would adversely affect our business.
Our relationships with healthcare professionals, independent
contractors, clinical investigators, CROs, consultants and vendors in connection with our current and future business activities may be
subject to federal and state healthcare fraud and abuse laws, false claims laws, transparency laws, government price reporting, and health
information privacy and security laws. If we are unable to comply, or have not fully complied, with such laws, we could face penalties.
We may currently be or may become subject to various
U.S. federal and state health care laws, including those intended to prevent health care fraud and abuse.
The federal Anti-Kickback Statute prohibits,
among other things, persons or entities from knowingly and willfully soliciting, offering, receiving or paying any remuneration (including
any kickback, bribe or rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward either the referral
of an individual for, or the purchase, lease, order or recommendation of, any good, facility, item or service, for which payment may be
made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid Remuneration has been broadly defined to include
anything of value, including, but not limited to, cash, improper discounts, and free or reduced price items and services.
Federal false claims laws, including the federal
False Claims Act, or FCA, and civil monetary penalties law impose penalties against individuals or entities for, among other things, knowingly
presenting, or causing to be presented, to the federal government, claims for payment or approval that are false or fraudulent or making
a false record or statement to avoid, decrease or conceal an obligation to pay money to the federal government. The FCA has been used
to, among other things, prosecute persons and entities submitting claims for payment that are inaccurate or fraudulent, that are for services
not provided as claimed, or for services that are not medically necessary. The FCA includes a whistleblower provision that allows individuals
to bring actions on behalf of the federal government and share a portion of the recovery of successful claims.
Many states have similar fraud and abuse statutes
and regulations that may be broader in scope and may apply regardless of payor, in addition to items and services reimbursed under Medicaid
and other state programs. State and federal authorities have aggressively targeted medical technology companies for, among other things,
alleged violations of these anti-fraud statutes, based on improper research or consulting contracts with doctors, certain marketing
arrangements that rely on volume-based pricing, off-label marketing schemes, and other improper promotional practices.
The federal Health Insurance Portability and Accountability
Act of 1996, or HIPAA, among other things, imposes criminal liability for knowingly and willfully executing, or attempting to execute,
a scheme to defraud any healthcare benefit program or knowingly and willfully falsifying, concealing or covering up a material fact or
making any materially false statement in connection with the delivery of or payment for healthcare benefits, items or services.
Additionally, HIPAA, as amended by the Health Information
Technology for Economic and Clinical Health Act, or HITECH Act, and their implementing regulations, also impose certain obligations, including
mandatory contractual terms, on certain types of individuals and entities with respect to safeguarding the privacy, security and transmission
of individually identifiable health information without proper written authorization.
Our operations will also be subject to the federal
transparency requirements under the ACA, which require certain manufacturers of drugs, devices, biologicals and medical supplies for which
payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to annually
report to the Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S. Department of Health and Human Services,
or HHS, information related to payments and other transfers of value provided to physicians and teaching hospitals and certain ownership
and investment interests held by physicians and their immediate family members. We may also be subject to state laws that require drug
manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing
expenditures, and/or state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance
guidelines and the relevant compliance guidelines promulgated by the federal government.
If any of our business activities, including but
not limited to our relationships with healthcare providers, violate any of the aforementioned laws, we may be subject to administrative,
civil and/or criminal penalties, damages, monetary fines, disgorgement, individual imprisonment, possible exclusion from participation
in Medicare, Medicaid and other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings
and curtailment or restructuring of our operations.
Also, the U.S. Foreign Corrupt Practices Act and
similar worldwide anti-bribery laws generally prohibit companies and their intermediaries from making improper payments to non-U.S.
officials for the purpose of obtaining or retaining business. We cannot assure you that our internal control policies and procedures will
protect us from reckless or negligent acts committed by our employees, future distributors, partners, collaborators or agents. Violations
of these laws, or allegations of such violations, could result in fines, penalties or prosecution and have a negative impact on our business,
results of operations and reputation.
It may be difficult for us to profitably sell our product candidates
if coverage and reimbursement for these products is limited by government authorities and/or third-party payor policies.
In addition to any healthcare reform measures which
may affect reimbursement, market acceptance and sales of PrimeC and our other product candidates, if approved, will depend on the coverage
and reimbursement policies of government authorities and third-party payors. Government authorities and third-party payors,
such as private health insurers and health maintenance organizations, decide which medications they will cover and establish reimbursement
levels.
A primary trend in the U.S. healthcare industry
and elsewhere is cost containment. Third party payors decide which drugs they will pay for and establish reimbursement and co-payment levels.
Government and other third-party payors are increasingly challenging the prices charged for health care products, examining the cost
effectiveness of drugs in addition to their safety and efficacy, and limiting or attempting to limit both coverage and the level of reimbursement
for prescription drugs. We cannot be sure that coverage will be available for PrimeC or our other product candidates, if approved, or,
if coverage is available, the level of reimbursement.
There is significant uncertainty related to the
insurance coverage and reimbursement of newly approved products. In the United States, the principal decisions about reimbursement for
new medicines are typically made by CMS, an agency within the U.S. Department of HHS, as CMS decides whether and to what extent a new
medicine will be covered and reimbursed under Medicare. Private payors often follow CMS. It is difficult to predict what CMS as well as
other payors will decide with respect to reimbursement.
Reimbursement may impact the demand for, and/or
the price of, any product for which we obtain marketing approval. Assuming we obtain coverage for a given product by a third-party payor,
the resulting reimbursement payment rates may not be adequate or may require co-payments that patients find unacceptably high. Patients
who are prescribed medications for the treatment of their conditions, and their prescribing physicians, generally rely on third-party payors
to reimburse all or part of the costs associated with their prescription drugs. Patients are unlikely to use our products unless coverage
is provided and reimbursement is adequate to cover all or a significant portion of the cost of our products. Therefore, coverage and adequate
reimbursement is critical to new product acceptance. Coverage decisions may depend upon clinical and economic standards that disfavor
new drug products when more established or lower cost therapeutic alternatives are already available or subsequently become available.
There may be significant delays in obtaining coverage and reimbursement for newly approved drugs, and coverage may be more limited than
the purposes for which the drug is approved by the FDA or comparable foreign regulatory authorities. Moreover, eligibility for coverage
and reimbursement does not imply that a drug will be paid for in all cases or at a rate that covers our costs, including research, development,
manufacture, sale and distribution.
Reimbursement by a third-party payor may depend
upon a number of factors including the third-party payor’s determination that use of a product is:
| ● | a covered benefit under its health plan; |
| ● | safe, effective and medically necessary; |
| ● | appropriate for the specific patient; |
| ● | neither experimental nor investigational. |
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 for the use of our products to the payor. Further, no uniform policy requirement
for coverage and reimbursement for drug products exists among third-party payors in the United States. Therefore, coverage and reimbursement
for drug products can differ significantly from payor to payor. As a result, the coverage determination process may require us to provide
scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement
will be applied consistently or obtained in the first instance. We may not be able to provide data sufficient to gain acceptance with
respect to coverage and/or sufficient reimbursement levels. We cannot be sure that coverage or adequate reimbursement will be available
for PrimeC or any of our other product candidates, if approved. Also, we cannot be sure that reimbursement amounts will not reduce the
demand for, or the price of, our future products. If reimbursement is not available, or is available only to limited levels, we may not
be able to commercialize PrimeC or our other product candidates, or achieve profitably at all, even if approved.
Legislative or regulatory healthcare reforms in the United States
or abroad may make it more difficult and costly for us to obtain regulatory clearance or approval of PrimeC or any of our other product
candidates now or in the future and to produce, market, and distribute our products after clearance or approval is obtained.
From time to time, legislation is drafted and introduced in Congress
or by governments in foreign jurisdictions that could significantly change the statutory provisions governing the regulatory clearance
or approval, manufacture, and marketing of regulated products or the reimbursement thereof. In addition, FDA or foreign regulatory agency
regulations and guidance are often revised or reinterpreted by the FDA or the applicable foreign regulatory agency in ways that may significantly
affect our business and our products. Any new regulations or revisions or reinterpretations of existing regulations may impose additional
costs or lengthen review times of PrimeC or any of our other product candidates now or in the future. We cannot determine what effect
changes in regulations, statutes, legal interpretation or policies, when and if promulgated, enacted or adopted may have on our business
in the future. Such changes could, among other things, require:
| ● | changes to manufacturing methods; |
| ● | change in protocol design; |
| ● | additional treatment arm (control); |
| ● | recall, replacement, or discontinuance of one or more of our
products; and |
| ● | additional recordkeeping. |
Each of these would likely entail substantial time
and cost and could harm our business and our financial results. In addition, delays in receipt of or failure to receive regulatory clearances
or approvals for any future products would harm our business, financial condition, and results of operations.
Risks Related to an Investment in Our Ordinary Shares and Warrants
An active, liquid and orderly trading market for our ordinary
shares or Warrants may not develop, which may inhibit the ability of our shareholders to sell ordinary shares and Warrants.
Prior to our initial public offering in December
2021, there was no public market for our ordinary shares or Warrants. An active, liquid or orderly trading market in our ordinary shares
or Warrants may not develop, or if it does develop, it may not be sustained. The lack of an active market may impair your ability to sell
your shares or Warrants at the time you wish to sell them or at a price that you consider reasonable. The lack of an active market may
also reduce the fair market value of your shares. An inactive market may also impair our ability to raise capital in the future by selling
shares and may impair our ability to acquire other companies by using our shares as consideration.
The market price of our ordinary shares and Warrants may be subject
to fluctuation and you could lose all or part of your investment.
The stock market in general has been, and the market
price of our ordinary shares and Warrants in particular will likely be, subject to fluctuation, whether due to, or irrespective of, our
operating results and financial condition. The market price of our ordinary shares and Warrants on the Nasdaq Capital Market may fluctuate
as a result of a number of factors, some of which are beyond our control, including, but not limited to:
| ● | actual or anticipated variations in our and our competitors’
results of operations and financial condition; |
| ● | physician and market acceptance of our products; |
| ● | the mix of products that we sell; |
| ● | our success or failure to obtain approval for and commercialize
our product candidates; |
| ● | changes in earnings estimates or recommendations by securities
analysts, if our ordinary shares and Warrants are covered by analysts; |
| ● | development of technological innovations or new competitive
products by others; |
| ● | announcements of technological innovations or new products
by us; |
| ● | publication of the results of preclinical or clinical trials
for PrimeC or our other product candidates; |
| ● | failure by us to achieve a publicly announced milestone; |
| ● | delays between our expenditures to develop and market new
or enhanced product candidates and the generation of sales from those products; |
| ● | developments concerning intellectual property rights, including
our involvement in litigation brought by or against us; |
| ● | regulatory developments and the decisions of regulatory authorities
as to the approval or rejection of new or modified products; |
| ● | changes in the amounts that we spend to develop, acquire or
license new products, technologies or businesses; |
| ● | changes in our expenditures to promote our products; |
| ● | our sale or proposed sale, or the sale by our significant
shareholders, of our ordinary shares, Warrants or other securities in the future; |
| ● | changes in key personnel; |
| ● | success or failure of our research and development projects
or those of our competitors; |
| ● | the trading volume of our ordinary shares and Warrants; and |
| ● | general economic and market conditions and other factors,
including factors unrelated to our operating performance. |
These factors and any corresponding price fluctuations
may negatively impact the market price of our ordinary shares and Warrants and result in substantial losses being incurred by our investors.
In the past, following periods of market volatility, public company shareholders have often instituted securities class action litigation.
If we were involved in securities litigation, it could impose a substantial cost upon us and divert the resources and attention of our
management from our business.
If equity research analysts do not publish research or reports
about our business or if they issue unfavorable commentary or downgrade our ordinary shares and Warrants, the price of our ordinary shares
and Warrants could decline.
The trading market for our ordinary shares and Warrants
will rely in part on the research and reports that equity research analysts publish about us and our business, if at all. We do not have
control over these analysts and we do not have commitments from them to write research reports about us. The price of our ordinary shares
and Warrants could decline if no research reports are published about us or our business, or if one or more equity research analysts downgrade
our ordinary shares and Warrants or if those analysts issue other unfavorable commentary or cease publishing reports about us or our business.
Future sales of our ordinary shares could reduce the market price
of our ordinary shares and Warrants.
If our existing shareholders, particularly our directors,
their affiliates, or our executive officers, sell a substantial number of our ordinary shares and Warrants in the public market, the market
price of our ordinary shares and Warrants could decrease significantly. The perception in the public market that our shareholders might
sell our ordinary shares and Warrants could also depress the market price of our ordinary shares and Warrants and could impair our future
ability to obtain capital, especially through an offering of equity securities.
As of December 31, 2021, 6,582,606 of our ordinary
shares were subject to lock-up agreements with the underwriter that restrict the ability of their holders to transfer such shares
for 180 days after December 8, 2021. Consequently, upon expiration of the lock-up agreements, these ordinary shares will be eligible
for sale in the public market, of which approximately 4,196,307 ordinary shares will be subject to restrictions on volume and manner of
sale pursuant to Rule 144 under the Securities Act of 1933, or the Securities Act, as amended. However, we have filed a registration statement
on Form S-8 with the SEC covering all of the ordinary shares issuable under our 2018 Employee Share Option Plan, or the 2018 Plan,
and such shares will be available for resale following the expiration of the restrictions on transfer.
The market price of our ordinary shares and Warrants
may drop significantly when the restrictions on resale by our existing shareholders lapse and these shareholders are able to sell our
ordinary shares into the market. In addition, our sale of additional ordinary shares or similar securities in order to raise capital might
have a similar negative impact on the price of our ordinary shares and Warrants. A decline in the price of our ordinary shares and Warrants
might impede our ability to raise capital through the issuance of additional ordinary shares, Warrants or other equity securities, and
may cause you to lose part or all of your investment in our ordinary shares.
The significant share ownership position of our officers, directors
and entities affiliated with certain of our directors may limit your ability to influence corporate matters.
As of March 31, 2022, our officers, directors and entities affiliated
with certain of our directors beneficially own or control, directly or indirectly, approximately 27.4% of our outstanding ordinary shares.
Accordingly, these persons will be able to significantly influence, though not independently determine, the outcome of matters required
to be submitted to our shareholders for approval, including decisions relating to the election of our board of directors, and the outcome
of any proposed merger or consolidation of our company. These interests may not be consistent with those of our other shareholders. In
addition, these persons’ significant interest in us may discourage third parties from seeking to acquire control of us, which may
adversely affect the market price of our ordinary shares and Warrants.
We have never paid cash dividends on our share capital, and we
do not anticipate paying any cash dividends in the foreseeable future.
We have never declared or paid cash dividends on
our share capital, nor do we anticipate paying any cash dividends on our share capital in the foreseeable future. We currently intend
to retain all available funds and any future earnings to fund the development and growth of our business. As a result, capital appreciation,
if any, of our ordinary shares and Warrants will be investors’ sole source of gain for the foreseeable future. In addition, Israeli
law limits our ability to declare and pay dividends, and may subject our dividends to Israeli withholding taxes.
We will incur significant increased costs as a result of operating
as a public company in the United States, and our management will be required to devote substantial time to new compliance initiatives.
As a public company whose ordinary shares and Warrants are listed in
the United States, we are subject to an extensive regulatory regime, requiring us, among other things, to maintain various internal controls
and facilities and to prepare and file periodic and current reports and statements, including reports on the effectiveness of our internal
control over financial reporting pursuant to Section 404 of the Sarbanes-Oxley Act of 2002. Complying with these requirements will
be costly and time consuming. We will need to retain additional employees to supplement our current finance staff, and we may not be able
to do so in a timely manner, or at all. In the event that we are unable to demonstrate compliance with our obligations as a public company
in a timely manner, or are unable to produce timely or accurate financial statements, we may be subject to sanctions or investigations
by regulatory authorities, such as the SEC or the Nasdaq Capital Market, and investors may lose confidence in our operating results and
the price of our ordinary shares and Warrants could decline.
Our independent registered public accounting firm
was not engaged to perform an audit of our internal control over financial reporting, and as long as we remain an emerging growth company,
as such term is defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act, we are exempt from the requirement to have
an independent registered public accounting firm perform such audit. Accordingly, no such opinion was expressed or will be expressed any
during any such period. Once we cease to qualify as an emerging growth company our independent registered public accounting firm will
be required to attest to our management’s annual assessment of the effectiveness of our internal controls over financial reporting,
which will entail additional costs and expenses.
Furthermore, we are only in the early stages of
determining formally whether our existing internal controls over financial reporting systems are compliant with Section 404 and whether
there are any material weaknesses or significant deficiencies in our existing internal controls. These controls and other procedures are
designed to ensure that information required to be disclosed by us in the reports that we file with the SEC is disclosed accurately and
is recorded, processed, summarized and reported within the time periods specified in SEC rules and forms.
The Warrants may not have any value.
The Warrants are exercisable
for five years from the date of initial issuance at an initial exercise price equal to $6.00. There can be no assurance that the market
price of our ordinary shares will ever equal or exceed the exercise price of the Warrants. In the event that our ordinary share price
does not exceed the exercise price of the Warrants during the period when the Warrants are exercisable, the Warrants may not have any
value.
A Warrant does not entitle the holder
to any rights as a holder of our ordinary shares until the holder exercises the Warrant for an ordinary shares.
Until you acquire an ordinary
share upon exercise of your Warrants, your Warrants will not provide you any rights as a holder of ordinary shares. Upon exercise of your
Warrants, you will be entitled to exercise the rights of a holder of ordinary shares only as to matters for which the record date occurs
after the exercise date.
If we are a “passive foreign investment company”
for U.S. federal income tax purposes, there could be adverse U.S. federal income tax consequences to U.S. investors.
We may be classified as a passive foreign investment
company, or PFIC, for the taxable year ending December 31, 2021, and we may be treated as a PFIC in the current taxable year as well
as in future taxable years. The determination of our PFIC status is made annually based on the factual tests described below. Consequently,
we cannot provide any assurances regarding our PFIC status for the current or future taxable years or that the IRS will agree with our
conclusion regarding our PFIC status. Generally, if, for any taxable year, at least 75 percent of our gross income is “passive
income” or at least 50 percent of our gross assets during the taxable year (based on the average of the fair market values
of the assets determined at the end of each quarterly period) are assets that produce or are held for the production of passive income,
we would be characterized as a PFIC for U.S. federal income tax purposes. Passive income for this purpose generally includes, among other
things, dividends, interest, rents, royalties, gains from commodities and securities transactions, and gains from assets that produce
passive income. However, rents and royalties received from unrelated parties in connection with the active conduct of a trade or business
are not considered passive income for purposes of the PFIC test. If we are a PFIC for any taxable year in which a U.S. Holder (as defined
in “Taxation—Material United States federal income tax considerations”) holds our common shares or Warrants, certain
adverse United States federal income tax consequences could apply to such U.S. Holder. See “Taxation—Material United States
federal income tax considerations—Passive Foreign Investment Company considerations.”
Whether we are a PFIC for any taxable year will
depend on the composition of our income and the composition and value of our assets from time to time. Each U.S. Holder is strongly urged
to consult its tax advisor regarding these issues and any available elections to mitigate such tax consequences.
As a foreign private issuer, we are permitted, and intend, to
follow certain home country corporate governance practices instead of otherwise applicable Nasdaq requirements, and are not be subject
to certain U.S. securities laws including, but not limited to, U.S. proxy rules and the filing of certain Exchange Act reports.
As a foreign private issuer, we are permitted, and
intend, to follow certain home country corporate governance practices instead of those otherwise required by the Nasdaq Stock Market for
domestic U.S. issuers. Following our home country governance practices as opposed to the requirements that would otherwise apply
to a U.S. company listed on the Nasdaq Capital Market may provide less protection to you than what is accorded to investors under the
Nasdaq Rules applicable to domestic U.S. issuers. See Item 16G.
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, including disclosures with
respect to executive compensation. Nevertheless, pursuant to regulations promulgated under the Israeli Companies Law, 5759-1999, or the
Israeli Companies Law, we are required to disclose the annual compensation of our five most highly compensated office holders on an individual
basis. Such disclosure will not be as extensive as that required of a U.S. domestic issuer. Our officers, directors and principal shareholders
will also be exempt from the reporting and short-swing profit recovery provisions contained in Section 16 of the Exchange Act. In
addition, we are required under the Exchange Act to file reports and financial statements with the SEC as frequently or as promptly as
U.S. domestic companies whose securities are registered under the Exchange Act and are exempt from filing quarterly reports with the SEC
under the Exchange Act. Moreover, we are not required to comply with Regulation FD, which restricts the selective disclosure of material
information, although we have voluntarily adopted a corporate disclosure policy substantially similar to Regulation FD. These exemptions
and leniencies will reduce the frequency and scope of information and protections to which you may otherwise have been eligible in relation
to a U.S. domestic 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. 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. We may also be required to modify certain of our policies to comply with
accepted governance practices associated with U.S. domestic issuers. Such conversion and modifications will involve additional costs.
In addition, we would lose our ability to rely upon exemptions from certain corporate governance requirements on U.S. stock exchanges
that are available to foreign private issuers.
We are an emerging growth company and the reduced disclosure
requirements applicable to emerging growth companies may make our ordinary shares less attractive to investors.
We are an emerging growth company, as defined in
the JOBS Act, and we may take advantage of certain exemptions from various requirements that are applicable to other public companies
that are not emerging growth companies.
For as long as we remain an emerging growth company
we are permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies that
are not “emerging growth companies.” These exemptions include:
| ● | not being required to comply with the auditor attestation
requirements in the assessment of our internal control over financial reporting; |
| ● | not being required to comply with any requirement that may
be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor’s
report providing additional information about the audit and the financial statements; |
| ● | reduced disclosure obligations regarding executive compensation;
and |
| ● | exemptions from the requirements of holding a nonbinding advisory
vote on executive compensation and shareholder approval of any golden parachute payments not previously approved. |
We will remain an emerging growth company until
the earliest of: (i) the last day of our fiscal year during which we have total annual gross revenues of at least $1.07 billion;
(ii) the last day of our fiscal year following the fifth anniversary of the closing of our initial public offering; (iii) the date on
which we have, during the previous three-year period, issued more than $1.0 billion in non-convertible debt; or (iv) the
date on which we are deemed to be a “large accelerated filer” under the Exchange Act. We have opted out of the extended transition
period made available to emerging growth companies to comply with newly adopted public company accounting requirements.
When we are no longer deemed to be an emerging growth
company, we will not be entitled to the exemptions provided in the JOBS Act discussed above. We cannot predict if investors will find
our ordinary shares or Warrants less attractive as a result of our reliance on exemptions under the JOBS Act. If some investors find our
ordinary shares or Warrants less attractive as a result, there may be a less active trading market for our ordinary shares or Warrants
and our share price may be more volatile.
Risks Related to our Operations in Israel
Our headquarters, research and development and other significant
operations are located in Israel and, therefore, our results may be adversely affected by political, economic and military instability
in Israel.
Our corporate headquarters is located in Herzliya,
Israel. If these or any future facilities in Israel were to be damaged, destroyed or otherwise unable to operate, whether due to war,
acts of hostility, earthquakes, fire, floods, hurricanes, storms, tornadoes, other natural disasters, employee malfeasance, terrorist
acts, power outages or otherwise, or if performance of our research and development is disrupted for any other reason, such an event could
delay our clinical trials or, if our product candidates are approved and we choose to manufacture all or any part of them internally,
jeopardize our ability to manufacture our products as promptly as our prospective customers will likely expect, or possibly at all. If
we experience delays in achieving our development objectives, or if we are unable to manufacture an approved product within a timeframe
that meets our prospective customers’ expectations, our business, prospects, financial results and reputation could be harmed.
Political, economic and military conditions in Israel
may directly affect our business. Since the establishment of the State of Israel in 1948, a number of armed conflicts have taken place
between Israel and its neighboring countries, Hamas (an Islamist militia and political group that controls the Gaza Strip) and Hezbollah
(an Islamist militia and political group based in Lebanon). In addition, several countries, principally in the Middle East, restrict doing
business with Israel, and additional countries may impose restrictions on doing business with Israel and Israeli companies whether as
a result of hostilities in the region or otherwise. Any hostilities involving Israel, terrorist activities, political instability or violence
in the region or the interruption or curtailment of trade or transport between Israel and its trading partners could adversely affect
our operations and results of operations and adversely affect the market price of our ordinary shares and Warrants.
Our commercial insurance does not cover losses that
may occur as a result of an event associated with the security situation in the Middle East. Although the Israeli government is currently
committed to covering the reinstatement value of direct damages that are caused by terrorist attacks or acts of war, there can be no assurance
that this government coverage will be maintained, or if maintained, will be sufficient to compensate us fully for damages incurred. Any
losses or damages incurred by us could have a material adverse effect on our business, financial condition and results of operations.
Further, our operations could be disrupted by the obligations of our
employees to perform military service. As of December 31, 2021, all of our employees were based in Israel. Of these employees, some may
be military reservists, and may be called upon to perform military reserve duty for several weeks until they reach the age of 40 (or older
for reservists who are military officers or have certain occupations). Additionally, they may be called to active duty at any time under
emergency circumstances. In response to increased tension and hostilities in the region, there have been, at times, call-ups of military
reservists, and it is possible that there will be additional call-ups in the future. Our operations could be disrupted by the absence
of these employees due to military service. Such disruption could harm our business and operating results.
Provisions of Israeli law and our amended and restated articles
of association may delay, prevent or otherwise impede a merger with, or an acquisition of, us, even when the terms of such a transaction
are favorable to us and our shareholders.
Israeli corporate law regulates mergers, requires
tender offers for acquisitions of shares above specified thresholds, requires special approvals for transactions involving directors,
officers or significant shareholders and regulates other matters that may be relevant to such types of transactions. For example, a tender
offer for all of a company’s issued and outstanding shares can only be completed if shareholders not accepting the tender offer
hold less than 5% of the issued share capital. Completion of the tender offer also requires approval of a majority of the offerees that
do not have a personal interest in the tender offer, unless shareholders not accepting the tender offer hold less than 2% of the company’s
outstanding shares. Furthermore, the shareholders, including those who indicated their acceptance of the tender offer, may, at any time
within six months following the completion of the tender offer, petition an Israeli court to alter the consideration for the acquisition,
unless the acquirer stipulated in its tender offer that a shareholder that accepts the offer may not seek such appraisal rights.
Furthermore, Israeli tax considerations may make
potential transactions unappealing to us or to our shareholders whose country of residence does not have a tax treaty with Israel exempting
such shareholders from Israeli tax. For example, Israeli tax law does not recognize tax-free share exchanges to the same extent as
U.S. tax law. With respect to mergers, Israeli tax law allows for tax deferral in certain circumstances but makes the deferral contingent
on the fulfillment of a number of conditions, including, in some cases, a holding period of two years from the date of the transaction
during which sales and dispositions of shares of the participating companies are subject to certain restrictions. Moreover, with respect
to certain share swap transactions, the tax deferral is limited in time, and when such time expires, the tax becomes payable even if no
disposition of the shares has occurred. These provisions could delay, prevent or impede an acquisition of us or our merger with another
company, even if such an acquisition or merger would be beneficial to us or to our shareholders.
It may be difficult to enforce a judgment of a U.S. court against
us or our officers and directors in Israel or the United States, to assert U.S. securities laws claims in Israel or to serve process on
our officers and directors and these experts.
We are incorporated in Israel. The majority of our
directors and all of our executive officers reside outside of the United States, and most of our assets and most of the assets of these
persons are located outside of the United States. Therefore, a judgment obtained against us, or any of these persons, including a judgment
based on the civil liability provisions of the U.S. federal securities laws, may not be collectible in the United States and may not be
enforced by an Israeli court. It may also be difficult for you to effect service of process on these persons in the United States or to
assert U.S. securities law claims in original actions instituted in Israel. Israeli courts may refuse to hear a claim based on an alleged
violation of U.S. securities laws reasoning that Israel is not the most appropriate forum in which to bring such a claim. In addition,
even if an Israeli court agrees to hear a claim, it may determine that Israeli law and not U.S. law is applicable to the claim. If U.S.
law is found to be applicable, the content of applicable U.S. law must be proven as a fact by expert witnesses, which can be a time consuming
and costly process. Certain matters of procedure will also be governed by Israeli law.
There is little binding case law in Israel that
addresses the matters described above. As a result of the difficulty associated with enforcing a judgment against us in Israel, you may
not be able to collect any damages awarded by either a U.S. or foreign court.
Your rights and responsibilities as a shareholder will be governed
by Israeli law, which differs in some material respects from the rights and responsibilities of shareholders of U.S. companies.
The rights and responsibilities of the holders of
our ordinary shares are governed by our amended and restated articles of association and by Israeli law. These rights and responsibilities
differ in some material respects from the rights and responsibilities of shareholders in U.S. companies. In particular, a shareholder
of an Israeli company has a duty to act in good faith and in a customary manner in exercising its rights and performing its obligations
towards the company and other shareholders, and to refrain from abusing its power in the company, including, among other things, in voting
at a general meeting of shareholders on matters such as amendments to a company’s articles of association, increases in a company’s
authorized share capital, mergers and acquisitions and related party transactions requiring shareholder approval, as well as a general
duty to refrain from discriminating against other shareholders. In addition, a shareholder who is aware that it possesses the power to
determine the outcome of a vote at a meeting of the shareholders or to appoint or prevent the appointment of a director or executive officer
in the company has a duty of fairness toward the company.
There is limited case law available to assist us
in understanding the nature of these duties or the implications of these provisions. These provisions may be interpreted to impose additional
obligations and liabilities on holders of our ordinary shares that are not typically imposed on shareholders of U.S. companies.
Our amended and restated articles of association provide that,
unless we consent otherwise, the District Court (Economic Division), located in Tel Aviv, Israel shall be the sole and exclusive forum
for substantially all disputes between us and our shareholders under the Companies Law and the Israeli Securities Law, which could limit
our shareholders’ ability to bring claims and proceedings against, as well as obtain favorable judicial forum for disputes with,
us, our directors, officers and other employees.
The District Court (Economic Division), located
in Tel Aviv, Israel shall be the exclusive forum for (i) any derivative action or proceeding brought on behalf of us, (ii) any action
asserting a claim of breach of fiduciary duty owed by any director, officer or other employee of ours to us or our shareholders, or (iii)
any action asserting a claim arising pursuant to any provision of the Companies Law or the Israeli Securities Law. This exclusive forum
provision is intended to apply to claims arising under Israeli law and would not apply to claims brought pursuant to the Securities Act
or the Exchange Act or any other claim for which U.S. federal courts would have exclusive jurisdiction. Such exclusive forum provision
in our amended and restated articles of association will not relieve us of our duties to comply with federal securities laws and the rules
and regulations thereunder, and our shareholders will not be deemed to have waived our compliance with these laws, rules and regulations.
This exclusive forum provision may limit a shareholder’s ability to bring a claim in a judicial forum of its choosing for disputes
with us or our directors, officers or other employees, which may discourage lawsuits against us, our directors, officers and other employees.
ITEM 4. INFORMATION ON THE COMPANY
A. History and Development of the Company
Our legal and commercial name is NeuroSense
Therapeutics Ltd. Our company was incorporated on February 13, 2017 and was registered as a private company limited by shares under the
laws of the State of Israel. Our principal executive offices are located at 11 Hamenofim, Herzliya, Israel. Our telephone number is +972-9-7996183.
Our website address is https://www.neurosense-tx.com. The information contained therein, or that can be accessed therefrom, 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 agent for service of process in the United States is Cogency Global Inc., located
at 122 East 42nd Street, 18th Floor, New York, New York 10168.
In December 2021 we completed our initial public
offering on The Nasdaq Capital Market, pursuant to which we received net proceeds of approximately $9.9 million, after deducting
underwriting discounts and commissions and offering expenses.
Our Ordinary Shares and Warrants are traded on The
Nasdaq Capital Market under the symbols “NRSN” and “NRSNW,” respectively.
Our capital expenditures for the years ended December
31, 2021 and 2020 were approximately $17 thousand and $9 thousand, respectively. Our current capital expenditures involve purchase of
equipment.
B. Business Overview
Our goal is to develop therapeutics to defeat neurodegenerative
diseases. We are a clinical-stage biotechnology company focused on discovering and developing treatments for patients suffering from
debilitating neurodegenerative diseases. We believe that these diseases, which include Amyotrophic Lateral Sclerosis, or ALS, Alzheimer’s
disease and Parkinson’s disease, among others, represent one of the most significant unmet medical needs of our time, with limited
effective therapeutic options available for patients. The burden of these diseases on both patients and society is substantial. For example,
the average annual cost of ALS alone is $180,000 per patient, and its estimated annual burden on the U.S. healthcare system is greater
than $1 billion. Due to the complexity of neurodegenerative diseases, our strategy is to develop combined therapies targeting multiple
pathways associated with these diseases.
Our lead product candidate, PrimeC, is a novel extended-release,
or ER, oral formulation of a fixed dose combination of two generic FDA-approved drugs, ciprofloxacin and celecoxib, combined in a
specific ratio. Ciprofloxacin was approved to treat or prevent a variety of bacterial infections and celecoxib was approved as a prescription
nonsteroidal anti-inflammatory drug used to treat pain. PrimeC is designed to treat ALS by regulating microRNA, or miRNA, synthesis,
influencing iron accumulation and reducing neuroinflammation, all of which are hallmarks of ALS pathologies. The U.S. Food and Drug Administration,
or FDA, and the European Medicines Agency, or EMA, have both granted PrimeC an orphan drug designation for the treatment of ALS. We believe
PrimeC’s multifactorial mechanism of action has the potential to significantly prolong lifespan and improve ALS patients’
quality of life, thereby reducing the burden of this debilitating disease on both patients and healthcare systems.
In addition to PrimeC, we recently initiated research
and development efforts in Alzheimer’s disease and Parkinson’s disease, with a similar strategy of combined products. The
following chart represents our current product development pipeline:
In February 2021, we completed a Phase IIa clinical
trial with an intermediate immediate release formulation of PrimeC in ALS patients at the Tel Aviv Sourasky Medical Center, Israel, which
we refer to as NST002. The primary endpoint of the NST002 trial, PrimeC’s safety and tolerability, was met. In this trial, we observed
a safety profile consistent with known safety profiles of ciprofloxacin and celecoxib, and that was mild and transient in nature. There
were no new or unexpected safety signals detected during the trial.
Specifically, 67% of patients experienced at least
one treatment emergent adverse event, or TEAE. While most of the TEAEs were assessed by the investigator as unrelated to study drug, 27%
experienced a TEAE that was assessed by the investigator as related to the study drug, most of which were gastrointestinal disorders.
The TEAEs in descending order of frequency were gastrointestinal disorders (38.4%), infections (15.4%), injury (12.8%), general disorders,
psychiatric disorders, and nervous system disorders (7.7% each), and investigative, musculoskeletal, skin, and surgical procedures (2.6%
each).
Most of the TEAEs (67%) were mild or moderate in
intensity. Six patients (40%) experienced at least one severe TEAE. No clinically meaningful treatment-emergent changes were noted
for any patient in the laboratory safety parameters, vital signs, or electrocardiograms.
Additionally, we observed positive clinical signals
in comparison to virtual controls, and a serum biomarker analysis showed significant changes following treatment, indicating biological
activity of the drug. All 12 patients who completed the NST002 trial elected to continue into an extension study with PrimeC.
Based on the results of the NST002 trial and further
studies in the interim, in conjunction with our discussions with the FDA on potential trial design, we intend to initiate a pivotal Phase
III trial to further evaluate the treatment of PrimeC in the second half of 2023.
Prior to commencing the pivotal Phase III trial,
we intend to initiate three additional studies to further support our future regulatory submissions. First, we plan to initiate a three-month toxicity
study in rats to confirm the safety of PrimeC in high doses, in response to a request from the FDA. Additionally, the ER formulation of
PrimeC encompasses a novel delivery mechanism of ciprofloxacin and celecoxib, and is designed to maximize the profile of each of the drugs
in order to capitalize on synergies between the two. To this end, we also plan to evaluate PrimeC’s ER formulation in a pharmacokinetic,
or PK, study to assess the exposure levels and to ensure the desired PK profile. On March 18, 2022 we received clearance from the FDA
to initiate the PK study of PrimeC in healthy adult subjects.
In addition, we intend to conduct a Phase IIb placebo-controlled clinical
study with PrimeC’s ER formulation that will evaluate several biomarkers, with the goal of increasing our understanding of the changes
in the pathological pathways of ALS and informing the final trial design for our pivotal Phase III trial.
We have secured U.S. Patent 10,980,780 relating
to methods for treatment of ALS using ciprofloxacin and celecoxib, the components of PrimeC, which expires in 2038. In September 2021,
we received notice that our pending patent application, related to our lead candidate, PrimeC, had been allowed in Australia, and in December
of 2021, the patent granted. Similar patents applications have been allowed in the European Patent Office and Canada and are pending in
Israel. We also expect to take advantage of orphan drug exclusivity for PrimeC, if approved, for seven years in the United States and
ten years in the European Union.
Our organization is built around a management team
with extensive experience in the pharmaceutical industry, with a particular focus on ALS research and clinical trials. We believe that
our leadership team is well-positioned to lead us through clinical development, regulatory approval and commercialization of our
product candidates.
Overview of ALS
ALS, which is also commonly referred to as Lou Gehrig’s
disease, is a rapidly progressing neurological disease with the onset typically occurring between 40 to 70 years of age, and patient mortality
occurring in most patients within two to five years of diagnosis. ALS causes the death of motor neurons, which are responsible for controlling
muscles, resulting in weakness and paralysis of limbs, and impacts speaking, chewing, swallowing and breathing, leading to progressive
disability and eventually death, typically from respiratory failure and aspiration pneumonia. In addition, up to 50% of patients with
ALS develop cognitive impairment associated with frontotemporal dementia. The underlying cause of damage to the motor neurons is unknown,
but many pathologies can be observed, including dysregulation of miRNA, iron accumulation, neuroinflammation, glutamate excitotoxicity,
protein misfolding and oxidative stress.
About 10% of ALS cases are inherited, commonly referred
to as “familial ALS,” and are associated with pathogenic mutations, while the remaining 90% of cases present with sporadic
onset. Over the last decade, sequencing of patients’ genomes has helped pinpoint the genetic mutations that are most commonly correlated
with ALS, including TDP-43, SOD1, FUS and C9ORF72.
Despite being classified as a rare disease, ALS
is considered one of the more common neuromuscular diseases worldwide. The Centers for Disease Control and Prevention estimates that there
are approximately 20,000 cases of ALS in the United States and that approximately 5,000 new cases are diagnosed each year. The number
of total cases for the largest five markets in Europe (Germany, France, Italy, Spain and the United Kingdom) is estimated to be slightly
higher and for the broader European geography the estimate is approximately 30,000 cases. Overall, it is estimated that our planned target
market is currently over 80,000 patients, and that the patient population in the United States and Europe will grow by 24% by 2040.
ALS also imposes a significant burden on the healthcare
system, with an estimated $180,000 patient cost per year and an estimated annual burden greater than $1 billion on the U.S. healthcare
system.
Current Treatment Options and Unmet Need
There are currently a limited number of available
treatments for ALS and these treatments only impart a modest effect, extending a patient’s life expectancy by only a few months
on average. Patients are often managed by specialized multidisciplinary care sites, of which there are approximately 200 in the United
States, or by community practices and clinics.
Until recently, the only approved drug used for
slowing disease progression in ALS was Rilutek (riluzole). It was the first drug to be approved by the FDA for the treatment of ALS over
25 years ago. In May 2017, the FDA approved Radicava (edaravone), which is administered through chronic cycles of ten days of intravenous
infusions followed by a two-week treatment-free period. In recent years, the FDA has also approved two new formulations of riluzole
that address the need for an improved route of administration in patients who suffer from swallowing complications. In September 2018,
the FDA approved Tiglutik, the oral suspension of riluzole administered via syringe, and in November 2019, the FDA approved Exservan,
a new soluble oral formulation which dissolves on the tongue. In Europe, edaravone is not approved, and therefore the only approved drug
for ALS is riluzole. As both riluzole and edaravone have been shown to have minimal effect on prolonging patient lifespans or improving
their quality of life and independence, we believe there is still a need for new treatments for patients with ALS in order to improve
the disease course and to further extend survival.
There are currently several treatments for ALS under
development by competitors such as Biogen Inc., Amylyx Pharmaceuticals Inc., AB Science SA, Prilenia Therapeutics B.V, and Apellis Pharmaceuticals.
Biogen is developing injectable targeted therapies for specific genetic mutations in ALS, such as Tofersen, a SOD1 antisense-oligonucleotide (ASO),
which is currently being evaluated following a Phase III clinical trial that did not achieve its primary endpoint. Amylyx, who recently
completed a Phase IIb trial, is developing an oral combination drug made up of two generic compounds, targeting dysfunction of the endoplasmic
reticulum (ER) and mitochondria, named AMX0035. AB Science is currently running a Phase III trial with its product Masitinib, an oral
treatment targeting mast cells and microglia cells. Prilenia, whose oral product Pridopidine was originally developed for Huntington’s
disease, is currently running a Phase II trial in patients with ALS as well. Lastly, Apellis is developing Pegcetacoplan, an injectable
targeted C3 therapy, currently being tested in a Phase II clinical trial.
As shown in the chart below, PrimeC is well positioned
when compared to our aforementioned competitors. This chart is representative of publicly available information regarding the efforts
of our competitors and does not capture all differences in approach, such as trial constructs, which could have an impact in their relative
success in developing, acquiring or licensing treatments for ALS when compared to us.
Our Solution — PrimeC for ALS
Our lead product candidate, PrimeC, is a novel formulation
of a fixed dose combination of two generic FDA-approved drugs, ciprofloxacin and celecoxib, combined in a specific ratio. PrimeC
is designed to treat ALS by regulating miRNA synthesis, influencing iron accumulation and reducing neuroinflammation, all of which are
hallmarks of ALS pathologies.
miRNA are small non-coding RNAs which play a critical role in
regulating gene expression. Studies show that miRNA are dysregulated in motor neurons of autopsy tissues from patients with ALS, and that
reduction in miRNA is sufficient to cause spinal motor neuron degeneration in-vivo. Consequently, dysregulation of miRNA levels
due to inefficient activity of Dicer enzyme which plays a key role in their generation, is common in multiple forms of ALS. Dysregulated
miRNAs are found in multiple ALS models and patient-based microglia cells, motor neurons and skeletal muscles controlling multiple
targets, such as neuroinflammation, synaptic formation, neuronal activity and differentiation.
Iron accumulation has been shown to be present in
many neurodegenerative diseases including ALS. As such, iron chelation therapies have been shown to have a positive effect in preclinical
models of neurodegeneration.
Finally, chronic neuroinflammation is increasingly
recognized as a major factor that promotes ALS disease progression and amplifies the motor neuron death-inducing processes. Neuroinflammation
is characterized by extensive astrogliosis, microglial activation, and infiltration of peripheral immune cells at sites of neurodegeneration.
Since the many pathological pathways of ALS are
convoluted and highly complex, we are developing a synergistic multifactorial treatment strategy to target multiple ALS-related pathways
simultaneously.
Ciprofloxacin is a fluoroquinolone antibiotic often
used to treat bacterial infections, which has been safely used for many years in large and diverse patient populations. Ciprofloxacin
is approved for use in gram-negative bacterial infections such as lower respiratory tract infections, chronic sinusitis, genital
tract infections and infections of the skin and soft tissues. Additionally, ciprofloxacin is approved for chronic ear infections, urinary
tract infections, gastro-intestinal and intra-abdominal infections, malignant external otitis, infections of the bones and joints,
prophylaxis of invasive infections due to Neisseria meningitidis, inhalation anthrax, and broncho-pulmonary infections in cystic
fibrosis caused by Pseudomonas aeruginosa. Ciprofloxacin may also be used to treat severe infections in children and adolescents when
this is considered to be necessary.
Studies have shown that besides its antibiotic mechanisms,
ciprofloxacin is also able to upregulate the expression of miRNAs by inducing dicer activity and is a moderate iron chelator.
Celecoxib is a prescription nonsteroidal anti-inflammatory drug,
or NSAID, used to treat pain through the inhibition of cyclooxygenase-2, or COX-2, and the reduction of inflammatory processes, thereby
affecting glutamate excitotoxicity and oxidative stress, among others. Celecoxib is approved for use for the management of the signs and
symptoms of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis in patients two years and older, and ankylosing spondylitis.
Additionally, celecoxib is approved for the management of acute pain in adults, and for the management of primary dysmenorrhea. Although
not shown to be beneficial in ALS when given at high doses as a single agent, low doses of celecoxib were shown to be effective in pain
management and played a synergistic role with ciprofloxacin in preclinical models of ALS zebrafish (SOD1 and TDP-43).
With PrimeC, we aim to target three key features
of ALS that contribute to motor neuron degeneration — impaired miRNA regulation, accumulation of iron, and inflammation of the nervous
system. Through analysis of blood samples from healthy subjects and patients with ALS, we observed the relevance of PrimeC’s mechanism
of action using a novel method involving neuron-derived exosomes. Additionally, the primary endpoint of safety and tolerability was
met in our NST002 trial in ALS patients, which was completed in February 2021. Through analysis of blood samples from this study using
the same exosomal method, we observed significant changes in ALS-related biomarkers, indicating biological activity of PrimeC.
Our Competitive Strengths
We believe we have the potential to transform the
lives of individuals living with devastating neurodegenerative diseases beginning with patients suffering from ALS. Our key competitive
strengths include:
| ● | PrimeC uses a combined therapeutic strategy targeting multiple
ALS pathways. PrimeC is designed to work synergistically on multiple targets affected in ALS, regulating miRNA synthesis, influencing
iron accumulation and reducing neuroinflammation. We believe PrimeC’s multifactorial mechanism of action has the potential to prolong
lifespan significantly and improve patients’ quality of life, thereby reducing the burden of disease on both patients and healthcare
systems. |
| ● | PrimeC is designed as an orally administered, non-invasive treatment.
Many drugs being developed for ALS are invasive by nature as they include infusions, lumbar punctures and additional medical procedures,
causing a negative effect on patient quality of life. Of the two treatments for ALS that have been approved by the FDA, although one
is oral, the other is delivered by regular intravenous infusions. In contrast, PrimeC is delivered orally. The oval shape of the tablet
and its small size make PrimeC easy to swallow, minimizing disruption to patients’ quality of life. |
| ● | Decreased potential time to market and known safety profiles.
Based on interactions with the FDA to date, we expect the review process for PrimeC to be conducted according to the FDA’s 505(b)(2)
regulatory pathway, which permits us to rely, in part, upon the FDA’s previous findings of safety and efficacy for an approved
product, thereby reducing the time to market. More specifically, in January 2021, in written comments to our pre-IND package, the
FDA stated that a 505(b)(2) application would be an acceptable approach based on the information we provided. Ciprofloxacin and celecoxib,
which form the components of PrimeC, have known safety profiles and have each already been approved by the FDA. |
| ● | Our lead product candidate, PrimeC, is covered by an issued
U.S. patent relating to methods for treatment of ALS using ciprofloxacin and celecoxib, the components of PrimeC, and additional regulatory
exclusivity protections through orphan designations granted by FDA and EMA. We have an issued U.S. patent relating to methods for
treatment of ALS using ciprofloxacin and celecoxib, the components of PrimeC, which expires in 2038, as well as a pending provisional
patent application in the U.S. relating to the formulation of PrimeC. An additional U.S. patent application is pending relating to methods
for treatment of other neurodegenerative diseases using ciprofloxacin and celecoxib. In addition, the FDA and EMA have each granted PrimeC
orphan drug designation for the treatment of ALS in January 2020 and January 2021, respectively. We expect to take advantage of the orphan
drug exclusivity for PrimeC, if approved, for seven years in the United States and ten years in the European Union. |
| ● | Combined therapeutic approach potentially relevant to multiple
complex neurodegenerative diseases. Our philosophy is based on the treatment of complex diseases using combined therapies in order
to target multiple underlying pathophysiological pathways. Our preclinical pipeline includes two additional product candidates, StabiliC
and CogniC, that utilize a combination of ciprofloxacin and celecoxib for the treatment of Parkinson’s disease and Alzheimer’s
disease, respectively. We are also exploring the use of ciprofloxacin and celecoxib for additional neurological indications beyond Parkinson’s
disease and Alzheimer’s disease. |
| ● | Deep scientific expertise of management, our board of directors
and scientific advisory board. Our management team and scientific advisory board members have extensive experience in neurodegenerative
research and clinical trials. We believe that our leadership team is well-positioned to lead us through clinical development, regulatory
approval and commercialization of our product candidates. We are recruiting additional professional team members in relevant positions
to ensure an efficient execution of our overall business strategy. |
Our Strategy
The key pillars of our business strategy include:
| ● | Complete registrational studies and secure regulatory approvals
in the United States and European Union for PrimeC for the treatment of ALS. Based on results from our NST002 trial and other studies
we will conduct in the interim, we intend to initiate a Phase IIb trial in the first half of 2022 and then a pivotal registrational trial
in the second half of 2023 that we expect, if successful, could provide the basis for an NDA submission to the FDA, as well as a submission
to the EMA. |
| ● | Actively expand and advance our pipeline, including developing
our preclinical product candidates, StabiliC and CogniC, for the treatment of Parkinson’s disease and Alzheimer’s disease,
respectively. Many pathological pathways involve neuroinflammation, protein aggregation, mitophagy, excitotoxicity, oxidative stress,
iron accumulation, and dysregulation of microRNAs (miRNAs) between neurodegenerative diseases, leading to the hypothesis that an effective
drug for one neurodegenerative disease can lay the foundations for other diseases-modifying drugs. Therefore, we are evaluating
the neuroprotective effects of our product candidates and their effectiveness in treating Parkinson’s disease and Alzheimer’s
disease. |
| ● | Evaluate and pursue potential collaborations to develop
our preclinical pipeline. We plan to evaluate the merits of entering into collaboration agreements with other pharmaceutical or biotechnology
companies that may contribute to our ability to efficiently advance our preclinical product candidates, build our product pipeline and
concurrently advance a range of research and development programs. Such collaborations would allow us to obtain financial support and
to capitalize on the expertise and resources of our potential partners, which could accelerate the development and commercialization
of additional product candidates. |
Our Product Candidates
PrimeC
Our lead product candidate, PrimeC, is a novel ER
oral formulation of a fixed dose combination of two generic FDA-approved drugs, ciprofloxacin and celecoxib, combined in a specific
ratio. PrimeC is designed to treat ALS by regulating miRNA synthesis, influencing iron accumulation and reducing neuroinflammation.
Clinical Results — NST002 Phase IIa Trial in ALS
In February 2021, we completed our Phase IIa NST002
trial of PrimeC for the treatment of ALS. NST002 was an open label study that was designed to assess the safety and tolerability of an
intermediate immediate-release formulation of PrimeC (PrimeC-IR), as well as routine disease progression measures. Fifteen patients
with familial or sporadic ALS received a fixed dose of PrimeC-IR three times per day for 12 months. Patients were then evaluated
by phone every 1.5 months and at a clinical site visit every three months.
The primary endpoint of the trial was PrimeC-IR’s
safety and tolerability, which was measured by the number of patients with one or more treatment-emergent adverse events, the number
of patients who discontinued treatment prematurely, the number of patients who discontinued treatment prematurely due to adverse events
and the number of patients with significant abnormal laboratory values. The primary endpoint was met, with PrimeC-IR showing a safety
profile that was consistent with known safety profiles of ciprofloxacin and celecoxib, and was mild and transient in nature. There were
no new or unexpected safety signals detected during the trial.
Specifically, of the 15 patients in the safety population,
ten patients (67%) experienced at least one treatment emergent adverse event, or TEAE. While most of the TEAEs were assessed by the investigator
as unrelated to study drug, four patients (27%) experienced a TEAE that was assessed by the investigator as related to the study drug.
Of TEAEs that were assessed as related to study drug, 11 were gastrointestinal disorders (flatulence was reported four times, nausea three
times, dyspepsia twice, and abdominal pain and constipation once each), as well as dizziness and insomnia being reported once each. None
of the TEAEs related to the study drug were serious.
The TEAEs in descending order of frequency were
gastrointestinal disorders (38.4%), infections (15.4%), injury (12.8%), general disorders, psychiatric disorders, and nervous system disorders
(7.7% each), and investigative, musculoskeletal, skin, and surgical procedures (2.6% each).
Most of the TEAEs (67%) were mild or moderate in
intensity. Six patients (40%) experienced at least one severe TEAE. No clinically meaningful treatment-emergent changes were noted
for any patient in the laboratory safety parameters, vital signs, or electrocardiograms. Two male patients died at home during the trial,
and these events were considered by the investigator to be unrelated to the study drug.
Summary of NST002 Adverse Events
Adverse event | |
No: of patients (% of total) | | |
No: of times reported | | |
Rate (per 100 patient-months) | |
Any adverse event | |
| 10 (67% | ) | |
| 39 | | |
| 24.6 | |
Serious adverse event | |
| 3
(20% | ) | |
| 3 | | |
| 1.9 | |
Severity | |
| | | |
| | | |
| | |
Mild | |
| 7
(47% | ) | |
| 14 | | |
| 8.8 | |
Moderate | |
| 6
(40% | ) | |
| 12 | | |
| 7.6 | |
Severe | |
| 6
(40% | ) | |
| 13 | | |
| 8.2 | |
System Organ Class | |
| | | |
| | | |
| | |
Gastrointestinal disorders | |
| 7
(47% | ) | |
| 15 | | |
| 9.5 | |
General disorder | |
| 3
(20% | ) | |
| 3 | | |
| 1.9 | |
Infections and infestations | |
| 2
(13% | ) | |
| 6 | | |
| 3.8 | |
Injury | |
| 3
(20% | ) | |
| 5 | | |
| 3.2 | |
Investigations | |
| 1
(7% | ) | |
| 1 | | |
| 0.6 | |
Musculoskeletal | |
| 1
(7% | ) | |
| 1 | | |
| 0.6 | |
Nervous system disorders | |
| 3
(20% | ) | |
| 3 | | |
| 1.9 | |
Psychiatric disorders | |
| 2
(13% | ) | |
| 3 | | |
| 1.9 | |
Skin | |
| 1
(7% | ) | |
| 1 | | |
| 0.6 | |
Surgical and medical procedures | |
| 1
(7% | ) | |
| 1 | | |
| 0.6 | |
Related to drug | |
| 4
(27% | ) | |
| 13 | | |
| 8.2 | |
System Organ Class | |
| | | |
| | | |
| | |
Gastrointestinal disorders | |
| | | |
| | | |
| | |
Flatulence | |
| 2
(13% | ) | |
| 4 | | |
| — | |
Dyspepsia | |
| 1
(7% | ) | |
| 2 | | |
| — | |
Nausea | |
| 2
(13% | ) | |
| 3 | | |
| — | |
Abdominal pain | |
| 1
(7% | ) | |
| 1 | | |
| — | |
Constipation | |
| 1
(7% | ) | |
| 1 | | |
| — | |
Nervous system disorder | |
| | | |
| | | |
| | |
Dizziness | |
| 1
(7% | ) | |
| 1 | | |
| — | |
Psychiatric disorders | |
| | | |
| | | |
| | |
Insomnia | |
| 1 (7% | ) | |
| 1 | | |
| — | |
All 12 patients who completed the NST002 trial elected
to continue into an extension study with PrimeC-IR. The primary endpoint of the extension study is safety, and we may use this additional
data in communications with the FDA when presenting on long-term safety of the combined use of ciprofloxacin and celecoxib.
Investigators also measured PrimeC-IR’s potential
efficacy using two accepted ALS clinical endpoints: the ALS Functional Rating Scale—Revised, or ALSFRS-R, and forced vital capacity,
or FVC. The ALSFRS-R is a validated rating scale for monitoring the progression of disability in patients with ALS. Patients are
scored within the range of 0-48 points (with 48 indicating full function and zero indicating no function). ALSFRS-R scores correlate
significantly with quality of life as measured by the Sickness Impact Profile, a behaviorally-based measure of health status, indicating
that the quality of function is a strong determinant of quality of life in ALS patients. Historical data indicates that the average deterioration
of ALS patients is one point per month in the ALFRS-R. FVC is a standard measure of pulmonary function that measures the amount of air
that can be exhaled forcefully and quickly after a deep inhalation.
To better understand the ALSFRS-R and FVC data,
we compared the open-label results to two prediction models and virtual patient arms. The first was a virtual placebo generated by
Origent Data Sciences, which projected an individual patient’s deterioration and survival for 12 months. This comparison indicated
another aspect of safety, as it showed that the PrimeC-IR treated patients exceeded their projected survival and did not deteriorate
more than predicted. This was strengthened by the use of the ENCALS survival prediction model, which also indicated that treated patients
exceeded their projected survival.
Additionally, PrimeC-IR treated patients were
compared to a historical placebo by matching patients in the trial with similar patients in the PRO-ACT database, one of the largest
publicly available repositories of merged ALS clinical trials data. Patients were matched using a propensity score matching method, which
is a statistical method that seeks to approximate a random experiment by matching each patient in the trial with a patient from the PRO-ACT database.
At 12 months, the average ALSFRS-R total
score declined only by -0.84 points per month for patients treated with PrimeC, whereas the ALSFRS-R total score deteriorated -1.02
for the PRO-ACT group, a difference of 18%. Additionally, when breaking down the ALSFRS-R into the sub-domains of the four
categories (bulbar, fine motor, gross motor and respiratory functions), PRO-ACT patients showed higher deterioration in gross motor
functions and respiratory functions compared to the PrimeC cohort.
Respiratory function was further assessed by FVC.
The FVC of PRO-ACT patients deteriorated by 2.99% of the predicted value, and PrimeC patients deteriorated by 2.09% of the predicted
value, or a difference of 30%, matching the results from the ALSFRS-R respiratory function section.
Despite the p-values not showing statistical
significance (i.e., p-value < 0.05), we believe the study results indicate a clinical trend of slowing disease progression, achieved
with an intermediate formulation of PrimeC. Based on the trend we observed, we believe that in a study with a larger sample size and with
the optimal PrimeC dosage and formulation, there is much higher potential to achieve statistically significant clinical benefit with PrimeC.
Efficacy Endpoints of Our PrimeC Trial versus PRO-ACT
| |
Summary statistics | |
| |
| | |
| | |
Mean difference | | |
| |
Efficacy endpoint | |
Rate of decline
(PrimeC) | | |
Rate of decline
(PRO-ACT) | | |
Estimate | | |
95% CI | | |
P-value | |
ALSFRS-R | |
| | |
| | |
| | |
| | |
| |
Total score | |
| (0.84 | ) | |
| (1.02 | ) | |
| 0.18 | | |
| (0.23) to 0.59 | | |
| 0.39 | |
Bulbar | |
| (0.17 | ) | |
| (0.15 | ) | |
| (0.02 | ) | |
| (0.15) to 0.11 | | |
| 0.78 | |
Fine motor | |
| (0.34 | ) | |
| (0.34 | ) | |
| 0.00 | | |
| (0.14) to 0.15 | | |
| 0.99 | |
Gross motor | |
| (0.24 | ) | |
| (0.31 | ) | |
| 0.07 | | |
| (0.08) to 0.22 | | |
| 0.33 | |
Respiratory | |
| (0.11 | ) | |
| (0.20 | ) | |
| 0.09 | | |
| (0.04)
to 0.23 | | |
| 0.16 | |
FVC, % predicted | |
| (2.09 | ) | |
| (2.99 | ) | |
| 0.90 | | |
| (0.52)
to 2.32 | | |
| 0.21 | |
Mechanism of Action Evaluation — Healthy vs ALS blood sample
analysis
Neuron derived exosomes (NDEs) have been shown to
cross the blood-brain-barrier and enter blood circulation, enabling their isolation from patients’ blood using minimally invasive
procedures. NDEs carry neural molecular signatures echoing the content of the cells from which they originated, providing potentially
valuable information of disease pathogenesis. As a result, we believe neuron-derived exosomes can serve as sources of potential biomarkers
in neurodegenerative disorders, including ALS.
In parallel to our NST002 trial, we explored the
relevance of PrimeC’s mechanism of action in ALS by examination of the changes in expression or activation of a number of disease
biomarkers and key drug target biomarkers. The measurements were performed in neuronal extracellular vesicles, extracted from the blood
serum of patients diagnosed with ALS and then compared to corresponding healthy volunteers, in collaboration with Mass General Hospital
(MGH) in Boston.
We examined and further validated key enzymes known
the be affected in ALS in the same manner. It is well established that TDP-43 levels are increased in ALS patients, leading to a
toxic accumulation. Additionally, a growing body of evidence shows decreased expression of LC3, a marker for autophagy in a number of
ALS models, suggesting reduced basal levels and a decreased overall capacity for autophagy. Lastly, Cathepsin D (CatD) is a regularly
expressed lysosomal protease that is involved in proteolytic degradation, cell invasion, and apoptosis. Growing evidence suggests that
endolysosomal and autophagic defects are key pathogenic processes in various neurodegenerative disorders such as ALS. In examining these
three biomarkers, we observed a significant difference between ALS and healthy subjects (TDP-43 p-value = 0.002, LC3 p-value <
0.001, CatD p-value < 0.001).
Furthermore, since PrimeC aims to target miRNA dysregulation,
iron accumulation, and neuroinflammation, the target engagement markers we explored were EIF2C2 (Ago2), a component of the Dicer complex,
which is essential to the regulation of miRNA and is affected in ALS, as well as Ferroportin-1, an iron pump serving as a marker of iron
accumulation, and PGJ2, an endogenous product of inflammation, which induces neuronal death and the accumulation of proteins into aggregates.
It has been previously demonstrated that PGJ2 was accumulated in the spinal cord of sporadic ALS patients. In this evaluation we observed
clear differences between ALS and healthy subjects in these three key PrimeC targets (EIF2C2 p-value = 0.007, PGJ2 p-value >
0.05, Ferroportin p-value = 0.005).
We believe these biomarker evaluation results support
the potential relevance of PrimeC’s mechanism of action for the treatment of ALS.
We plan to further explore these mechanism-of-action-related biomarkers
on longitudinal blood samples from untreated patients with ALS compared to healthy subjects.
NST002 Biomarker Analysis — Assessing the Effect of PrimeC
on Key Biomarkers
Based on the parameters validated in the comparison
of healthy vs ALS patient samples, we examined the effect of PrimeC on these biomarkers. To that end, we used our previously established
NDE paradigm to examine the levels of the biomarkers in NDEs extracted from longitudinal blood samples obtained from the participants
in our NST002 clinical trial. These samples were collected at three time points throughout the study, namely, prior to initiation of PrimeC
treatment, during their interim visit between the 3-6 month point and at the 12-month end of study visit.
In analyzing the samples we observed statistically
significant changes in the levels of TDP-43, following PrimeC treatment. TDP-43 is a protein highly associated with ALS pathology,
and in a recent publication neuron-derived exosomal TDP-43 was shown to increase in longitudinal serum samples of patients with
ALS. TDP-43 in PrimeC treated patients were observed to have a statistically significant decrease throughout the study (p-value =
0.002), indicating positive biological signs of the treatment. Analysis of additional ALS-associated pathological markers also showed
significant positive changes, including LC3, a central protein in the autophagy pathway. Among PrimeC treated patients, LC3 levels were
observed to elevate and stabilize (p-value = 0.054), suggesting that such treatment has positive effects on autophagy. Another ALS
biomarker we examined was CatD, which remained in a stable state before showing a decrease (p-value = 0.015), indicating a potential
benefit for lysosomal activity. Lastly, we assessed the change in PGJ2, downstream of COX-2, representing neuroinflammation. Levels of
PGJ2 were observed to significantly decrease during PrimeC treatment (p-value<0.001), indicating a reduction in neuroinflammatory processes.
We believe these results indicate positive biological
activity of PrimeC, in a manner that attenuates disease-related pathologies, as well as indicating target engagement. This biological
activity may serve to indicate clinical outcomes, as can be seen from the relative correlation between the reduction in TDP-43 levels
and slower deterioration in ALSFRS-R, as demonstrated below.
Clinical Results — NST001 Phase I Trial in ALS
We recently completed our Phase I NST001 trial of
PrimeC for the treatment of ALS, and expect final results and analysis in the first quarter of 2022. NST001 was an open label, IND-exempt study
designed to assess the safety and tolerability of an intermediate immediate-release formulation of PrimeC, at slightly different
doses than NST002. The study was conducted at the Barrow Neurological Institute (BNI) in Phoenix, Arizona. Six patients with familial
or sporadic ALS received a fixed dose of PrimeC-IR twice per day for 12 months. Patients were evaluated by phone every three
months.
The primary endpoint of the trial was PrimeC-IR’s
safety and tolerability, measured in the same manner as in NST002: number of patients with one or more treatment-emergent adverse
events, number of patients who discontinued treatment prematurely, number of patients who discontinued treatment prematurely due to adverse
events and number of patients with significant abnormal laboratory values.
NST001 and NST002 began simultaneously since both
these studies were designed with the goal of assessing the safety and tolerability of two different doses and regimens of PrimeC-IR, and
were therefore considered independent of each other. Since no safety issues were expected due to the well-understood nature of both
generic drugs comprising PrimeC, we determined that there was not a need to wait for the completion of NST001 in order to begin NST002.
Moreover, while NST001 was an IND-exempt clinical trial, NST002 was conducted in Israel, according to Israeli regulations, and did
not require FDA input. Nonetheless, in January 2021, we participated in a pre-IND meeting with the FDA to discuss our past and future
development plans.
Preclinical Results
In preclinical studies of two models of ALS zebrafish,
SOD1 and TDP-43, PrimeC was observed to improve locomotor and cellular deficits, indicating a potential neuroprotective effect. In the
SOD1 studies, treatment with PrimeC was observed to improve motor performance of the mutant larvae by 84%, and elicited recovery of motor
neuron morphology and neuromuscular junction structure (NMJ), as well as preserving ramified morphology of microglia cells.
mSOD1 larvae exhibited a substantial recovery of
motor neuron morphology and NMJ structure, suggesting a potential neuroprotective role for PrimeC treatment. As shown in the graphic titled
“Neuromuscular Junction Structures” below, following treatment with PrimeC, we observed a higher number of intact organized
synapses (yellow), with reduced proportion of orphaned pre-(red) and post-synaptic (green) puncta, resembling WT zebrafish. A second
study, conducted in TDP-43 mutant zebrafish, substantiated these results and showed a significant improvement in their swimming abilities
with an increase of 110% in distance and 43.8% in maximum swim velocity.
The image below depicts the improvements in swim
patterns and distances compared to controls, as well as motor neurons morphology and neuromuscular junction structures observed with PrimeC.
Preclinical Pipeline
Our preclinical pipeline includes two additional
product candidates, StabiliC and CogniC, for the treatment of Parkinson’s disease and Alzheimer’s disease, respectively. We
are currently conducting preclinical studies on these product candidates. Following completion of these studies, we plan to initiate Phase
I/II studies. In the event that the preclinical data indicates that the current dose of PrimeC is relevant for either of the diseases,
we may initiate the clinical phase following cross-referencing the data we shared previously with the FDA. However, in any event
it is likely that we will choose to consult with the FDA with regards to our findings prior to the initiation, and in order to obtain
their advice and consent for the study design and clinical plan forward for each of the indications.
StabiliC
Many pathological pathways involve neuroinflammation,
protein aggregation, mitophagy, excitotoxicity, oxidative stress, iron accumulation, and dysregulation of miRNAs between neurodegenerative
diseases, leading to the hypothesis that an effective drug for one neurodegenerative disease can lay the foundations for other diseases-modifying drugs.
Therefore, we aimed to evaluate the putative neuroprotective effects of celecoxib and ciprofloxacin in a zebrafish pharmacological neurotoxin
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced, or “MPTP”-induced, Parkinson’s disease model. The objective of
this study was to determine if celecoxib and ciprofloxacin were able to prevent and/or rescue MPTP-induced altered behaviour. Locomotor
activity was assessed through a “tapping” assay.
Results indicated that the symptomatic MPTP model
is not relevant for StabiliC, suggesting that a different model with underlying Parkinson’s disease pathologies may be required.
We therefore plan to further explore StabiliC’s mode of action and to assess its ability to effect or alter key Parkinson’s
disease-related hallmarks by utilizing both the in-vitro patients’ derived cells method and the in-vivo rodent adeno-associated-virus alpha
synuclein, or AAV-SYN, model. StabiliC is planned to be a combination of ciprofloxacin and celecoxib, and/or another molecule to be determined
during ongoing preclinical development. These assays will focus on the ability of StabiliC to reduce AAV-SYN aggregation and to improve
morphological and functional markers.
CogniC
As to the treatment of Alzheimer’s disease,
we are currently conducting a robust in-vitro study of CogniC utilizing co-cultures of neurons and glial cells, with the goal
of exploring the potential therapeutic effects of CogniC on microglial, neuronal and neuro-glia co-cultures. CogniC is planned to
be a combination of ciprofloxacin and celecoxib, and/or another molecule to be determined during ongoing preclinical development. Under
our current plans, murine microglial BV2 cells and human neuroblastoma SH-SY5Y cells treated with amyloidβoligomers, or AβO,
will be used as a model that recapitulates a part of the Alzheimer’s Disease pathology. We plan to assess the ability of CogniC
in its different variations to effect AβO aggregation, microglia activation and morphology, caspase3 apoptosis/necrosis, mitochondrial
dysfunction, autophagy, neuronal markers, inflammation and cytokines. This robust in-vitro analysis could help further de-risk CogniC
treatment for future clinical developments targeting Alzheimer’s disease. Following completion of this study, we intend to conduct
both a patient-derived cell study and an in-vivo study in murine Alzheimer’s disease-models to establish CogniC’s
mechanism of action and its effect on Alzheimer’s disease-related pathologies.
Manufacturing
We do not own or operate manufacturing facilities
for the production of our product candidates, nor do we have plans to develop our own manufacturing operations in the foreseeable future.
We currently rely on third-party contract manufacturers for all of our required raw materials, active ingredients and finished products
for our preclinical research and clinical trials. We are in the process of negotiating commercial supply agreements with our primary third-party vendors
and anticipate that these agreements will be executed in advance of commercial approval for PrimeC. We also intend to negotiate back-up supply
agreements with other third-party manufacturers for the commercial production of those products.
Development and commercial quantities of any products
that we successfully develop will need to be manufactured in facilities, and by processes, that comply with the requirements of the FDA
and the regulatory agencies of other jurisdictions in which we are seeking approval. We currently employ internal resources to manage
our manufacturing contractors. The relevant manufacturers of our drug products for our current preclinical and clinical trials have advised
us that they are compliant with both current good laboratory practice, or cGLP, and current good manufacturing practices, or cGMP.
Our
product candidates, if approved, are expected to be producible in sufficient commercial quantities, in compliance with regulatory requirements
or at an acceptable cost. We and our contract manufacturers are, and will be, subject to extensive governmental regulation in connection
with the manufacture of any pharmaceutical products. We and our contract manufacturers must ensure that all of the processes, methods
and equipment are compliant with cGMP and cGLP for drugs on an ongoing basis, as mandated by the FDA and foreign regulatory authorities,
and conduct extensive audits of vendors, contract laboratories and suppliers.
Competition
We
compete in an industry characterized by rapidly advancing technologies, significant competition and a complex intellectual property landscape.
We face substantial competition from many different sources, including large pharmaceutical, specialty pharmaceutical, and biotechnology
companies. Recently we have also seen that academic research institutions and governmental agencies can and will continue to compete
in this rapidly evolving environment with support from public and private research institutions. Below is a description of competition
surrounding each of our disease targets and other technologies in development in the neurodegenerative field:
| ● | ALS.
Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology companies
and academic institutions, including Amylyx Pharmaceuticals Inc., AB Science SA, Prilenia Therapeutics B.V, and Apellis Pharmaceuticals
in various stages of clinical trials. |
| ● | Alzheimer’s
Disease. Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology
companies, including Biogen, Eli Lilly, Eisai, Roche (including Genentech, its wholly owned subsidiary) and Alector in various stages
of clinical trials. |
| ● | Parkinson’s
Disease. Potentially disease modifying therapeutics are being developed by several large and specialty pharmaceutical and biotechnology
companies, including Prothena, Roche (including Genentech, its wholly owned subsidiary), Prevail/Eli Lilly, AstraZeneca, and Takeda in
various stages of clinical trials. |
Many
of our competitors, either alone or through their collaborations, have significantly greater financial resources and expertise in research
and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved
products than we do. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative
arrangements with large and established companies. These competitors also compete, or will compete, with us in recruiting and retaining
qualified scientific and management personnel and establishing clinical trial sites and patient enrollment in clinical trials, as well
as in acquiring technologies complementary to, or necessary for, our programs. As a result, our competitors may discover, develop, license,
commercialize and market products before or more successfully than we do.
Intellectual
Property
Our
commercial success depends, in part, on obtaining and maintaining patent, trade secret and other intellectual property and proprietary
protection of our technology, current product candidates, future product candidates and methods used to develop and manufacture them.
We cannot be sure that a patent will be granted with respect to any of our currently pending patent applications or with respect to any
patent applications that we may file in the future, nor can we be sure that our existing patent or any patents that may be granted to
us in the future will be sufficient to protect our technology or will not be challenged, invalidated or circumvented. Our success also
depends on our ability to operate our business without infringing, misappropriating or otherwise violating any patents and other intellectual
property or proprietary rights of third parties.
Patents
Our
patent portfolio includes U.S. Patent 10,980,780, which relates to methods for treatment of ALS using ciprofloxacin and celecoxib, and
which expires in 2038. In December 2021, a patent related to our lead candidate, PrimeC, was granted in Australia. Similar patent applications
have been allowed in the European Patent Office and Canada are pending in Japan and in and Israel. In addition, U.S. patent application
16/623,467, which relates to methods of treatment of neurodegenerative disease using combinations of ciprofloxacin and celecoxib, is
currently pending. The patent based on this application is expected to expire on June 20, 2038.
In
addition, we have developed a pharmaceutical composition comprising, as active ingredients, ciprofloxacin and celecoxib, and have filed
a U.S. provisional application directed to the compositions. Our U.S. provisional application 63/257,130 relates to pharmaceutical formulations.
Applications claiming priority from the U.S. provisional application are expected to expire in October 2042.
Government
Regulation
Product
Approval Process in the United States
Review
and approval of drugs
In
the United States, pharmaceutical products are subject to extensive regulation by the FDA. The Federal Food, Drug and Cosmetic Act, or
FDCA, and other federal and state statutes and implementing regulations govern, among other things, the research, development, testing,
manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting,
sampling, and import and export of pharmaceutical products. Failure to comply with the applicable U.S. 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 and enforcement actions brought by the FDA, the U.S. Department of Justice, or DOJ, or other governmental entities. Possible
sanctions may include the FDA’s refusal to approve pending applications, withdrawal of an approval, imposition of a clinical hold,
issuance of warning letters or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution,
injunctions, fines, refusals of government contracts, restitution, disgorgement and civil or criminal penalties.
FDA
approval of a new drug application is required before any new unapproved drug or dosage form, including a new use of a previously approved
drug, can be marketed in the United States. Section 505 of the FDCA describes three types of new drug applications: (1) an application
that contains full reports of investigations of safety and effectiveness (section 505(b)(1)); (2) an application that contains full reports
of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies or
investigations that were not conducted by or for the applicant and by which the applicant has not obtained a right of reference or use
from the person by or for whom the investigations were conducted (section 505(b)(2)); and (3) an application that contains information
to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality,
performance characteristics, and intended use, among other things, to a previously approved product (section 505(j)). Section 505(b)(1)
and 505(b)(2) new drug applications are referred to as NDAs, and section 505(j) applications are referred to as ANDAs. We believe that
the applications for PrimeC will be a section 505(b)(2) NDA.
In
general, the process required by the FDA prior to marketing and distributing a new drug, as opposed to a generic drug subject to section
505(j), in the United States usually involves the following:
| ● | completion
of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practices,
or GLP, requirements or other applicable regulations; |
| ● | submission
to the FDA of an IND, which must become effective before human clinical trials in the United States may begin; |
| ● | approval
by an independent institutional review board, or IRB, at each clinical site before each trial may be initiated; |
| ● | performance
of adequate and well-controlled human clinical trials in accordance with good clinical practice, or GCP, requirements to establish the
safety and efficacy of the proposed drug for its intended use; |
| ● | preparation
and submission to the FDA of an NDA; |
| ● | satisfactory
completion of an FDA advisory committee review, if applicable; |
| ● | satisfactory
completion of one or more FDA inspections of the manufacturing facility or facilities at which the product or components thereof are
produced, to assess compliance with cGMPs, and to assure that the facilities, methods and controls are adequate to preserve the drug’s
identity, strength, quality and purity; |
| ● | satisfactory
completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data; |
| ● | payment
of user fees and FDA review and approval of the NDA; and |
| ● | compliance
with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy, or REMS,
and the potential requirement to conduct post-approval studies. |
Preclinical
studies
Preclinical
studies include laboratory evaluation or product chemistry, formulation and toxicity, as well as animal studies to assess the potential
safety and efficacy of the product candidate. Preclinical safety tests must be conducted in compliance with the FDA regulations. The
results of the preclinical studies, together with manufacturing information and analytical data, are submitted to the FDA as part of
an IND which must become effective before clinical trials may commence. Long-term preclinical studies, such as animal tests of reproductive
toxicity and carcinogenicity, may continue after the IND application is submitted.
Clinical
trials
Clinical
trials involve the administration of an investigational product to human subjects under the supervision of qualified investigators in
accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed
consent in writing before their participation in any clinical trial. Clinical trials are conducted under written trial protocols detailing,
among other things, the objectives of the trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be
evaluated. A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.
An
IND automatically becomes effective 30 days after receipt by the FDA unless the FDA, within the 30-day time period, raises concerns
or questions related to a proposed clinical trial and places the trial on clinical hold. In such a case, the IND sponsor and the FDA
must resolve any outstanding concerns before the clinical trial can begin. In addition, information about certain clinical trials must
be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on the NIH-maintained
website, www.clinicaltrials.gov.
An
IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before
it commences at that institution, and the IRB must conduct continuing review at least annually. The IRB must review and approve, among
other things, the trial protocol information to be provided to trial subjects. An IRB must operate in compliance with FDA regulations.
Information about certain clinical trials must be submitted within specific timeframes to the NIH for public dissemination on the NIH-maintained
website, www.clinicaltrials.gov. The FDA, the IRB, or the sponsor may suspend or discontinue a clinical trial at any
time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk. Clinical testing also
must satisfy extensive GCP requirements, including the requirements for informed consent.
Clinical
trials are typically conducted in three sequential phases, which may overlap or be combined:
| ● | Phase
I: The drug 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
and to determine optimal dosage. |
| ● | Phase
II: The drug is administered to a limited patient population to identify possible short-term 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. |
| ● | Phase
III: The drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled
clinical trials 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. |
Submission
of an NDA to the FDA
The
results of the preclinical studies and clinical trials, together with other detailed information, including information on the
manufacture, control and composition of the product, are submitted to the FDA as part of an NDA requesting approval to market the
product candidate for a proposed indication. Under the Prescription Drug User Fee Act, as amended, applicants are required to
pay fees to the FDA for reviewing an NDA. These user fees, as well as the annual fees required for commercial manufacturing
establishments and for approved products, can be substantial. The NDA review fee alone can exceed $2 million, subject to
certain limited deferrals, waivers and reductions that may be available. The FDA reviews an NDA to determine, among other things,
whether a drug is safe and effective for its intended use.
The
FDA has 60 days from its receipt of an NDA to determine whether the application will be accepted for filing based on the agency’s
threshold determination that it is sufficiently complete to permit substantive review. The FDA may request additional information rather
than accept an NDA for filing. In this event, the NDA must be resubmitted with the additional information and is subject to payment of
additional user fees. The resubmitted application is also subject to review before the FDA accepts it for filing. If found complete,
the FDA will accept the NDA for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review.
Under
the Prescription Drug User Fee Act, the FDA has agreed to certain performance goals in the review of NDAs through a two-tiered classification
system, Standard Review and Priority Review. Priority Review designation is given to drugs that offer major advances in treatment, or
provide a treatment where no adequate therapy exists. The FDA endeavors to review applications subject to Standard Review within approximately
10 to 12 months of receipt, whereas the FDA’s goal is to review Priority Review applications within approximately six to eight
months of receipt, depending on whether the drug is a new molecular entity. The FDA, however, may not approve a drug within these established
goals, and its review goals are subject to change from time to time.
Before
approving a NDA, the FDA will inspect the facility or facilities at which the product is manufactured or facilities that are significantly
involved in the product development and distribution process, and will not approve the product unless cGMP compliance is satisfactory.
Additionally, the FDA will typically inspect one or more clinical sites to assure compliance with GCP requirements. The FDA may also
refer applications for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee
for review, evaluation and recommendation as to whether the application should be approved and under what conditions. The FDA is not
bound by the recommendation of an advisory committee.
After
the FDA evaluates the NDA and the manufacturing facilities, it issues either an approval letter or a complete response letter to indicate
that the review cycle for an application is complete and that the application is not ready for approval. An approval letter authorizes
commercial marketing of the drug with specific prescribing information for specific indications. A complete response letter indicates
that the review cycle of the application is complete, and that the NDA will not be approved in its present form. If a complete response
letter is issued, the sponsor must resubmit the NDA and address all of the deficiencies identified in the letter, or withdraw the application.
Even if such data and information are submitted, the FDA may decide that the NDA does not satisfy the criteria for approval.
A
complete response letter generally outlines the deficiencies in the NDA submission and may require substantial additional testing and/or
clinical data and/or other requirements related to clinical trials, nonclinical studies or manufacturing, in order for the FDA to reconsider
the application. For example, as a condition of NDA approval, the FDA may require a REMS to ensure that the benefits of the drug outweigh
the potential risks. For example, as a condition of NDA approval, the FDA may require a REMS to ensure that the benefits of the drug
outweigh the potential risks. If the FDA determines a REMS is necessary during review of the application, the drug sponsor must agree
to the REMS plan at the time of approval. A REMS may be required to include various elements, such as a medication guide or patient package
insert, a communication plan to educate healthcare providers of the drug’s risks, limitations on who may prescribe or dispense
the drug, or other elements to assure safe use, such as special training or certification for prescribing or dispensing, dispensing only
under certain circumstances, special monitoring and the use of patient registries. In addition, the REMS must include a timetable to
periodically assess the strategy. The requirement for a REMS can materially affect the potential market and profitability of a drug.
Even
with submission of additional information, the approval may be for fewer or more limited indications than requested, indicated uses for
which the product may be marketed, may require that warning statements be included in the product labeling, may require that additional
studies or trials be conducted following approval as a condition of the approval, may impose restrictions and conditions on product distribution.
If, or when, the deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an
approval letter.
Post-Approval
Requirements
Any
drug products for which we may receive FDA approval will be subject to continuing regulation by the FDA. Certain requirements include,
among other things, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety
and efficacy information on an annual basis or more frequently for specific events, product sampling and distribution requirements, complying
with certain electronic records and signature requirements and complying with FDA promotion and advertising requirements. These promotion
and advertising requirements include standards for direct-to-consumer advertising, prohibitions against promoting drugs for uses
or patient populations that are not described in the drug’s approved labeling, known as “off-label use,” and other
promotional activities, such as those considered to be false or misleading. Failure to comply with FDA requirements can have negative
consequences, including the immediate discontinuation of noncomplying materials, adverse publicity, enforcement letters from the FDA,
mandated corrective advertising or communications with doctors, and civil or criminal penalties. Such enforcement may also lead to scrutiny
and enforcement by other government and regulatory bodies.
The
manufacturing of any of our product candidates will be required to comply with applicable FDA manufacturing requirements contained in
the FDA’s cGMP regulations. The FDA’s cGMP regulations require, among other things, quality control and quality assurance,
as well as the corresponding maintenance of comprehensive records and documentation. Drug manufacturers and other entities involved in
the manufacture and distribution of approved drugs are also required to register their establishments and list any products they make
with the FDA and to comply with related requirements in certain states. 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. These entities are further subject to periodic unannounced inspections by the FDA and certain state agencies
for compliance with cGMP and other laws. Accordingly, manufacturers must continue to expend time, money and effort in the area of production
and quality control to maintain cGMP compliance.
Discovery
of problems with a product after approval may result in serious and extensive restrictions on a product, manufacturer or holder of an
approved NDA, as well as lead to potential market disruptions. These restrictions may include recalls, suspension of a product until
the FDA is assured that quality standards can be met, and continuing oversight of manufacturing by the FDA under a “consent decree,”
which frequently includes the imposition of costs and continuing inspections over a period of many years, as well as possible withdrawal
of the product from the market. In addition, changes to the manufacturing process generally require prior FDA approval before being implemented.
Other types of changes to the approved product, such as adding new indications and additional labeling claims, are also subject to further
FDA review and approval. There also are continuing, annual user fee requirements for any marketed products and the establishments at
which such products are manufactured, as well as new application fees for supplemental applications with clinical data.
The
FDA also may require post-marketing testing, or Phase IV testing, as well as risk minimization action plans and surveillance to monitor
the effects of an approved product or place conditions on an approval that could otherwise restrict the distribution or use of our product
candidates.
Once
approval 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 trials
to assess new safety risks; or imposition of distribution or other restrictions under a REMS program. Other potential consequences include,
among other things:
| ● | restrictions
on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls; |
| ● | fines,
warning letters or holds on post-approval clinical trials; |
| ● | refusal
of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product approvals; |
| ● | product
seizure or detention, or refusal to permit the import or export of products; or |
| ● | injunctions
or the imposition of civil or criminal penalties. |
The
Hatch-Waxman Amendments
505(b)(2)
NDAs
Section
505(b)(2) was enacted as part of the Hatch-Waxman Amendment, and permits the filing of an NDA where at least some of the information
required for approval comes from studies or trials not conducted by or for the applicant and for which the applicant has not obtained
a right of reference. As an alternative path to FDA approval for modifications to formulations or uses of products previously approved
by the FDA, an applicant may submit an NDA under Section 505(b)(2) of the FDCA. Section 505(b)(2) was enacted as part of the Hatch-Waxman
Amendment, and permits the filing of an NDA where at least some of the information required for approval comes from studies or trials
not conducted by or for the applicant and for which the applicant has not obtained a right of reference. If the 505(b)(2) applicant can
establish that reliance on the FDA’s previous findings of safety and effectiveness is scientifically appropriate, it may eliminate
the need to conduct certain pre-clinical studies or clinical trials for the new product. The FDA may also require companies to perform
additional studies or measurements, including clinical trials, to support the change from the approved branded reference drug. The FDA
may then approve the new product candidate for all, or some, of the labeled indications for which the branded reference drug has been
approved, as well as for any new indication sought by the 505(b)(2) applicant.
Orange
Book Listing
In
seeking approval for a drug through an NDA, including a 505(b)(2) NDA, applicants are required to list with the FDA certain patents whose
claims cover the applicant’s product. Upon approval of an NDA, each of the patents listed in the application for the drug is then
published in the FDA’s Publication of Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the “Orange
Book.” Any applicant who submits a Section 505(b)(2) NDA referencing a drug listed in the Orange Book must certify to the FDA that
(1) no patent information on the drug product that is the subject of the application has been submitted to the FDA; (2) such patent has
expired; (3) the date on which such patent expires; or (4) such patent is invalid or will not be infringed upon by the manufacture, use,
or sale of the drug product for which the application is submitted. This last certification is known as a Paragraph IV certification.
The applicant may also elect to submit a “section viii” statement certifying that its proposed label does not contain (or
carves out) any language regarding the patented method-of-use rather than certify to a listed method-of-use patent.
If
the applicant does not challenge one or more listed patents through a Paragraph IV certification, the FDA will not approve the Section
505(b)(2) NDA until all the listed patents claiming the referenced product have expired. Further, the FDA will also not approve a Section
505(b)(2) NDA until any non-patent exclusivity, as described in greater detail below, has expired.
If
the Section 505(b)(2) NDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the
Paragraph IV certification to the owner of the referenced NDA for the previously approved product and relevant patent holders within
20 days after the Section 505(b)(2) NDA has been accepted for filing by the FDA. The NDA and patent holders may then initiate a patent
infringement suit against the Section 505(b)(2) applicant. Under the FDCA, the filing of a patent infringement lawsuit within 45 days
of receipt of the notification regarding a Paragraph IV certification automatically prevents the FDA from approving the Section 505(b)(2)
NDA until the earliest to occur of 30 months beginning on the date the patent holder receives notice, expiration of the patent,
settlement of the lawsuit, or until a court deems the patent unenforceable, invalid or not infringed. Even if a patent infringement claim
is not brought within the 45-day period, a patent infringement claim may be brought under traditional patent law, but it does not invoke
the 30-month stay.
Moreover,
in cases where a Section 505(b)(2) application containing a Paragraph IV certification is submitted after the fourth year of a previously
approved drug’s five-year NCE exclusivity period, as described more fully below, and the patent holder brings suit within 45 days
of notice of the Paragraph IV certification, the 30-month period is automatically extended to prevent approval of the Section 505(b)(2)
application until the date that is seven and one-half years after approval of the previously approved reference product that has the
five-year NCE exclusivity. The court also has the ability to shorten or lengthen either the 30-month or the seven and one-half year period
if either party is found not to be reasonably cooperating in expediting the litigation.
Notwithstanding
the approval of many products by the FDA pursuant to Section 505(b)(2), over the last few years, some pharmaceutical companies and others
have objected to the FDA’s interpretation of Section 505(b)(2). If the FDA changes its interpretation of Section 505(b)(2), or
if the FDA’s interpretation is successfully challenged in court, this could delay or even prevent the FDA from approving any Section
505(b)(2) NDA that we submit.
Non-Patent
Exclusivity
In
addition to patent exclusivity, the holder of the NDA for the listed drug may be entitled to a period of non-patent exclusivity, during
which the FDA cannot approve a 505(b)(2) application that relies on the listed drug. For example, a pharmaceutical manufacturer may obtain
five years of non-patent exclusivity upon NDA approval of a new chemical entity, or NCE, which is a drug that contains an active moiety
that has not been approved by FDA in any other NDA. An “active moiety” is defined as the molecule or ion responsible for
the drug substance’s physiological or pharmacologic action. During the five year exclusivity period, the FDA cannot accept for
filing any ANDA seeking approval of a generic version of that drug or any 505(b)(2) NDA for the same active moiety and that relies on
the FDA’s findings regarding that drug, except that FDA may accept an application for filing after four years if the follow-on
applicant makes a paragraph IV certification.
Another
form of non-patent exclusivity is clinical investigation exclusivity. A drug, including one approved under Section 505(b)(2), may obtain
a three-year period of exclusivity for a particular condition of approval, or change to a marketed product, such as a new formulation
for a previously approved product, if one or more new clinical trials (other than bioavailability or bioequivalence studies) was essential
to the approval of the application and was conducted/ sponsored by the applicant. Should this occur, the FDA would be precluded from
approving any ANDA or 505(b)(2) application for the protected modification until after that three-year exclusivity period has run. However,
unlike NCE exclusivity, the FDA can accept an application and begin the review process during the exclusivity period.
Patent
Term Restoration and Extension
Depending
upon the timing, duration and specifics of our product candidates, some of our U.S. patents claiming a new drug product may be eligible
for limited patent term extension under the Hatch-Waxman Amendments, which permit a patent term restoration of up to five years
for the patent term lost during product development and the FDA regulatory review process. However, a patent term restoration cannot
be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date. The patent term restoration
period granted is typically one-half the time between the effective date of an IND and the submission date of an NDA, plus the time between
the submission date of an NDA and the approval date of that NDA. Only one patent applicable to an approved drug product is eligible for
the extension, and the application for the extension must be submitted prior to the expiration of the patent. A patent that covers multiple
drugs for which approval is sought can only be extended in connection with one of the approvals. The U.S. Patent and Trademark Office
reviews and approves the PTE application in consultation with the FDA.
Review
and Approval of Drug Products Outside the United States
In
addition to regulations in the United States, if we target non-U.S. markets, we will be subject to a variety of foreign regulations governing
manufacturing, clinical trials, commercial sales and distribution of our product candidates. Whether or not we obtain FDA approval for
a product candidate, we must obtain approval of the product by the comparable regulatory authorities of foreign countries before commencing
clinical trials or marketing in those countries. The approval process varies from country to country, and the time may be longer or shorter
than that required for FDA approval. The requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement
vary greatly from country to country.
European
Union
Under
European Union regulatory systems, marketing authorizations may be submitted either under a centralized, decentralized or mutual recognition
procedure. The centralized procedure provides for the grant of a single marketing authorization that is valid for all European Union
member states. The decentralized procedure includes selecting one “reference member state,” or RMS, and submitting to more
than one member state at the same time. The RMS National Competent Authority conducts a detailed review and prepares an assessment report,
to which concerned member states provide comment. The mutual recognition procedure provides for mutual
recognition
of national approval decisions. Under this procedure, the holder of a national marketing authorization may submit an application to the
remaining member states post-initial approval. Within 90 days of receiving the applications and assessment report, each member state
must decide whether to recognize the approval.
Israel
Regulations
regarding clinical trials
The
conduct of clinical studies in Israel is subject to the study sponsor’s receipt of specific authorization from the ethics committee
(the equivalent of an Institutional Review Board) and general manager of the institution in which the sponsor intends to conduct its
study, as required under the Guidelines for Clinical Trials in Human Subjects implemented pursuant to the Israeli Public Health Regulations
(Clinical Trials in Human Subjects), as amended from time to time, and other applicable legislation, including applicable guidelines
issued by the Israeli Ministry of Health, or the MOH. These regulations also require authorization from the MOH, except in certain circumstances,
and in the case of genetic trials, special fertility trials and certain other trials, an additional authorization of the overseeing institutional
ethics committee.
Regulations
regarding new drugs approvals
The
registration of medicinal and biological products is regulated by the Pharmacists Regulations promulgated under the Pharmacists Ordinance
[New Version], 5741-1981, or the Pharmacists Ordinance, and by guidelines issued by the MOH. According to the Pharmacists Ordinance,
a person may not manufacture, market, import or order the use of a medicinal or a biological product in Israel, unless it is a registered
form of therapeutic drug that have been processed, or a Pharmaceutical, and in accordance to its registration terms (subject to certain
listed exceptions). The application to register a Pharmaceutical in the Pharmaceutical Registry should be submitted in person, during
a meeting at the MOH. For an imported Pharmaceutical, the application shall also include CPP (Certificate of Pharmaceutical Product)
approval, and GMP Approval from a competent authority of a Pharmaceutical Recognized Country (as defined in the regulations) that in
the site mentioned therein complies with GMP.
A
first Pharmaceutical registration approval shall be granted for a period of no longer than five years. A renewal of a Pharmaceutical
approval may be granted for consecutive periods no longer than ten years each. The first batch of a Pharmaceutical marketed in Israel
must be approved by the MOH as a pre-condition to its marketing. The MOH shall approve such batch only after it has confirmed that
the Pharmaceutical batch conforms to the registration certificate, the requirements mentioned in the registration files and after the
packaging, labeling and leaflets for both physicians and consumers have been approved. In addition, the following Pharmaceuticals need
to receive MOH approval before the marketing of each batch: (i) a Pharmaceutical derived from human blood or plasma prepared by a method
involving an industrial process, excluding whole blood or blood cells; (ii) human vaccines; (iii) a registered Pharmaceutical imported
pursuant to an import and marketing approval of a Compatible Pharmaceutical (as defined in the regulations); and (iv) other Pharmaceuticals
that the MOH determines should be examined to ensure public safety.
Other
Healthcare Laws and Regulations and Legislative Reform in the United States
U.S.
Healthcare Laws and Regulations
Healthcare
providers, physicians and third-party payors will play a primary role in the recommendation and prescription of any product candidates
for which we obtain marketing approval. Our operations, including any arrangements with healthcare providers, physicians, third-party payors
and customers may expose us to broadly applicable fraud and abuse and other healthcare laws that may affect the business or financial
arrangements and relationships through which we would market, sell and distribute our products. Our current and future operations are
subject to regulation by various federal, state, and local authorities in addition to the FDA, including but not limited to the Centers
for Medicare & Medicaid Services, or CMS, the Department of Health and Human Services, or HHS, (including the Office of Inspector
General, Office for Civil Rights and the Health Resources and Services Administration), the DOJ and individual U.S. Attorney offices
within the DOJ, and state and local governments. The healthcare laws that may affect our ability to operate include, but are not limited
to:
| ● | The
federal Anti-Kickback Statute, which prohibits any person or entity from, among other things, knowingly and willfully soliciting,
receiving, offering or paying any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward
either the referral of an individual for, or the purchase, order or recommendation of an item or service reimbursable, in whole or in
part, under a federal healthcare program, such as the Medicare and Medicaid programs. The term “remuneration” has
been broadly interpreted to include anything of value. The federal Anti-Kickback Statute has also been interpreted to apply to arrangements
between pharmaceutical manufacturers on the one hand and prescribers, purchasers and formulary managers on the other hand. There are
a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, but the exceptions and
safe harbors are drawn narrowly and require strict compliance in order to offer protection. Additionally, 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; |
| ● | Federal
civil and criminal false claims laws, such as the False Claims Act, which can be enforced by private citizens through civil qui tam actions,
and civil monetary penalty laws prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented,
false, fictitious or fraudulent claims for payment of federal funds, and knowingly making, using or causing to be made or used a false
record or statement material to a false or fraudulent claim to avoid, decrease or conceal an obligation to pay money to the federal government.
As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes “any request or demand”
for money or property presented to the U.S. government. Drug manufacturers can be held liable under the False Claims Act even when they
do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.
For example, pharmaceutical companies have been prosecuted under the False Claims Act in connection with their alleged off-label promotion
of drugs, purportedly concealing price concessions in the pricing information submitted to the government for government price reporting
purposes, and allegedly providing free product to customers with the expectation that the customers would bill federal healthcare programs
for the product. In addition, a claim including items or services resulting from a violation of the federal Anti-Kickback Statute
constitutes a false or fraudulent claim for purposes of the False Claims Act; |
| ● | The
Health Insurance Portability and Accountability Act, or HIPAA, among other things, imposes criminal liability for executing or attempting
to execute a scheme to defraud any healthcare benefit program, including private third-party payors, knowingly and willfully embezzling
or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, and creates federal
criminal laws that prohibit knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false,
fictitious or fraudulent statement or representation, or making or using any false writing or document knowing the same to contain any
materially false, fictitious or fraudulent statement or entry in connection with the delivery of or payment for healthcare benefits,
items or services. Similar to the federal Anti-Kickback Statute, 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; |
| ● | HIPAA,
as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their implementing regulations,
which impose privacy, security and breach reporting obligations with respect to individually identifiable health information upon entities
subject to the law, such as health plans, healthcare clearinghouses and certain healthcare providers, known as covered entities, and
their respective business associates that perform services for them that involve individually identifiable health information. HITECH
also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business
associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in U.S. federal courts to
enforce HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions; |
| ● | Federal
and state consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially
harm consumers; |
| ● | The
federal transparency requirements under the Physician Payments Sunshine Act, created under the Patient Protection and Affordable Care
Act, or ACA, which requires, among other things, certain manufacturers of drugs, devices, biologics and medical supplies reimbursed under
Medicare, Medicaid, or the Children’s Health Insurance Program (with certain exceptions) to report annually to CMS information
related to payments and other transfers of value provided to physicians, defined to include doctors, dentists, optometrists, podiatrists
and chiropractors, and teaching hospitals and physician ownership and investment interests, including such ownership and investment interests
held by aphysician’s immediate family members. Effective January 1, 2022, these reporting obligations will extend to include
transfers of value made during the previous year to certain non-physician providers, including physician assistants, nurse practitioners,
clinical nurse specialists, certified registered nurse anesthetists and anesthesiologist assistants, and certified nurse midwives; |
| ● | Federal
government price reporting laws, which require us to calculate and report complex pricing metrics in an accurate and timely manner to
government programs; |
| ● | State
and foreign laws that are analogous to each of the above federal laws, such as anti-kickback and false claims laws, that may impose
similar or more prohibitive restrictions, and may apply to items or services reimbursed by non-governmental third-party payors,
including private insurers, and state laws that require manufacturers to report information related to payments and other transfers of
value to physicians and other healthcare providers or marketing expenditures and pricing information; and |
| ● | State
and foreign laws that require pharmaceutical companies to implement compliance programs, comply with the pharmaceutical industry’s
voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, or to track and report gifts,
compensation and other remuneration provided to physicians and other healthcare providers; state laws that require the reporting of marketing
expenditures or drug pricing, including information pertaining to and justifying price increases; state and local laws that require the
registration of pharmaceutical sales representatives; state laws that prohibit various marketing-related activities, such as the
provision of certain kinds of gifts or meals; state laws that require the posting of information relating to clinical trials and their
outcomes; and other federal, state and foreign laws that govern the privacy and security of health information or personally identifiable
information in certain circumstances, including state health information privacy and data breach notification laws which govern the collection,
use, disclosure and protection of health-related and other personal information, many of which differ from each other in significant
ways and often are not preempted by HIPAA, thus requiring additional compliance efforts. |
If
our operations are found to be in violation of any of these laws or any other current or future healthcare laws that may apply to us,
we may be subject to significant civil, criminal and administrative penalties, damages, fines, disgorgement, imprisonment, exclusion
from government funded healthcare programs, such as Medicare and Medicaid, contractual damages, reputational harm, diminished profits
and future earnings, additional reporting obligations and oversight if we become subject to a corporate integrity agreement or other
agreement to resolve allegations of non-compliance with these laws, and the curtailment or restructuring of our operations, any
of which could substantially disrupt our operations. Although effective compliance programs can mitigate the risk of investigation and
prosecution for violations of these laws, these risks cannot be entirely eliminated. Any action against us for an alleged or suspected
violation could cause us to incur significant legal expenses and could divert our management’s attention from the operation of
our business, even if our defense is successful. In addition, if any of the physicians or other healthcare providers or entities with
whom we expect to do business is found not to be in compliance with applicable laws, they may be subject to significant criminal, civil
or administrative sanctions, including exclusions from government funded healthcare programs.
Legislative
Reform
We
operate in a highly regulated industry, and new laws, regulations and judicial decisions, or new interpretations of existing laws, regulations
and decisions, related to healthcare availability, the method of delivery and payment for healthcare products and services could negatively
affect our business, financial condition and prospects. There is significant interest in promoting healthcare reforms, and it is likely
that federal and state legislatures within the United States and the governments of other countries will continue to consider changes
to existing healthcare legislation.
For
example, the United States and state governments continue to propose and pass legislation designed to reduce the cost of healthcare.
In 2010, the U.S. Congress enacted the ACA, which included changes to the coverage and reimbursement of drug products under government
healthcare programs such as:
| ● | increased
the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program; |
| ● | established
a branded prescription drug fee that pharmaceutical manufacturers of certain branded prescription drugs must pay to the federal government; |
| ● | expanded
the list of covered entities eligible to participate in the 340B drug pricing program by adding new entities to the program; |
| ● | established
a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% (increased to 70%, effective as of
2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap
period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D; |
| ● | extended
manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations; |
| ● | expanded
eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional individuals
and by adding new mandatory eligibility categories for individuals with income at or below 133% of the federal poverty level, thereby
potentially increasing manufacturers’ Medicaid rebate liability; |
| ● | created
a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for certain drugs and
biologics, including our product candidates, that are inhaled, infused, instilled, implanted or injected; |
| ● | established
a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness
research, along with funding for such research; |
| ● | established
the Center for Medicare & Medicaid Innovation at the CMS to test innovative payment and service delivery models to lower Medicare
and Medicaid spending, potentially including prescription drug spending; and |
| ● | created
a licensure framework for follow-on biologic products. |
There
have been executive, judicial and congressional challenges to certain aspects of the ACA. For example, in 2017, the U.S. Congress enacted
a law informally known as the Tax Cuts and Jobs Act, or TCIA, which eliminated the tax-based shared responsibility payment imposed
by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred
to as the “individual mandate.” On December 14, 2018, the U.S. District Court for the Northern District of Texas held
that the individual mandate is a critical and inseverable feature of the ACA, and therefore, because it was repealed by the TCIA, the
remaining provisions of the ACA are invalid as well. On December 18, 2019, the U.S. Court of Appeals for the Fifth Circuit upheld
the District Court ruling that the individual mandate was unconstitutional and remanded the case back to the District Court to determine
whether the remaining provisions of the ACA are invalid as well. The U.S. Supreme Court recently decided this case; oral arguments were
heard on November 10, 2020 and the Supreme Court’s decision was published on June 17, 2021. The U.S. Supreme Court refused
to hear the plaintiff’s claims on the merits because they held the plaintiff had no standing to bring the lawsuit. Consequently,
the U.S. Supreme Court reversed the lower courts and ordered the case be dismissed. On January 28, 2021, President Biden issued
an executive order to initiate a special enrollment period from February 15, 2021 through May 15, 2021 for purposes of obtaining
health insurance coverage through the ACA marketplace. The executive order also instructs certain governmental agencies to review and
reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration
projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health
insurance coverage through Medicaid or the ACA. Further, on February 10, 2021, the Biden Administration withdrew the federal government’s
support for overturning the ACA. It is unclear how the Supreme Court ruling, other such litigation and the healthcare reform measures
of the Biden administration will impact the ACA. It is difficult to predict the future legislative landscape in healthcare and the effect
on our business, results of operations, financial condition and prospects.
In
addition, there have been and continue to be a number of initiatives at the United States federal and state levels that seek to reduce
healthcare costs. In 2011, the U.S. Congress enacted the Budget Control Act, or BCA, which included provisions intended to reduce the
federal deficit. The BCA resulted in the imposition of 2% reductions in Medicare payments to providers beginning in 2013 and, due to
subsequent legislative amendments to the statute, will remain in effect through 2030, with the exception of a temporary suspension from
May 1, 2020 through March 31, 2021 absent additional congressional action. Legislation is currently pending to extend the suspension
through December 31, 2021. In addition, in 2012, the U.S. Congress enacted the American Taxpayer Relief Act, which, among other
things, further reduced Medicare payments to several types of providers, including hospitals, imaging centers and cancer treatment centers,
and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. If
government spending is further reduced, anticipated budgetary shortfalls may also impact the ability of relevant agencies, such as the
FDA, to continue to function at current levels, which may impact the ability of relevant agencies to timely review and approve research
and development, manufacturing and marketing activities, which may delay our ability to develop, market and sell any product candidates
we may develop. Moreover, any significant spending reductions affecting Medicare, Medicaid or other publicly funded or subsidized health
programs that may be implemented, or any significant taxes or fees that may be imposed on us, as part of any broader deficit reduction
effort or legislative replacement to the BCA, could have an adverse impact on our anticipated product revenues.
Furthermore,
there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which
has resulted in several congressional inquiries and proposed legislation designed to, among other things, bring more transparency to
product pricing, review the relationship between pricing and manufacturer patient programs and reform government program reimbursement
methodologies for drug products. At the federal level, the Trump administration used several means to propose or implement drug pricing
reform, including through federal budget proposals, executive orders and policy initiatives.
For
example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to prescription
drug pricing that attempt to implement several of the administration’s proposals. The FDA also released a final rule on September 24,
2020 providing guidance for states to build and submit importation plans for drugs from Canada. Further, on November 20, 2020, HHS
finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under
Medicare Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law. The implementation
of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.
The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed
fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed until January 1,
2023. Further, in November 2020, CMS issued an interim final rule implementing the Most Favored Nation, or MFN, Model under which Medicare
Part B reimbursement rates will be calculated for certain drugs and biologicals based on the lowest price drug manufacturers receive
in Organization for Economic Cooperation and Development countries with a similar gross domestic product per capita. The MFN Model regulations
mandate participation by identified Medicare Part B providers and will apply in all U.S. states and territories for a seven-year period
beginning January 1, 2021, and ending December 31, 2027. The Interim Final Rule has not been finalized and is subject to revision
and challenge. For example, on December 28, 2020, the United States District Court for the Northern District of California issued
a nationwide preliminary injunction against the implementation of this interim final rule.
Individual
states in the United States have also become increasingly active in passing legislation and implementing 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. In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine
what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs. Further,
it is possible that additional governmental action is taken in response to the COVID-19 pandemic. We expect that additional U.S.
federal healthcare reform measures will be adopted in the future, particularly in light of the new presidential administration.
Facilities
Our
corporate headquarters is located in Herzliya, Israel, where we lease and occupy approximately 2,300 square feet of office space. The
current term of our Herzliya lease commenced January 2022 and expires on December 31, 2024, however we have an option to extend
the term of the lease for additional four years. In September 2021, we entered into an agreement which provides us access to co-working spaces,
including office space in Cambridge, Massachusetts. The license pursuant to which we can access the co-working spaces is terminable
at will by either us or the licensor for any reason upon 30 days’ written notice.
We
believe our existing facility is sufficient for our needs for the foreseeable future. To meet the future needs of our business, we may
lease additional or alternate space, and we believe suitable additional or alternative space will be available in the future on commercially
reasonable terms.
Legal
Proceedings
From
time to time, we are subject to various legal proceedings and claims that arise in the ordinary course of our business activities. Although
the results of litigation and claims cannot be predicted with certainty, as of the date of this annual report, we do not believe we are
party to any claim or litigation, the outcome of which, if determined adversely to us, would individually or in the aggregate be reasonably
expected to have a material adverse effect on our business. Regardless of the outcome, litigation can have an adverse impact on us because
of defense and settlement costs, diversion of management resources and other factors.
Scientific
Advisory Board
We
maintain a Scientific Advisory Board. The current chair of our Scientific Advisory Board is Professor Jeremy Shefner. The other members
of our Scientific Advisory Board are Professor Orla Hardiman, Professor Merit Cudkowicz, Dr. Jinsy Andrews and Dr. Jeffery Rosenfeld.
C.
Organizational Structure
Not
applicable.
D.
Property, Plant and Equipment
See
“Item 4. Information on the Company—B. Business Overview—Facilities”.
ITEM
4A. UNRESOLVED STAFF COMMENTS
None.
ITEM
5. OPERATING AND FINANCIAL REVIEW AND PROSPECTS
You
should read the following discussion of our financial condition and results of operations in conjunction with the consolidated financial
statements and the notes thereto included elsewhere in this annual report. The following discussion contains forward-looking statements
that reflect our plans, estimates and beliefs. Our actual results could differ materially from those discussed in the forward-looking
statements. Factors that could cause or contribute to these differences include those discussed below and elsewhere in this annual
report, particularly those in “Item 3. Key Information – D. Risk Factors.”
Overview
We
are a clinical-stage biotechnology company focused on discovering and developing treatments for patients suffering from debilitating
neurodegenerative diseases. We believe that these diseases, which include ALS, Alzheimer’s disease and Parkinson’s disease,
among others, represent one of the most significant unmet medical needs of our time, with limited effective therapeutic options available
for patients. The burden of these diseases on both patients and society is substantial. For example, the average annual cost of ALS alone
is $180,000 per patient, and its estimated annual burden on the U.S. healthcare system is greater than $1 billion. Due to the complexity
of neurodegenerative diseases, our strategy is to develop combined therapies targeting multiple pathways associated with these diseases.
Our
lead product candidate, PrimeC, is a novel extended-release, or ER, oral formulation of a fixed dose combination of two generic FDA-approved drugs,
ciprofloxacin and celecoxib, combined in a specific ratio. Ciprofloxacin was approved to treat or prevent a variety of bacterial infections
and celecoxib was approved as a prescription nonsteroidal anti-inflammatory drug used to treat pain.
PrimeC
is designed to treat ALS by regulating microRNA, or miRNA, synthesis, influencing iron accumulation and reducing neuroinflammation, all
of which are hallmarks of ALS pathologies. The U.S. Food and Drug Administration, or FDA, and the European Medicines Agency, or EMA,
have both granted PrimeC an orphan drug designation for the treatment of ALS. We believe PrimeC’s multifactorial mechanism of action
has the potential to significantly prolong lifespan and improve ALS patients’ quality of life, thereby reducing the burden of this
debilitating disease on both patients and healthcare systems.
In
addition to PrimeC, we recently initiated research and development efforts in Alzheimer’s disease and Parkinson’s disease,
with a similar strategy of combined products.
We have incurred operating losses in each year since our inception.
We incurred net losses of $4.04 million and $2.83 million for the years ended December 31, 2021 and 2020, respectively.
As of December 31, 2021, we had an accumulated deficit of $8.45 million. We expect to incur significant expenses and operating losses
for the foreseeable future as we advance our product candidates from formulation development through preclinical development and clinical
trials, seek regulatory approval and pursue commercialization of any approved product candidate. In addition, we expect that our expenses
will increase substantially in connection with our ongoing activities as we:
| ● | commence
a Phase IIb trial and a pivotal Phase III trial for PrimeC, in addition to additional clinical studies to support our future regulatory
submissions; |
| ● | continue
the preclinical development of our other product candidates; |
| ● | file
an NDA seeking regulatory approval for any product candidates; |
| ● | establish
a sales, marketing and distribution infrastructure and scale up external manufacturing capabilities to commercialize any products for
which we obtain manufacturing approval; |
| ● | maintain,
expand and protect our intellectual property portfolio; |
| ● | add
equipment and physical infrastructure to support our research and development; |
| ● | hire
additional clinical development, quality control and manufacturing personnel; |
| ● | incur
additional expenses associated with operating as a U.S. public company, including significant legal, accounting, investor relations and
other expenses that we did not incur as a private company; and |
| ● | add
operational, financial and management information systems and personnel, including personnel to support our product development and planned
future commercialization. |
A.
Operating Results
Revenue
We
have not recognized any revenue to date and we do not expect to generate revenue from the sale of products in the near future.
Operating
Expenses
Our
current operating expenses consist primarily of research and development as well as general and administrative expenses.
Research
and Development Expenses
The
largest component of our total operating expenses has historically been, and we expect will continue to be, research and development.
Research and development expenses consist primarily of:
| ● | salaries
for research and development staff and related expenses, including employee benefits and share-based compensation expenses; |
| ● | expenses
for production of our product candidates by contract manufacturers; |
| ● | expenses
paid to contract research organizations and other third parties in connection with the performance of preclinical studies, clinical trials
and related expenses; |
| ● | expenses
incurred under agreements with other third parties, including subcontractors, suppliers and consultants that conduct formulation development,
regulatory activities and preclinical studies; |
| ● | expenses
incurred to acquire, develop and manufacture preclinical study and clinical trial materials. |
Expenses
on research activities is recognized in profit or loss when incurred. Development expenditures, including patent registration costs,
are capitalized only if development costs can be measured reliably, the product or process is technically and commercially feasible,
future economic benefits are probable, and we intend to and have sufficient resources to complete development and to use or sell the
asset. As of December 31, 2021, no development expenditures have met the recognition criteria and thus we have expensed all of our development
expenditures as incurred.
We
are currently focused on advancing our product candidates, and our future research and development expenses will depend on their clinical
success. Research and development expenses will continue to be significant and will increase over at least the next several years as
we continue to develop our product candidates and conduct preclinical studies and clinical trials of our product candidates.
We
do not believe that it is possible at this time to accurately project total expenses required for us to reach commercialization of our
product candidates. Due to the inherently unpredictable nature of preclinical and clinical development, we are unable to estimate with
certainty the costs we will incur and the timelines that will be required in the continued development and approval of our product candidates.
Clinical and preclinical development timelines, the probability of success and development costs can differ materially from expectations.
See “Risk Factors—Risks Related to Our Business and Strategy.” In addition, we cannot forecast which product candidates
may be subject to future collaborations, if and when such arrangements will be entered into, if at all, and to what degree such arrangements
would affect our development plans and capital requirements.
General
and Administrative Expenses
General
and administrative expenses consist primarily of personnel costs, including share-based compensation, related to directors, executive,
finance, and human resource functions, facility costs and external professional service costs, including legal, accounting, marketing
and audit services and other consulting fees.
We
anticipate that our general and administrative expenses will increase in the future as we increase our administrative headcount and infrastructure
to support our continued research and development programs and the potential approval and commercialization of our product candidates.
We also anticipate that we will incur increased expenses related to audit, legal, regulatory and tax-related services associated with
maintaining compliance with Nasdaq and SEC requirements, director and officer insurance premiums, director compensation, and other costs
associated with being a public company.
In
addition, if any of our product candidates receives regulatory approval and if we determine to invest in building a commercial infrastructure
to support the marketing of our products, we expect to incur greater expenses.
Financing
income (Expenses), net
Our
net financing expenses (income), net consist primarily of fair value revaluation of warrants, issuance costs and differences in the exchange
rate between NIS and the U.S. Dollar.
Income
Taxes
We have yet to generate taxable income in Israel, as we have historically
incurred operating losses resulting in carry forward tax losses totaling approximately $3.96 million as of December 31, 2021. We anticipate
that we will continue to generate tax losses for the foreseeable future and that we will be able to carry forward these tax losses indefinitely
to future taxable years. Accordingly, we do not expect to pay taxes in Israel until we have taxable income after the full utilization
of our carry forward tax losses.
Results
of Operations
Our
results of operations for the years ended December 31, 2021 and 2020 were as follows:
| |
For the Years Ended
December 31, | |
(U.S. dollars in thousands except share and
per share data) | |
2021 | | |
2020 | |
Statement of Operations: | |
| | |
| |
Research and Development Expenses | |
| (3,082 | ) | |
| (2,495 | ) |
General and Administrative Expenses | |
| (2,505 | ) | |
| (393 | ) |
Operating Loss | |
| (5,587 | ) | |
| (2,888 | ) |
Financing Expenses | |
| (1,186 | ) | |
| (1 | ) |
Financing Income | |
| 2,732 | | |
| 61 | |
Net Loss and Comprehensive Loss | |
| (4,041 | ) | |
| (2,828 | ) |
Basic and Diluted Net Loss per Share | |
| (0.65 | ) | |
| (0.51 | ) |
Weighted average number of shares outstanding used in computing basic and diluted net loss per share | |
| 6,243,411 | | |
| 5,519,061 | |
Research
and Development Expenses
The
following table describes the breakdown of our research and development expenses for the indicated periods:
| |
For the Years Ended
December 31, | |
(U.S. dollars in thousands except share and per share data) | |
2021 | | |
2020 | |
Subcontractors and consultants | |
$ | 628 | | |
| 452 | |
Share-based compensation | |
| 1,969 | | |
| 1,804 | |
Salaries and social benefits | |
| 447 | | |
| 227 | |
Others | |
| 38 | | |
| 12 | |
Total research and development expenses | |
$ | 3,082 | | |
| 2,495 | |
Our
research and development expenses for the years ended December 31, 2021 and 2020 were $3,082 thousand and $2,495 thousand, respectively.
The increase of $587 thousand, or 23%, is mainly attributed to (i) an increase of $220 thousand in salaries and social benefits, mainly
due to additional compensation paid to our executive officers upon our IPO and an increase in the number of employees, (ii) an increase
of $165 thousand in share-based compensation expenses due to grants of additional options and RSUs to our employees and service providers
and (iii) an increase of $176 thousand in subcontractor and consulting expenses relating to clinical programs.
General
and Administrative Expenses
The
following table describes the breakdown of our general and administrative expenses for the indicated periods:
| |
For the year ended
December 31, | |
| |
2021 | | |
2020 | |
| |
U.S. dollars in thousands | |
Professional services | |
$ | 372 | | |
| 49 | |
Share-based compensation | |
| 1,849 | | |
| 257 | |
Salaries and social benefits | |
| 74 | | |
| 52 | |
Insurance | |
| 68 | | |
| 14 | |
Traveling abroad | |
| 50 | | |
| 8 | |
Others | |
| 92 | | |
| 13 | |
| |
$ | 2,505 | | |
| 393 | |
Our
general and administrative expenses for the years ended December 31, 2021 and 2020 were $2,505 thousand and $393 thousand, respectively.
The increase of $2,112 thousand, or 537% was primarily attributable to (i) a $1,592 thousand increase in share-based compensation expenses
due to grants of additional options and RSUs to our employees, directors and service providers and (ii) a $323 thousand increase in professional
services expenses.
Financing
Expenses
Our
financing expenses for the years ended December 31, 2021 and 2020, were $1,186 thousand and $1 thousand, respectively. The increase of
$1,185 thousand was primary attributable to $1,152 thousand of issuance costs with respect with the IPO allocated to the issuance of
the Warrants and recorded in the statements of comprehensive loss and $32 thousand due to exchange rates.
Financing
Income
Our
financing income for the years ended December 31, 2021 and 2020 was $2,732 thousand and $61 thousand, respectively. The change in financing
income was primarily attributable to revaluation of the warrants.
B. Liquidity
and Capital Resources
Overview
Since our inception, we have incurred losses and negative cash flows
from our operations. For the year ended December 31, 2021, we incurred a net loss of $4.04 million while net cash of $1.54 million was
used in our operating activities. As of December 31, 2021, we had working capital of $10.77 million, and an accumulated deficit of $8.45
million. As of December 31, 2021, our cash and cash equivalents totaled approximately $11.06 million. Based on current expected level
of operating expenditures, our cash resources as at December 31, 2021 and the $3.87 million received in March 2022 with respect to the
exercise of certain warrants will be sufficient for at least the next twelve months beyond the date of the filing of our financial statements.
Through December 31, 2021, we have financed our operations primarily through our initial public offering, private placements and crowd
funding of equity securities. Total gross invested capital as of December 31, 2021 was $16.5 million, which included ordinary shares,
SAFE Agreements, options and warrants to purchase ordinary shares. In May, June and July we received $0.80 million from SAFE agreement,
in September 2021, we received an additional $1.23 million from previous investors as a result of their exercise of outstanding warrants,
and in December 2021, we received gross proceeds of approximately $12.0 million from our initial public offering.
In
March 2022, we received proceeds of $3.87 million from exercise of warrants.
Cash
flows
The
following table summarizes our statement of cash flows for the years ended December 31, 2021 and 2020:
| |
For the Years Ended
December 31, | |
(U.S. dollars in thousands except share and per share data) | |
2021 | | |
2020 | |
Net cash used in operating activities and exchange rates | |
$ | (1,521 | ) | |
| (695 | ) |
Net cash used in investing activities | |
| (17 | ) | |
| (9 | ) |
Net cash provided by financing activities | |
| 11,902 | | |
| 508 | |
(Decrease) increase in cash and cash equivalents | |
$ | 10,364 | | |
| (196 | ) |
Net cash
used in operating activities
Net
cash used in operating activities was $1,521 thousand and $695 thousand for the years ended December 31, 2021 and 2020, respectively.
The $826 thousand increase was attributable primarily to the increase in our net loss, mainly due to an increase in (i) our research
and development expenses relating to our clinical study and (ii) general and administrative expenses mainly due to an increase in professional
services and salary and related benefits.
Net cash
used in investing activities
Net
cash used in investing activities was $17 thousand and $9 thousand for the years ended December 31, 2021 and 2020, respectively.
Net cash
provided by financing activities
Net
cash provided by financing activities was $11,902 thousand and $508 thousand for the years ended December 31, 2021 and 2020, respectively.
The increase was due to the issuance of shares and warrants in our initial public offering, exercise of warrants and options and issuance
of SAFE instruments.
Funding
Requirements
Since
our inception, almost all of our resources have been dedicated to the preclinical and clinical development of our lead product candidate,
PrimeC. As of December 31, 2021, we had cash and cash equivalents of $11.06 million. We believe that our existing cash and cash equivalents,
including the additional funds received or receivable after the balance sheet date upon the exercise of warrants described above, will
be sufficient to fund the Company’s operations for a period of at least 12 months from the date of approval of our financial statements.
Our
present and future funding requirements will depend on many factors, including, among other things:
| ● | the
progress, timing and completion of clinical trials for PrimeC; |
| ● | preclinical
studies and clinical trials for our other product candidates; |
| ● | the
costs related to obtaining regulatory approval for PrimeC and any of our other product candidates, and any delays we may encounter as
a result of regulatory requirements or adverse clinical trial results with respect to any of these product candidates; |
| ● | selling,
marketing and patent-related activities undertaken in connection with the commercialization of PrimeC and any of our other product candidates,
and costs involved in the development of an effective sales and marketing organization; |
| ● | the
costs involved in filing and prosecuting patent applications and obtaining, maintaining and enforcing patents or defending against claims
or infringements raised by third parties, and license royalties or other amounts we may be required to pay to obtain rights to third
party intellectual property rights; |
| ● | potential
new product candidates we identify and attempt to develop; and |
| ● | revenues
we may derive either directly or in the form of royalty payments from future sales of PrimeC and any other product candidates. |
For
more information as to the risks associated with our future funding needs, see “Risk Factors — We will require substantial
additional financing to achieve our goals, and a failure to obtain this capital when needed and on acceptable terms, or at all, could
force us to delay, limit, reduce or terminate our product development, commercialization efforts or other operations.”
Contractual
Obligations and Commitments
As
of December 31, 2021, we did not have any material contractual obligation and commitments.
Off-Balance
Sheet Arrangements
We
did not have during the periods presented, and we do not currently have, any off-balance sheet arrangements that have or are reasonably
likely to have a current or future effect on our financial condition, revenues or expenses, results of operations, liquidity, capital
expenditures or capital resources.
C.
Research and Development, Patents and Licenses
For
a description of our research and development programs and the amounts that we have incurred over the last three years pursuant to those
programs, please see “Item 5. Operating and Financial Review and Prospects — A. Operating Results — Research and Development
Expenses.”
D.
Trend Information
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, 2021 to December 31, 2021 that are reasonably likely to have a material adverse effect on our revenue, income,
profitability, liquidity or capital resources, or that caused that disclosed financial information to be not necessarily indicative of
future operating results or financial condition.
E. Critical
Accounting Policies and Use of Estimates
We
describe our significant accounting policies and estimates in Note 3 to our annual financial statements contained elsewhere in this annual
report. We believe that these accounting policies and estimates are critical in order to fully understand and evaluate our financial
condition and results of operations.
We
prepare our financial statements in accordance with IFRS as issued by the IASB.
In
preparing these financial statements, management has made judgments, estimates and assumptions that affect the application of our accounting
policies and the reported amounts recognized in the financial statements. On a periodic basis, we evaluate our estimates, including those
related to share-based compensation and derivatives. We base our estimates on historical experience, authoritative pronouncements and
various other assumptions that we believe to be reasonable under the circumstances. Actual results may differ from these estimates. For
more information, please see Note 2 to our annual financial statements contained elsewhere in this annual report.
Emerging
Growth Company Status
We
qualify as an “emerging growth company” as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act. An
emerging growth company may take advantage of specified reduced reporting and other burdens that are otherwise applicable generally to
public companies. These provisions include:
| ● | to
the extent that we no longer qualify as a foreign private issuer, (i) reduced disclosure obligations regarding executive compensation
in our periodic reports and proxy statements and (ii) exemptions from the requirement to hold a non-binding advisory vote on executive
compensation, including golden parachute compensation; |
| ● | an
exemption from the auditor attestation requirement in the assessment of our internal control over financial reporting pursuant to the
Sarbanes-Oxley Act of 2002; and |
| ● | an
exemption from compliance with the requirement that the Public Company Accounting Oversight Board has adopted regarding a supplement
to the auditor’s report providing additional information about the audit and the financial statements. |
We
may take advantage of these exemptions for up to five years or until such earlier time that we are no longer an emerging growth
company. We would cease to be an emerging growth company upon the earliest to occur of: (i) the last day of the fiscal year in which
we have total annual gross revenues of $1.07 billion or more; (ii) the date on which we have issued more than $1.0 billion in nonconvertible
debt during the previous three years; (iii) the date on which we are deemed to be a large accelerated filer under the rules of the SEC;
or (iv) the last day of the fiscal year following the fifth anniversary of our initial public offering. We may choose to take advantage
of some but not all of these exemptions. Section 107 of the JOBS Act provides that an “emerging growth company” can take
advantage of the extended transition period provided in Section 7(a)(2)(B) of the Securities Act for complying with new or revised accounting
standards. This means that an “emerging growth company” can delay the adoption of certain accounting standards until those
standards would otherwise apply to private companies. Given that we currently report and expect to continue to report our financial results
under IFRS as issued by the IASB, we will not be able to avail ourselves of this extended transition period and, as a result, we will
adopt new or revised accounting standards on the relevant dates on which adoption of such standards is required by the IASB.
ITEM
6. DIRECTORS, SENIOR MANAGEMENT AND EMPLOYEES
A.
Directors and Senior Management
The
following table sets forth information concerning our directors and senior management, including their ages, as of the date of this annual
report:
Name |
|
Position |
|
Age |
Executive Management |
|
|
|
|
Alon
Ben-Noon |
|
Chief Executive Officer, Director |
|
42 |
Or Eisenberg |
|
Chief Financial Officer |
|
40 |
Dr.
Ferenc Tracik |
|
Chief Medical Officer |
|
58 |
Non-Executive Directors |
|
|
|
|
Mark
Leuchtenberger * |
|
Chair of the Board of Directors |
|
65 |
Cary
Claiborne (1) (2) * |
|
External Director |
|
61 |
Christine
Pellizzari (1) (2) * |
|
External Director |
|
54 |
Caren
Deardorf (1) (2) * |
|
Director |
|
57 |
Dr.
Revital Mandil-Levin (1) (3) |
|
Director |
|
47 |
(1) | Member
of audit committee |
(2) | Member
of compensation committee |
* | Independent
director under Nasdaq rules |
Executive
Officers
Alon Ben-Noon,
Chief Executive Officer, Director.
Alon
Ben-Noon is our founder and has served as our chief executive officer and director since February 2017. Mr. Ben-Noon served
as Chair of our board of director since our founding until October 1, 2021. From 2014 until 2017, Mr. Ben-Noon served
as the founder and owner of MediCan Consulting, a pharmaceutical consulting firm that advised a number of successful pharmaceutical companies,
including MediWound Ltd., Chiasma Inc., Teva Pharmaceutical Industries Limited, Sol-Gel Technologies Ltd., FutuRx Ltd., NeuroDerm
Ltd. and others. Mr. Ben-Noon holds a B.S. in Industrial Engineering and an MBA from Ben-Gurion University.
Or Eisenberg,
Chief Financial Officer.
Or
Eisenberg has served as our chief financial officer since June 2021. Prior to joining the Company, Mr. Eisenberg served in various
finance and executive leadership roles with Mawson Infrastructure Group Inc. (formerly Wize Pharma Inc.). From March 2015 until November
2017, Mr. Eisenberg served as the chief financial officer and acting chief executive officer of Wize Pharma Ltd. From November 2017
until August 2021, Mr. Eisenberg served as the chief financial officer, treasurer and secretary of Mawson. Since August 2021, Mr. Eisenberg
has served as a consultant to Mawson. Mr. Eisenberg was previously the controller at the Katzir Fund Group and has served as the
external chief financial officer for a number of companies with securities listed on the Tel Aviv Stock Exchange. Mr. Eisenberg
began his career as an accountant with Ernst & Young. Mr. Eisenberg holds a B.A. in Economics and Accounting from Haifa University,
and is a Certified Public Accountant registered in the State of Israel.
Dr. Ferenc Tracik, Chief Medical Officer.
Dr. Ferenc Tracik has served as our chief medical
officer since December 1, 2021. Dr. Tracik has twenty years of experience in general management, medical affairs, clinical development
and commercialization in the biotech industry. Before joining the Company, he served as the Global Head Medical of Orphazyme A/S. From
May 2017 until November 2020, Dr. Tracik served as VP Medical Europe, Canada and Partner Markets of Biogen Inc. From November 2013 until
April 2017, Dr. Tracik served in various positions at Teva Pharmaceutical Industries Limited, including Managing Director Specialty Medicines
Germany. Dr. Tracik’s experience and expertise in therapy is extensive, and includes different disease areas such as CNS, respiratory,
oncology, ophthalmology, infectious diseases, and transplantation), with a specific focus on neurodegenerative and neuro-autoimmune diseases.
Before joining the pharmaceutical industry, Dr. Tracik worked at the university clinics of neurology at Charité Berlin and the
university clinic of Innsbruck. Dr. Tracik holds a doctoral degree in human medicine from the Free University of Berlin.
Non-Executive Directors
The following is a brief summary of the business
experience of the members of our board of directors who are not our executive officers.
Mark Leuchtenberger, Chair of the Board of Directors.
Mr. Leuchtenberger has served as the
chair of our Board of Directors since October 1, 2021. Mr. Leuchtenberger has served as the executive chairman of Aleta
Biotherapeutics Inc. since June 2019 and continues to serve in such role. From March 2017 until December 2019,
Mr. Leuchtenberger was the chief executive officer of Brooklyn ImmunoTherapeutics Inc. During the years 2015-2016,
Mr. Leuchtenberger was the president and chief executive officer, as well as a member of the Board of Directors at Chiasma,
Inc. (NASDAQ: CHMA). Mr. Leuchtenberger had also filled president and chief executive officer positions at both Acusphere Inc.
and Melinta Therapeutics Inc. (formerly Rib-X Pharmaceuticals Inc.). Mr. Leuchtenberger received his MBA from the Yale
School of Management and his BA from Wake Forest University.
Cary Claiborne, Director.
Mr. Claiborne became a member of our board of directors
immediately prior to the closing of our initial public offering and serves as an external director under the Companies Law. Mr. Claiborne
has served as the Chief Operating Officer since December 2021 and a director since November 2021 for Adial Pharmaceuticals Inc. a public
biopharmaceutical company. Prior to joining Adial, Mr. Claiborne served as the CEO of Prosperity Capital Management, LLC, a US based Private
Investment and Advisory firm that he founded. From 2014 until 2017, Mr. Claiborne served as the Chief Financial Officer and board member
of Indivior PLC. a public global commercial stage pharmaceutical company. Mr. Claiborne was also a director on the Board of Directors
of New Generation Biofuels Inc. and MedicAlert Foundation, where he also served as the chair of the audit and finance committees. From
2011 to 2014, Mr. Claiborne was the Chief Financial Officer of Sucampo Pharmaceuticals Inc., a public global biopharmaceutical company
focused on drug discovery, development, and commercialization. Mr. Claiborne graduated from Rutgers University with a B.A. in Business
Administration. He also holds an M.B.A from Villanova University and was previously a NACD Governance Fellow.
Christine Pellizzari, Director.
Ms. Pellizzari became a member of our
board of directors immediately prior to the closing of our initial public offering and serves as an external director under the Companies
Law. Ms. Pellizzari has served as the Chief Legal Officer of Science 37 since July 2021. Prior to joining Science 37, Ms. Pellizzari
served as the General Counsel and Corporate Secretary of Insmed, Inc., a public biotech company focused on serious and rare diseases,
from 2013 to 2018 and as Chief Legal Officer from 2018 to 2021. She also currently serves on the board of directors of Tempest Therapeutics,
a public clinical-stage oncology company, and Celsion Corporation, a public a clinical-stage development company focused on
DNA mediated immunotherapy and next-generation nucleic vaccines. Prior to Insmed, Christine held various legal positions of increasing
responsibility at Aegerion Pharmaceuticals, Inc., most recently as Executive Senior Vice President, General Counsel and Secretary. Prior
to Aegerion, she served as Senior Vice President, General Counsel and Secretary of Dendrite International, Inc. Christine joined Dendrite
from the law firm of Wilentz, Goldman & Spitzer, where she specialized in health care transactions and related regulatory matters.
She has nearly three decades of relevant experience, including having served for over 25 years as CLO and General Counsel of publicly
traded companies in biopharmaceutical and related industries. Christine earned her B.A. in Legal Studies from the University of Massachusetts,
Amherst and J.D. from the University of Colorado School of Law.
Caren Deardorf, Director.
Ms. Deardorf became a member of our board of directors
immediately prior to the closing of our initial public offering. Ms. Deardorf has more than 25 years of international biotechnology
leadership experience across a range of companies and therapeutic areas. Ms. Deardorf has served as the chief commercial officer
of Magenta Therapeutics, a clinical-stage company since July 2021 and continues to serve in such role. At Magenta, Ms. Deardorf is
responsible for crafting and executing the commercial pipeline strategy. From May 2019 until May 2021, Ms. Deardorf served as the chief
commercial officer at Ohana Biosciences and was responsible for developing a commercial strategy for fundraising and business development,
including planning for the company’s first commercial product launch. From 2016 until 2019, Ms. Deardorf served as vice president,
product development & commercialization at Biogen, where she helped execute the global launch of SPINRAZA® for
spinal muscular atrophy, a rare condition. Ms. Deardorf also serves on the board of directors for the Pan Mass Challenge, a non-profit organization
which has raised over $700 million for the Dana Farber Center Institute. Ms. Deardorf holds an MBA from Babson College and a bachelor
of science degree in biology from Tufts University.
Dr. Revital Mandil-Levin, Director.
Dr. Mandil-Levin became a member of our board
of directors in January 2022. Dr. Mandil-Levin has more than 15 years’ experience in biotech startups and product development in
the pharmaceutical industry. She is currently the CEO and founder of Nanocarry Therapeutics Ltd., a private company developing a proprietary
platform technology for the delivery of biologics across the blood-brain barrier for CNS indications. From September 2019 to November
2020, she served as VP Corporate Development of Anima Biotech, a private company with a novel approach for the discovery of small molecules
involved in mRNA translation, and from April 2018 to February 2019, she served as Chief Business Development Officer of CollPlant Ltd.
(NASDAQ: CLGN), a public regenerative and aesthetic medicine company. From January 2014 to February 2018, Dr. Mandil-Levin served as Vice
President Business Development at NeuroDerm Ltd (NASDAQ: NDRM), a clinical-stage pharmaceutical company developing next-generation treatments
for CNS disorders, where she had a major role in the acquisition of NeuroDerm by Mitsubishi Tanabe Pharma Corporation for $1.1 billion.
From 2004 to 2013, Dr. Mandil-Levin served as Vice President Business Development at HealOr Ltd, a clinical-stage biopharmaceutical company
that developed novel drugs for skin regeneration in hard to heal wounds and dermatological diseases. Prior to that she served as Business
Development Manager at Proteologics Ltd. Dr. Mandil-Levin holds a PhD in Biochemistry from Bar-Ilan University, Israel and an MBA from
the Israeli College of Management School of Business.
B. Compensation
The aggregate compensation, including share-based compensation, paid
by us to our executive officers and directors for the year ended December 31, 2021 was approximately $1,993 thousand. This
amount includes accruals 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 officers, and other benefits commonly reimbursed or
paid by companies in Israel.
Below is an outline of compensation granted
or paid to our executive officers during the year ended December 31, 2021. The value of equity compensation is determined based on accounting
rules that involve certain assumptions and key variables, as discussed in Note 8 of our financial statements. Additionally, as each of
our executives received an inaugural equity award in connection with our IPO, the accounting valuation of equity compensation for 2021
is not necessarily representative of our compensation practices for the future. Social benefits provided to management consist of payments
to the National Insurance Institute, advanced education funds, managers’ insurance and pension funds, vacation pay, and recuperation
pay as mandated by Israeli law.
During the year ended December 31, 2021, we paid a base salary or other
payments of $176 thousand to Mr. Ben-Noon, social benefits valued at $8 thousand and equity compensation valued at $232 thousand, for
a total of $416 thousand. Mr. Ben-Noon does not receive extra compensation for his service as a member of the board of directors.
During the year ended December 31, 2021, we paid a base salary of $33
thousand to Mr. Eisenberg, social benefits valued at $5 thousand and equity compensation valued at $713 thousand, for a total of $751
thousand. From the commencement of his employment until our IPO, Mr. Eisenberg agreed to the minimum monthly salary allowed by Israeli
law. The amount of equity compensation mentioned reflects the accounting value of options and vested RSUs as mentioned above.
During the year ended December 31, 2021, we paid a base salary of $25
thousand to Dr. Tracik, social benefits valued at $6 thousand, equity compensation valued at $92 thousand and other costs related to his
employment with the Company of $5 thousand, for a total of $128 thousand.
During the year ended December 31, 2021,
we paid a cash retainer of $20 thousand to Mr. Leuchtenberger and equity compensation valued at $663 thousand, for a total of $683 thousand.
During the year ended December 31, 2021,
we paid a cash retainer of $3 thousand to each of Mr. Claiborne, Ms. Pellizzari, and Ms. Deardorf, and equity compensation valued at $6
thousand to Ms. Deardorf.
As
of December 31, 2021, 216,000 RSUs and options to purchase 393,000 ordinary
shares granted to our executive officers and directors were outstanding under our 2018 Plan at a weighted average exercise price of $3.32.
Each option will expire ten years from the date of the grant thereof.
We pay each of our non-employee directors
an annual retainer of $40,000 plus applicable VAT, with an additional annual payment for service on board committees as follows: $15,000
plus applicable VAT for the chairperson of any board committee (such additional payment for only one committee chair) and an additional
amount of $10,000 plus VAT for membership on any board committee (such additional payment for up to two committees, provided that if a
director is serving as chair of one committee and member of one or more other committees, such director would receive one payment as committee
chair and one payment as committee member). In addition, each non-employee director was granted options to acquire 72,000 ordinary shares,
one-third of which will vest one year from the grant date and the remainder to vest quarterly and become fully vested three years from
the grant date at an exercise price equal to the closing price per share on Nasdaq on the closing date of our initial public offering
(and in the case of external directors, at the closing price per share on the date of the shareholder meeting at which their appointment
as external directors was ratified), subject to such director’s continued service through such date.
Equity Compensation. Since January 1, 2018,
we have granted options to purchase our ordinary shares to our officers and certain of our directors. Such option agreements may contain
acceleration provisions upon certain merger, acquisition, or change of control transactions. We describe our 2018 Plan under “Management—2018
Employee Share Option Plan.” If our relationship with an executive officer or a director is terminated, except for cause (as defined
in the various option plan agreements), all options that are vested will remain exercisable for 90 days after such termination. If the
relationship is terminated due to the death of the executive officer or a director, the participant may exercise any portion of the options
which have vested within 60 days of the death of the executive officer or a director, at any time but no later than the one year anniversary
of the executive officer or a director’s death or the end of the term, whichever is earlier. If our relationship with an executive
officer or a director is terminated by reason of retirement or disability the participant may exercise any portion of the options which
have vested within 90 days of the executive officer or a director’s retirement or disability, at any time but no later than the
one year anniversary of the executive officer or a director’s retirement or disability or the end of the term, whichever is earlier.
On November 7, 2021 the Company granted Mr.
Ben-Noon 108,000 RSUs. The RSUs vest on a quarterly basis over three years, commencing December 13, 2021.
In July 2021, the Company granted Mr. Eisenberg
options to purchase 21,000 shares at an exercise price of $0.03 per share. The options vested monthly over seven months commencing
June 2021. Pursuant to his employment agreement, the Company agreed that to the extent the value of such options at the time of the
Company’s IPO is less than $200,000, the Company shall grant additional options. In addition, on November 7, 2021, the Company
granted Mr. Eisenberg 108,000 RSUs. The RSUs vest on a quarterly basis over three years, commencing December 13, 2021.
On November 7, 2021, the Company granted Dr. Tracik
options to purchase 108,000 shares at a price of $3.51 per share. The options vest on a quarterly basis over three years, commencing December
13, 2021.
Exculpation, Indemnification and Insurance.
Our amended and restated 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 our 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, to the extent that these liabilities are not covered by insurance. See “Management—Exculpation, Insurance
and Indemnification of Directors and Officers.”
Compensation Policy
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 an 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 executive officers’ 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 for equity-based compensation.
The compensation policy provides that compensation
will be determined based on our executive officers’ respective positions, education, scope of responsibilities and contributions,
and that we will consider the ratio 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. In addition,
the total variable compensation components (cash bonuses and equity-based compensation) may not exceed 90% of each executive officer’s
total compensation package with respect to any given calendar year.
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 the chief executive officer. Performance objectives may be recommended by our chief
executive officer and will be approved by the compensation committee (and, if required by law, by our board of directors). We may also
grant annual cash bonuses to our executive officers on a discretionary basis.
The performance objectives and targets of our chief
executive officer will be determined by our compensation committee and board of directors. Up to 30% of the chief executive officer’s
annual cash bonus may be based on a discretionary evaluation of his overall performance by the compensation committee and the board of
directors based on quantitative and qualitative criteria.
The equity-based compensation for our executive
officers under the compensation policy is designed in a manner consistent with the underlying objectives for determining the base salary
and the annual cash bonus. Primary objectives include enhancing the alignment between the executive officers’ interests and our
long-term interests and those of our shareholders and strengthening the retention and the motivation of executive officers in the
long term. Equity-based compensation may be granted in the form of options or other equity-based awards, such as restricted
shares and restricted share units, in accordance with a share incentive plan. All equity-based incentive awards granted to executive
officers will be subject to vesting periods in order to promote long-term retention of the grantee. Equity-based compensation
will be granted from time to time and be awarded according to the performance, educational background, prior business experience, qualifications,
role and the personal responsibilities of the executive officer.
In addition, the compensation policy contains compensation
recovery provisions that apply in the event of an accounting restatement enables our chief executive officer to approve immaterial changes
in the terms of employment of an executive officer (provided that the changes of the terms of employment are in accordance with our compensation
policy) and allows us to exculpate, indemnify and insure our executive officers and directors subject to certain limitations as set forth
therein.
The 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
on Stock Exchanges Outside of Israel) of 2000, as such regulations may be amended from time to time, or (ii) in accordance with the
amounts determined in the compensation policy.
Employment and Consulting Agreements
Our employees are employed under the terms prescribed
in their respective employment contracts. The employees are entitled to the social benefits prescribed by law and as otherwise provided
in their agreements. These agreements each contain provisions standard for a company in our industry regarding non-competition, confidentiality
of information and assignment of inventions. Under currently applicable labor laws, we may not be able to enforce covenants not to compete
and therefore may be unable to prevent our competitors from benefiting from the expertise of some of our former employees. Each of the
executive officers with whom we have entered into an employment or service agreement may be terminated with immediate effect if terminated
for cause as defined in their respective agreements. In cases where an executive officer is terminated for cause they will not be entitled
to receive any compensation during the notice period. See “Risk Factors—Risks Related to Our Business and Strategy”
for a further description of the enforceability of non-competition clauses. We also provide certain of our employees with a company car,
which is leased from a leasing company.
Our executive officers are also employed on the
terms and conditions prescribed in their employment or service agreements or terms. These agreements and terms provide for notice periods
of varying duration for termination of the agreement without cause, by us or by the relevant executive officer, during which time the
executive officer will continue to receive base salary and benefits.
C. Board Practices
Board of Directors
Under the Companies Law and our amended and restated
articles of association, our business and affairs will be managed under the direction of our board of directors. Our board of directors
may exercise all powers and may take all actions that are not specifically granted to our shareholders or to executive management. Our
chief executive officer (referred to as a “general manager” under the Companies Law) is responsible for our day-to-day management.
Our chief executive officer is appointed by, and serves at the discretion of, our board of directors, subject to the agreed upon employment
terms approved by our shareholders. All other executive officers are appointed by the chief executive officer, subject to applicable corporate
approvals, and are subject to the terms of any applicable employment or consulting agreements that we may enter into with them. Under
our amended and restated articles of association, other than external directors, for whom special election requirements apply under the
Companies Law, as detailed below, the number of directors on our board of directors will be no less than five and no more than nine directors
divided into three classes with staggered three-year terms. Each class of directors consists, as nearly as possible, of one-third of the
total number of directors constituting the entire board of directors (other than the external directors). At each annual general meeting
of our shareholders, the election or re-election of directors following the expiration of the term of office of the directors of that
class of directors will be for a term of office that expires on the third annual general meeting following such election or re-election,
such that from the annual general meeting of 2022 and after, each year the term of office of only one class of directors will expire.
Our directors who are not external directors will be divided among the three classes as follows:
| ● | the Class I director will be Dr. Revital Mandil-Levin,
and her term will expire at our annual general meeting of shareholders to be held in 2022; |
| ● | the Class II director will be Caren Deardorf, and her
term will expire at our annual meeting of shareholders to be held in 2023; and |
| ● | the Class III directors will be Alon Ben-Noon and Mark
Leuchtenberger, and their term will expire at our annual meeting of shareholders to be held in 2024. |
Cary Claiborne and Christine Pellizzarri serve as
our external directors and each has a term of three years.
Our directors, aside from our external 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 shall 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, aside from our external directors, 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 amended and restated articles of association,
the approval of the holders of at least 662/3% of the total voting power of our shareholders is generally required to remove
any of our directors (other than the external directors) from office and any amendment to this provision shall require the approval of
at least 662/3% of the total voting power of our shareholders. 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 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 maximum number of directors stated in our amended and restated articles of association, until
the next annual general meeting of our shareholders for the class of directors to which such director has been assigned by our board of
directors.
Chair of the Board
Our amended and restated articles of association
provide that the chair of the board is appointed by the members of the board of directors and serves as chair of the board throughout
his or her term as a director, unless resolved otherwise by the board of directors. Under the Companies Law, in a public company, the
chief executive officer (or any relative of the chief executive officer) may not serve as the chair of the board of directors, and the
chair (or any relative of the chair) may not be vested with authorities of the chief executive officer without shareholder approval consisting
of a majority vote of the shares present and voting at a shareholders meeting, provided that either:
| ● | at least a majority of the shares of non-controlling shareholders
or shareholders that do not have a personal interest in the approval voted at the meeting are voted in favor (disregarding abstentions);
or |
| ● | the total number of shares of non-controlling shareholders
and shareholders who do not have a personal interest in such appointment voting against such appointment does not exceed 2% of the aggregate
voting rights in the company. |
The shareholders’ approval can be provided
for a period of five years following an initial public offering, and subsequently, for additional periods of up to three years.
In addition, a person subordinated, directly or
indirectly, to the chief executive officer may not serve as the chair of the board of directors; the chair of the board may not be vested
with authorities that are granted to those subordinated to the chief executive officer; and the chair of the board may not serve in any
other position in the company or a controlled company, but he or she may serve as a director or chair of a 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 generally
required to appoint at least two external directors.
Pursuant to the regulations promulgated under the
Companies Law, companies whose shares are traded on specified U.S. stock exchanges, including Nasdaq, which do not have a controlling
shareholder (as such term is defined in the Companies Law) and which comply with the independent director requirements and the audit committee
and compensation committee composition requirements of U.S. law and the U.S. stock exchange applicable to domestic issuers, may (but are
not required to) elect to opt out of the requirement to maintain external directors and opt out of the composition requirements under
the Companies Law with respect to the audit and compensation committees. We currently do not qualify for such exemption.
The provisions of the Companies Law set forth special
approval requirements for the election of external directors. External directors must be elected by a majority vote of the shares present
and voting at a meeting of shareholders, provided that either:
| ● | such majority includes at least a majority of the shares
held by all shareholders who are not controlling shareholders and do not have a personal interest in the election of the external director
(other than a personal interest not deriving from a relationship with a controlling shareholder) that are voted at the meeting, excluding
abstentions, to which we refer as a disinterested majority; or |
| ● | the total number of shares voted by non-controlling shareholders
and by shareholders who do not have a personal interest in the election of the external director against the election of the external
director does not exceed 2% of the aggregate voting rights in the company. |
The term “controlling shareholder” as
used in the Companies Law for purposes of all matters related to external directors and for certain other purposes (such as the requirements
related to appointment to the audit committee or compensation committee, as described below), means a shareholder with the ability to
direct the activities of the company, other than by virtue of being an office holder. A shareholder is presumed to be a controlling shareholder
if the shareholder holds 50% or more of the voting rights in a company or has the right to appoint a majority of the directors of the
company or its general manager. With respect to certain matters (various related party transactions), a controlling shareholder is deemed
to include a shareholder that holds 25% or more of the voting rights in a public company if no other shareholder holds more than 50% of
the voting rights in the company, but excludes a shareholder whose power derives solely from his or her position as a director of the
company or from any other position with the company. For the purpose of determining the holding percentage stated above, two or more
shareholders who have a personal interest in a transaction that is brought for the company’s approval are deemed as joint holders.
The initial term of an external director is three years.
Thereafter, an external director may be re-elected, subject to certain circumstances and conditions, by shareholders to serve in that
capacity for up to two additional three-year terms, provided that either:
| (i) | his or her service for each such additional term is recommended
by one or more shareholders holding at least 1% of the company’s voting rights and is approved at a shareholders meeting by a disinterested
majority, where the total number of shares held by non-controlling, disinterested shareholders voting for such re-election exceeds 2%
of the aggregate voting rights in the company, subject to additional restrictions set forth in the Companies Law with respect to affiliations
of external director nominees; |
| (ii) | the external director proposed his or her own nomination,
and such nomination was approved in accordance with the requirements described in the paragraph above; or |
| (iii) | his or her service for each such additional term is
recommended by the board of directors and is approved at a meeting of shareholders by the same majority required for the initial election
of an external director (as described above). |
The term of office for external directors for Israeli
companies traded on certain foreign stock exchanges, including Nasdaq, may be extended indefinitely in increments of additional three-year
terms, in each case provided that the audit committee and the board of directors of the company confirm that, in light of the external
director’s expertise and special contribution to the work of the board of directors and its committees, the re-election for such
additional period(s) is beneficial to the company, and provided that the external director is re-elected subject to the same shareholder
vote requirements (as described above regarding the re-election of external directors). Prior to the approval of the re-election of the
external director at a general meeting of shareholders, the company’s shareholders must be informed of the term previously served
by him or her and of the reasons why the board of directors and audit committee recommended the extension of his or her term.
External directors may be removed from office by
a special general meeting of shareholders called by the board of directors, which approves such dismissal by the same shareholder vote percentage
required for their election or by a court, in each case, only under limited circumstances, including ceasing to meet the statutory qualifications
for appointment or violating their duty of loyalty to the company. An external director may also be removed by order of an Israeli court
if, following a request made by a director or shareholder of the company, the court finds that such external director has ceased to meet
the statutory qualifications for his or her appointment as stipulated in the Companies Law or has violated his or her duty of loyalty
to the company.
If an external directorship becomes vacant and there
are fewer than two external directors on the board of directors at the time, then the board of directors is required under the Companies
Law to call a meeting of the shareholders as soon as practicable to appoint a replacement external director. Each committee of the board
of directors that exercises the powers of the board of directors must include at least one external director, except that the audit committee
and the compensation committee must include all external directors then serving on the board of directors and an external director must
serve as chair thereof. Under the Companies Law, external directors of a company are prohibited from receiving, directly or indirectly,
any compensation from the company other than for their services as external directors pursuant to the Companies Law and the regulations
promulgated thereunder. Compensation of an external director is determined prior to his or her appointment and may not be changed during
his or her term subject to certain exceptions.
The Companies Law provides that a person is not
qualified to be appointed as an external director if (i) the person is a relative of a controlling shareholder of the company, or
(ii) if that person or his or her relative, partner, employer, another person to whom he or she was directly or indirectly subordinate,
or any entity under the person’s control, has or had during the two years preceding the date of appointment as an external
director: (a) any affiliation or other disqualifying relationship with the company, with any person or entity controlling the company
or a relative of such person, or with any entity controlled by or under common control with the company; or (b) in the case of a
company with no controlling shareholder or any shareholder holding 25% or more of its voting rights, had at the date of appointment as
an external director any affiliation or other disqualifying relationship with a person then serving as chair of the board or chief executive
officer, a holder of 5% or more of the issued share capital or voting power in the company or the most senior financial officer.
The term “relative” is defined in the
Companies Law as a spouse, sibling, parent, grandparent or descendant, a spouse’s sibling, parent or descendant and the spouse of
each of the foregoing persons. Under the Companies Law, the term “affiliation” and the similar types of disqualifying relationships
include (subject to certain exceptions):
| ● | an employment relationship; |
| ● | a business or professional relationship even if not maintained
on a regular basis (excluding insignificant relationships); |
| ● | service as an office holder, excluding service as a director
in a private company prior to the initial public offering of its shares if such director was appointed as a director of the private company
in order to serve as an external director following the initial public offering. |
The term “office holder” is defined
in the Companies Law as a general manager (i.e., chief executive officer), chief business manager, deputy general manager, vice general
manager, any other person assuming the responsibilities of any of these positions regardless of that person’s title, a director
and any other manager directly subordinate to the general manager.
In addition, no person may serve as an external
director if that person’s position or professional or other activities create, or may create, a conflict of interest with that person’s
responsibilities as a director or otherwise interfere with that person’s ability to serve as an external director or if the person
is an employee of the Israel Securities Authority, or ISA, or an Israeli stock exchange. A person may also not continue to serve as an
external director if he or she received direct or indirect compensation from the company including amounts paid pursuant to indemnification
or exculpation contracts or commitments and insurance coverage for his or her service as an external director, other than as permitted
by the Companies Law and the regulations promulgated thereunder.
Following the termination of an external director’s
service on a board of directors, such former external director and his or her spouse and children may not be provided a direct or indirect
benefit by the company, its controlling shareholder or any entity under its controlling shareholder’s control. This includes engagement
as an office holder of the company or a company controlled by its controlling shareholder or employment by, or provision of services to,
any such company for consideration, either directly or indirectly, including through a corporation controlled by the former external director.
This restriction extends for a period of two years with regard to the former external director and his or her spouse or child and
for one year with respect to other relatives of the former external director.
If at the time at which an external director is
appointed all members of the board of directors who are not controlling shareholders or relatives of controlling shareholders of the company
are of the same gender, the external director to be appointed must be of the other gender. A director of one company may not be appointed
as an external director of another company if a director of the other company is acting as an external director of the first company at
such time.
According to the Companies Law and regulations promulgated
thereunder, a person may be appointed as an external director only if he or she has professional qualifications or if he or she has accounting
and financial expertise (each, as defined below); provided that at least one of the external directors must be determined by our board
of directors to have accounting and financial expertise. However, if at least one of our other directors (i) meets the independence
requirements under the Exchange Act, (ii) meets the independence requirements of Nasdaq rules for membership on the audit committee
and (iii) has accounting and financial expertise as defined under the Companies Law, then neither of our external directors is required
to possess accounting and financial expertise as long as each possesses the requisite professional qualifications.
A director with accounting and financial expertise
is a director who, due to his or her education, experience and skills, possesses an expertise in, and an understanding of, financial and
accounting matters and financial statements, such that he or she is able to understand the financial statements of the company and initiate
a discussion about the presentation of financial data. A director is deemed to have professional qualifications if he or she has any of
the following: (i) an academic degree in economics, business management, accounting, law or public administration, (ii) an academic degree
or has completed another form of higher education in the primary field of business of the company or in a field which is relevant to his
or her position in the company or (iii) at least five years of experience serving in one of the following capacities or at least five
years of cumulative experience serving in two or more of the following capacities: (a) a senior business management position in a company
with a significant volume of business, (b) a senior position in the company’s primary field of business or (c) a senior position
in public administration or service. The board of directors is charged with determining whether a director possesses financial and accounting
expertise or professional qualifications.
Committees of the Board of Directors
Our board of directors has established the following
standing committees.
Audit Committee
Companies Law Requirements
Under the Companies Law, the board of directors
of a public company must appoint an audit committee. The audit committee must be comprised of at least three directors, including all
of the external directors, one of whom must serve as chair of the committee. The audit committee may not include the (i) chair of
the board; (ii) a controlling shareholder of the company; (iii) a relative of a controlling shareholder; (iv) a director
employed by or providing services on a regular basis to the company, to a controlling shareholder or to an entity controlled by a controlling
shareholder; or (v) a director who derives most of his or her income from a controlling shareholder. In addition, under the Companies
Law, the audit committee of a publicly traded company must consist of a majority of unaffiliated directors. In general, an “unaffiliated
director” under the Companies Law is defined as either an external director or as a director who meets the following criteria:
| ● | he or she meets the qualifications for being appointed as
an external director, except for the requirement (i) that the director be an Israeli resident (which does not apply to companies
such as ours whose securities have been offered outside of Israel or are listed for trading outside of Israel) and (ii) for accounting
and financial expertise or professional qualifications; and |
| ● | he or she has not served as a director of the company for
a period exceeding nine consecutive years. For this purpose, a break of less than two years in his or her service as a director
shall not be deemed to interrupt the continuity of the service. |
Each member of our audit committee (each, as identified
in the second paragraph under “—Listing Requirements” below) is an unaffiliated director under the Companies Law, thereby
fulfilling the foregoing Israeli law requirement for the composition of the audit committee.
Listing Requirements
Under the corporate governance rules of Nasdaq,
we are required to maintain an audit committee consisting of at least three independent directors, each of whom is financially literate
and one of whom has accounting or related financial management expertise.
Our audit committee consists of Cary Claiborne,
Christine Pellizzari and Caren Deardorf. Mr. Claiborne serves as the chair of the audit committee. All members of our audit committee
meet the requirements for financial literacy under the applicable rules and regulations of the SEC and the corporate governance rules
of Nasdaq. Our board of directors has determined that Mr. Claiborne is an audit committee financial expert as defined by the SEC rules
and has the requisite financial experience as defined by the corporate governance rules of Nasdaq.
Our board of directors has determined that each
member of our audit committee is “independent” as such term is defined in Rule 10A-3(b)(1) under the Exchange Act, which
is different from the general test for independence of board and committee members.
Audit Committee Role
Our board of directors has adopted an audit committee
charter setting forth the responsibilities of the audit committee, which is consistent with the Companies Law, the SEC rules and the corporate
governance rules of Nasdaq and includes:
| ● | retaining and terminating our independent auditors, subject
to ratification by the board of directors, and in the case of retention, to ratification by the shareholders; |
| ● | pre-approving audit and non-audit services to be provided
by the independent auditors and related fees and terms; |
| ● | overseeing the independence, compensation and performance
of the company’s independent auditors; |
| ● | reviewing with management and our independent auditor our
annual and quarterly financial statements prior to publication or filing (or submission, as the case may be) to the SEC; |
| ● | recommending to the board of directors the retention and
termination of the internal auditor, and the internal auditor’s engagement fees and terms, in accordance with the Companies Law
as well as approving the yearly or periodic work plan proposed by the internal auditor; |
| ● | identifying irregularities in our business administration
by, among other things, consulting with the internal auditor or with the independent auditor, and suggesting corrective measures to the
board of directors; |
| ● | reviewing policies and procedures with respect to transactions
between the Company and officers and directors (other than transactions related to the compensation or terms of service of the officers
and directors), or affiliates of officers or directors, or transactions that are not in the ordinary course of the Company’s business
and deciding whether to approve such acts and transactions if so required under the Companies Law; and |
| ● | establishing procedures for the handling of employees’
complaints as to the management of our business and the protection to be provided to such employees. |
Additionally, under the Companies Law, the role
of the audit committee includes the identification of irregularities in our business management, among other things, by consulting with
the internal auditor or our independent auditors and suggesting an appropriate course of action to the board of directors. In addition,
the audit committee or the board of directors, as set forth in the articles of association of the company, is required to approve the
yearly or periodic work plan proposed by the internal auditor. The audit committee is required to assess the company’s internal
audit system and the performance of its internal auditor. The Companies Law also requires that the audit committee assess the scope of
the work and compensation of the company’s external auditor. 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 whether certain transactions with a controlling shareholder will be subject to a competitive procedure.
The audit committee charter will state that in fulfilling
its role the committee is empowered to conduct or authorize investigations into any matters within its scope of responsibilities.
Compensation Committee
Companies Law Requirements
Under the Companies Law, the board of directors
of a public company must appoint a compensation committee. The compensation committee generally (subject to certain exceptions that do
not apply to the Company) must be comprised of at least three directors, including all of the external directors, who must constitute
a majority of the members of the compensation committee. The chair of the compensation committee must be an external director. Each compensation
committee member who is not an external director must be a director whose compensation does not exceed an amount that may be paid to an
external director. The compensation committee is subject to the same Companies Law restrictions as the audit committee as to who may not
be a member of the compensation committee. Each member of our compensation committee (each, as identified in the second paragraph under
“—Listing Requirements” below) fulfils the foregoing Israeli law requirements related to the composition of the compensation
committee.
Listing Requirements
Under the corporate governance rules of Nasdaq,
we are required to maintain a compensation committee consisting of at least two independent directors.
Our compensation committee consists of Christine
Pellizzari, Cary Claiborne, and Dr. Revital Mandil Levin. Ms. Pellizzari serves as chair of the committee. Our board of directors has
determined that each member of our compensation committee is independent under the corporate governance rules of Nasdaq, including the
additional independence requirements applicable to the members of a compensation committee.
Compensation Committee Role
In accordance with the Companies Law, the roles
of the compensation committee are, among others, as follows:
| ● | making recommendations to the board of directors with respect
to the approval of the compensation policy for office holders and, once every three years, regarding any extensions to a compensation
policy that was adopted for a period of more than three years; |
| ● | reviewing the implementation of the compensation policy and
periodically making recommendations to the board of directors with respect to any amendments or updates of the compensation policy; |
| ● | resolving whether or not to approve arrangements with respect
to the terms of office and employment of office holders; and |
| ● | exempting, under certain circumstances, transactions with
our chief executive officer from the approval of our shareholders. |
Our board of directors adopted a compensation committee
charter setting forth the responsibilities of the committee, which is consistent with the corporate governance rules of Nasdaq and includes
among others:
| ● | recommending to our board of directors for its approval a
compensation policy in accordance with the requirements of the Companies Law as well as other compensation policies, incentive-based
compensation plans and equity-based compensation plans, and overseeing the development and implementation of such policies and recommending
to our board of directors any amendments or modifications the committee deems appropriate, including as required under the Companies
Law; |
| ● | reviewing and approving the granting of options and other
incentive awards to our chief executive officer and other executive officers, including reviewing and approving corporate goals and objectives
relevant to the compensation of our chief executive officer and other executive officers, including evaluating their performance in light
of such goals and objectives; |
| ● | approving and exempting certain transactions regarding office
holders’ compensation pursuant to the Companies Law; and |
| ● | administering our equity-based compensation plans, including
without limitation, approving the adoption of such plans, amending and interpreting such plans and the awards and agreements issued pursuant
thereto, and making awards to eligible persons under the plans and determining the terms of such awards. |
Compensation Policy Under the Companies Law
In general, under the Companies Law, a public company
must have a compensation policy approved by its 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 recommendation of our compensation committee, and second, by a simple majority of the ordinary shares present, in person or by proxy,
and voting at a shareholders meeting, 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 |
| ● | 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 2% of
the aggregate voting rights in the Company. |
In the event that the shareholders fail to approve
the compensation policy in a duly convened meeting, the board of directors may nevertheless override that decision, provided that the
compensation committee and then the board of directors decide, on the basis of detailed reasons and after further review of the compensation
policy, that approval of the compensation policy is for the benefit of the company despite the failure of the shareholders to approve
the policy.
If a company that adopts a compensation policy in
advance of its initial public offering describes the policy in its prospectus for such offering, then that compensation policy shall be
deemed validly adopted in accordance with the Companies Law and will remain in effect for term of five years from the date such company
becomes a public company. Our compensation policy became effective immediately prior to the closing of our initial public offering and
will be in force for an initial period of five years.
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 relate to certain
factors as set forth in the Companies Law, including advancement of the company’s objectives, business plan and long-term strategy,
and creation of appropriate incentives for office holders. It must also consider, among other things, the company’s risk management,
size and the nature of its operations. The compensation policy must furthermore consider the following additional factors:
| ● | the education, skills, experience, expertise and accomplishments
of the relevant office holder; |
| ● | the office holder’s position, responsibilities and prior
compensation agreements with him or her; |
| ● | 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, the average and median salary of the employees of the company,
as well as the impact of such disparities 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 his or her compensation during such period, the company’s performance
during the such period, his or her 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 regard to variable components of compensation: |
| ● | with the exception of office holders who report directly
to the chief executive officer, provisions determining the variable components on the basis of long-term performance and on measurable
criteria; however, 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, if such amount is not higher than three monthly salaries per annum, while taking
into account such office holder’s contribution to the company; and |
| ● | the ratio between variable and fixed components, as well as
the limit on the values of variable components at the time of their 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 his or her 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; |
| ● | 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 on 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 an 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 executive officers’ 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 for equity-based compensation.
The compensation policy provides that compensation
will be determined based on our executive officers’ respective positions, education, scope of responsibilities and contributions,
and that we will consider the ratio 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. In addition,
the total variable compensation components (cash bonuses and equity-based compensation) may not exceed 90% of each executive officer’s
total compensation package with respect to any given calendar year.
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 the chief executive officer. Performance objectives may be recommended by our chief executive officer
and will be approved by the compensation committee (and, if required by law, by our board of directors). We may also grant annual cash
bonuses to our executive officers on a discretionary basis.
The performance objectives and targets of our chief
executive officer will be determined by our compensation committee and board of directors. Up to 30% of the chief executive officer’s
annual cash bonus may be based on a discretionary evaluation of his overall performance by the compensation committee and the board of
directors based on quantitative and qualitative criteria.
The equity-based compensation for our executive
officers under the compensation policy is designed in a manner consistent with the underlying objectives for determining the base salary
and the annual cash bonus. Primary objectives include enhancing the alignment between the executive officers’ interests and our
long-term interests and those of our shareholders and strengthening the retention and the motivation of executive officers in the long
term. Equity-based compensation may be granted in the form of options or other equity-based awards, such as restricted shares and restricted
share units, in accordance with a share incentive plan. All equity-based incentive awards granted to executive officers will be subject
to vesting periods in order to promote long-term retention of the grantee. Equity-based compensation will be granted from time to time
and be awarded according to the performance, educational background, prior business experience, qualifications, role and the personal
responsibilities of the executive officer.
In addition, the compensation policy contains compensation
recovery provisions that apply in the event of an accounting restatement enables our chief executive officer to approve immaterial changes
in the terms of employment of an executive officer (provided that the changes of the terms of employment are in accordance with our compensation
policy) and allows us to exculpate, indemnify and insure our executive officers and directors subject to certain limitations as set forth
therein.
The 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
on Stock Exchanges Outside of Israel) of 2000, as such regulations may be amended from time to time, or (ii) in accordance with the
amounts determined in the compensation policy.
Our compensation policy, which was approved by our
board of directors on October 31, 2021 and by our shareholders on November 7, 2021, became effective immediately prior to the closing
of our initial public offering and is filed as an exhibit to this annual report.
Internal Auditor
Under the Companies Law, the board of directors of a public company
must appoint an internal auditor based on the recommendation of the audit committee. The role of the internal auditor is, among other
things, to examine whether a company’s actions comply with applicable law and orderly business procedure. Under the Companies Law,
the internal auditor cannot be an interested party or an office holder or a relative of an interested party or an office holder, nor may
the internal auditor be the company’s independent auditor or its representative. An “interested party” is defined in
the Companies Law as: (i) a holder of 5% or more of the issued share capital or voting power in a company, (ii) any person or entity who
has the right to designate one or more directors or to designate the chief executive officer of the company, or (iii) any person who serves
as a director or as a chief executive officer of the company. On March 31, 2022, we have appointed an internal auditor.