Item 1A. Risk Factors
Any investment in our Common Stock involves
a high degree of risk. The following risk factors and other information included in this Quarterly Report on Form 10-Q should be
carefully considered. The risks and uncertainties described below are not the only ones we face. Additional risks and uncertainties
not presently known to us or that we currently believe to be immaterial may also adversely affect our business. We refer you to
our “Cautionary Note Regarding Forward-Looking Statements,” which identifies certain forward-looking statements contained
in this report that are qualified by these risk factors. If any of the following risks occur, our business, financial condition,
results of operations and future growth prospects could be materially and adversely affected.
Risks Related to Our Financial Condition and Need for Additional
Capital
We have a limited operating history and have incurred significant
losses since our inception, and we anticipate that we will continue to incur losses for the foreseeable future.
We are a late-stage biotechnology company, and
we have not commercialized any products or generated any revenues from the sale of products. We have incurred losses from operations
in each year since our inception, and our net losses were $28.5 million and $21.4 million for the years ended December 31, 2016
and 2015, respectively, and $6.5 million and $6.6 million for the three months ended March 31, 2017 and 2016, respectively. As
of March 31, 2017, we had an accumulated deficit of $166.3 million. We do not expect to generate any product revenues in the foreseeable
future. We do not know whether or when we will generate revenue or become profitable.
We have devoted most of our financial resources
to research and development, including our clinical and preclinical development activities. To date, we have financed our operations
primarily through the sale of equity securities and, prior to our initial public offering, the sale of convertible debt. Our current
product candidate, vonapanitase, is in clinical trials and we have no commercial sales, which, together with our limited operating
history, make it difficult to assess our future viability. The amount of our future net losses will depend, in part, on the rate
of our future expenditures and our ability to obtain funding through equity or debt financings or strategic collaborations. We
have not completed pivotal clinical trials for any product candidate and it will be several years, if ever, before we have vonapanitase
or any future product candidates ready for commercialization. Even if we obtain regulatory approval to market vonapanitase or any
additional product candidates, our future revenues will depend upon the size of any markets in which vonapanitase or any additional
product candidates have received approval, our ability to achieve sufficient market acceptance, reimbursement from third-party
payors and other factors.
We expect to continue to incur
significant expenses and increasing operating losses for the foreseeable future. We anticipate that our expenses will increase
substantially if and as we:
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continue our clinical development and seek regulatory approval of vonapanitase, particularly with
respect to its lead indication for radiocephalic arteriovenous fistulas;
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commercialize vonapanitase directly in the United States;
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undertake clinical development of vonapanitase in Europe and establish partnerships for commercialization
of vonapanitase in all or parts of Europe;
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pursue additional indications for vonapanitase including clinical development of vonapanitase for
brachiocephalic fistulas, patients requiring placement of an arteriovenous graft, and additional indications for the treatment
of patients with symptomatic peripheral artery disease, or PAD;
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in-license or acquire additional product opportunities and make milestone or other payments under
any in-license agreements;
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contract for the manufacture of commercial quantities of vonapanitase;
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establish a sales, marketing and distribution infrastructure to commercialize any products for
which we may obtain marketing approval;
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maintain, protect and expand our intellectual property portfolio;
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attract and retain skilled personnel;
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create additional infrastructure to support our operations as a public company and our product
development; and
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experience any delays or encounter issues with any of the above.
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The net losses we incur may fluctuate significantly
from quarter to quarter and year to year, such that a period-to-period comparison of our results of operations may not be a good
indication of our future performance. In any particular quarter or quarters, our operating results could be below the expectations
of securities analysts or investors, which could cause our stock price to decline.
We will require substantial additional financing to achieve
our goals, and a failure to obtain this necessary capital when needed on acceptable terms, or at all, could force us to delay,
limit, reduce or terminate our product development, any commercialization efforts or other operations.
Our operations have consumed substantial
amounts of cash since inception. As of March 31, 2017, our cash, cash equivalents and available-for-sale investments were $34.1
million. Our research and development expenses were $4.2 million and $4.3 million for the three months ended March 31, 2017 and
2016, respectively. We believe that we will continue to expend substantial resources for the foreseeable future developing vonapanitase
and any additional product candidates. These expenditures will include costs associated with research and development, potentially
acquiring new technologies, potentially obtaining regulatory approvals and manufacturing products, as well as marketing and selling
products approved for sale, if any. In addition, other unanticipated costs may arise. Because the outcome of our planned and anticipated
clinical trials is highly uncertain, we cannot reasonably estimate the actual amounts necessary to fund and successfully complete
the development and commercialization of vonapanitase or any additional product candidates.
We began enrolling patients in our first Phase
3 clinical trial of vonapanitase during the third quarter of 2014 for patients undergoing creation of radiocephalic fistulas,
completed patient enrollment in October 2015 and released top-line data in December 2016. We enrolled the first patient in our
second Phase 3 trial in August 2015, expect to complete enrollment in the first quarter of 2018 and expect to release top-line
data in the first quarter of 2019. Based on our current operating plan, and absent any future financings or strategic partnerships,
we believe that our existing cash, cash equivalents and available-for-sale investments will be sufficient to fund our projected
operating expenses and capital expenditure requirements into the third quarter of 2018, allowing us to complete enrollment in
our second Phase 3 clinical trial of vonapanitase in radiocephalic fistulas. Our cash runway could be shortened if there are any
significant and unexpected increases in spending on development programs or more rapid progress of development programs than anticipated.
We do not expect our existing capital resources to be sufficient to enable us to obtain results from our second Phase 3 trial.
In addition, we initiated two Phase 1 clinical trials of vonapanitase in patients with PAD in the fourth quarter of 2016. We may
increase the planned enrollment in the Phase 1 trial evaluating vonapanitase as an adjunct to angioplasty for PAD below the knee
and begin patient enrollment in the Phase 1 trial evaluating vonapanitase as a monotherapy for PAD above the knee. We may also
initiate other small Phase 1 or Phase 1/2 trials in additional indications, which would further reduce our capital resources.
However, we do not expect to initiate any other Phase 2 or Phase 3 trials prior to receiving and reviewing data from our second
Phase 3 clinical trial. Furthermore, 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 or debt financings, government or other
third-party funding, marketing and distribution arrangements and other collaborations, strategic alliances and licensing arrangements,
or a combination of these approaches. Even if we believe 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.
Additional fundraising efforts may
divert our management from their day-to-day activities, which may adversely affect our ability to develop and commercialize vonapanitase
or any additional product candidates. In addition, we cannot guarantee that future financing will be available in sufficient amounts
or on terms acceptable to us, or at all. We could also be required to seek funds through arrangements with collaborative partners
or otherwise at an earlier stage than would otherwise be ideal and we may be required to relinquish rights to vonapanitase or any
additional product candidates, or otherwise agree to terms unfavorable to us, any of which may have a material adverse effect on
our business, operating results and prospects.
If we are unable to obtain funding
on a timely basis, we may be required to significantly curtail, delay or discontinue one or more of our research or development
programs or the commercialization of any approved products or be unable to expand our operations or otherwise capitalize on our
business opportunities, as desired, which could materially adversely affect our business, financial condition and results of operations.
We have never generated any revenue from product sales and
may never be profitable.
As a company, we have never obtained regulatory
approval for, or commercialized, any product candidate. Our ability to generate substantial revenue and achieve profitability depends
on our ability, alone or with strategic collaboration partners, to successfully complete the development of, and obtain the regulatory
approvals necessary to commercialize, vonapanitase or any additional product candidates. We do not anticipate generating revenues
from product sales for at least the next several years, if ever. If vonapanitase or any additional product candidates fail in clinical
trials or do not gain regulatory approval, or if vonapanitase or any additional product candidates, if approved, fail to achieve
market acceptance, we may never become profitable. Even if we achieve profitability in the future, we may not be able to sustain
profitability in subsequent periods. Our ability to generate future revenues from product sales depends heavily on our success
in:
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completing clinical development of vonapanitase for one or more indications and research and preclinical
and clinical development of additional product candidates;
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seeking and obtaining regulatory and marketing approvals for vonapanitase if and when we complete
clinical trials;
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establishing and maintaining supply and manufacturing relationships with third parties that can
provide adequate (in amount and quality) products and services to support clinical development and the market demand for vonapanitase,
if approved;
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launching and commercializing vonapanitase if we obtain regulatory and marketing approval, either
by collaborating with a partner or, if launched independently, by establishing our own sales, marketing and distribution infrastructure;
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obtaining and maintaining adequate timely coverage and reimbursement from third-party payors for
vonapanitase;
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obtaining market acceptance of vonapanitase as a viable treatment option;
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addressing any competing technological and market developments;
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implementing additional internal systems and infrastructure, as needed;
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identifying and validating new product candidates;
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negotiating favorable terms in any collaboration, licensing or other arrangements into which we
may enter;
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maintaining, protecting and expanding our portfolio of intellectual property rights, including
patents and know-how;
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developing vonapanitase such that, if approved, it can be commercialized without infringing the
intellectual property rights of third parties; and
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attracting, hiring and retaining qualified personnel.
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Even if vonapanitase or any additional product
candidates that we may develop is approved for commercial sale, we anticipate incurring significant costs associated with commercializing
any approved product candidate. Our expenses could increase beyond expectations if we are required by the United States Food and
Drug Administration, or the FDA, the European Medicines Agency, or EMA, or other regulatory agencies, domestic or foreign, to perform
clinical trials and other studies in addition to those that we currently anticipate. Even if we are able to generate revenues from
the sale of any approved products, we may not become profitable and may need to obtain additional funding to continue operations.
Our failure to become and remain profitable would depress the market price of our Common Stock and could impair our ability to
raise capital, expand our business, diversify our product offerings or continue our operations. A decline in the value of our company
could also cause you to lose all or part of your investment.
Risks Related to Clinical Development, Regulatory Review and Approval
of Our Product
We are substantially dependent on the success of our current
product candidate, vonapanitase, and cannot guarantee that this product candidate will successfully complete Phase 3 clinical trials,
receive regulatory approval or be successfully commercialized.
We currently have no products approved for commercial
distribution. We have invested substantially all of our efforts and financial resources in the development of our current product
candidate, vonapanitase. Our business depends entirely on the successful development and commercialization of vonapanitase, in
vascular access or additional indications, which may never occur. Our ability to generate revenues in the near term is substantially
dependent on our ability to develop, obtain regulatory approval for, and then successfully commercialize vonapanitase. We currently
generate no revenues from sales of any products, and we may never be able to develop or commercialize a marketable product.
Vonapanitase will require additional clinical
development, regulatory approval, commercial manufacturing arrangements, establishment of a commercial organization, significant
marketing efforts and further investment before we generate any revenues from product sales. We are not permitted to market or
promote vonapanitase for any indication before we receive regulatory approval from the FDA or comparable foreign regulatory authorities,
and we may never receive this regulatory approval for any of our product candidates. If we do not receive FDA approval and successfully
commercialize vonapanitase, we will not be able to generate revenue from vonapanitase in the United States in the foreseeable future,
or at all. Moreover, any significant delays in obtaining approval for and commercializing vonapanitase will have a substantial
adverse impact on our business and financial condition.
We have not previously submitted a Biologics
License Application, or BLA, to the FDA, or similar drug or biologic approval filings to comparable foreign authorities, for any
product candidate, and we cannot be certain that vonapanitase or any additional product candidates will be successful in clinical
trials or receive regulatory approval. In our first Phase 3 clinical trial, our primary efficacy endpoint of primary unassisted
patency did not show statistically significant benefit for the 30 microgram dose versus placebo. While analyses of the first Phase
3 trial’s other efficacy endpoints, including secondary patency and fistula use for hemodialysis, suggested clinically meaningful
improvements over placebo, we cannot assure you that these results will be repeated in our second Phase 3 trial. Following our
review of the data from our first Phase 3 clinical trial of vonapanitase and discussions with the FDA, we amended the protocol
for our second Phase 3 clinical trial in the first quarter of 2017 to increase the planned enrollment from 300 to 500 patients,
which we subsequently increased to 600 patients in the second quarter of 2017. We also re-ordered the endpoints to include co-primary
endpoints of secondary patency (time to fistula abandonment) and fistula use for hemodialysis, each of which are required to show
a statistically significant benefit (p≤0.05) in order to provide the basis for a BLA submission for vonapanitase as a single
pivotal trial. Even though our second Phase 3 trial will evaluate co-primary endpoints for vonapanitase that showed improvements
in our first Phase 3 clinical trial, there are risks of failure inherent at any stage of product development, and we may not demonstrate
efficacy with regard to the co-primary endpoints of our ongoing Phase 3 clinical trial or our reordering of the endpoints could
otherwise adversely affect the success of the second Phase 3 trial, or unexpected adverse events may occur. Further, vonapanitase
or any additional product candidates may not receive regulatory approval even if they are successful in clinical trials. If approved
for marketing by applicable regulatory authorities, our ability to generate revenues from vonapanitase will depend on our ability
to, among other things:
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launch vonapanitase commercially, whether alone or in collaboration with others;
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create market demand for vonapanitase through our own marketing and sales organization, and through
any other promotional arrangements that we may otherwise establish;
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hire, train and deploy a specialty sales force, focused primarily on vascular surgeons, to commercialize
vonapanitase in the United States;
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manufacture vonapanitase in sufficient quantities and at acceptable quality and manufacturing cost
to meet commercial demand at launch and thereafter and establish and maintain agreements with wholesalers, distributors and group
purchasing organizations on commercially reasonable terms;
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create partnerships with third parties to promote and sell vonapanitase in any foreign markets
where we receive marketing approval;
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obtain and maintain patent protection and regulatory exclusivity for vonapanitase;
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achieve appropriate reimbursement for vonapanitase;
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effectively compete with other products should any be successfully developed and approved; and
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maintain a continued acceptable safety profile of vonapanitase following launch.
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If we develop vonapanitase for other indications,
including arteriovenous grafts, brachiocephalic fistula and symptomatic PAD, or develop additional product candidates, we will
face similar risks and challenges.
Clinical development is a lengthy and expensive process with
an uncertain outcome due to many factors. Because the results of early clinical trials are not necessarily predictive of future
results, vonapanitase may not have favorable results in current or future clinical trials or receive regulatory approval.
Clinical development is expensive, difficult
to design and implement, takes many years to complete and its outcome is inherently uncertain. Failure can occur at any time during
the clinical trial process and vonapanitase is subject to the risks of failure inherent in drug and biological development, including
failure to demonstrate efficacy in a pivotal clinical trial or in the patient population we intend to enroll, the occurrence of
severe or medically or commercially unacceptable adverse events, failure to comply with protocols or applicable regulatory requirements
and determination by the FDA or any comparable foreign regulatory authority that a drug and biological product is not approvable.
Results observed in earlier clinical trials may not be replicated in current or future clinical trials. For example, our first
Phase 3 clinical trial of vonapanitase failed to meet its primary endpoint of primary unassisted patency, despite encouraging results
from our Phase 2 trial. In addition, as is common with clinical trials, we explored a number of endpoints in our Phase 2 clinical
trial of vonapanitase. We also analyzed the data from our Phase 2 and Phase 3 clinical trials of vonapanitase in a number of ways.
Product candidates such as vonapanitase in Phase 3 clinical trials may fail to demonstrate sufficient efficacy despite having progressed
through earlier clinical trials, even if certain analyses of primary, secondary or tertiary endpoints in those early trials showed
statistical significance. Companies may suffer significant setbacks in late-stage clinical trials due to lack of efficacy, site
or investigator issues, manufacturing or formulation changes or adverse safety profiles, even after earlier clinical trials have
shown promising results. During the course of our clinical development, we modified our vonapanitase drug product formulation for
our Phase 3 trials and commercial launch in order to facilitate ease of administration and fill and finish of vials at our 30 microgram
dose. Our formulation changes could adversely affect results in our clinical trials, requiring us to make further formulation changes.
In addition, following our review of the data from our first Phase 3 clinical trial of vonapanitase and discussions with the FDA,
we amended the protocol for our second Phase 3 trial to include co-primary endpoints of secondary patency and fistula use for hemodialysis,
each of which was studied in earlier clinical trials. Our reordering of the endpoints could adversely affect the success of the
second Phase 3 trial. Additional changes or interactions with the FDA could also cause us to delay or repeat clinical trials, or
could cause FDA to request additional studies or data, and we could incur unexpected costs that would have an adverse effect on
our business, operating results, financial condition and prospects.
The design of a clinical trial can determine
whether its results will support approval of a product, and flaws in the design of a clinical trial may not become apparent until
the clinical trial is well advanced or completed. We have limited experience in designing clinical trials and we may be unable
to design and execute a clinical trial to support marketing approval. In addition, preclinical and clinical data are often susceptible
to varying interpretations and analyses. Many companies that believed their product candidates performed satisfactorily in preclinical
studies and clinical trials have nonetheless failed to obtain marketing approval for the product candidates. Even if we believe
that the results of clinical trials for our product candidates warrant marketing approval, the FDA or comparable foreign regulatory
authorities may disagree and may not grant marketing approval of vonapanitase or any additional product candidates.
In some instances, there can be significant
variability in safety or efficacy results between different clinical trials of the same product candidate due to numerous factors,
including changes in trial procedures set forth in protocols, differences in the size and type of the patient populations, changes
in and adherence to the clinical trial visit schedule or protocols, changes in practice patterns outside of the protocols and the
rate of dropout among clinical trial participants. Any Phase 3 or other clinical trial that we may conduct may not demonstrate
the efficacy and safety necessary to obtain regulatory approval to market vonapanitase or any additional product candidate.
Any delay or failure in our clinical trials
would delay our obtaining, or make us unable to obtain, applicable regulatory approvals, which would prevent us from commercializing
vonapanitase or any additional product candidates, generating revenues and achieving and sustaining profitability.
If clinical trials of vonapanitase or any additional product
candidates fail to demonstrate safety and efficacy to the satisfaction of the FDA and comparable foreign regulators, we may incur
additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization
of vonapanitase or any additional product candidates.
We are not permitted to commercialize, market,
promote or sell any product candidate in the United States without obtaining marketing approval from the FDA. Comparable foreign
regulatory authorities, such as the EMA, impose similar restrictions. We may never receive these regulatory approvals. We must
have completed extensive preclinical development and clinical trials to demonstrate the safety and efficacy of the product candidate
in humans before we will be able to obtain these approvals. Clinical testing is expensive, is difficult to design and implement,
can take many years to complete and is inherently uncertain as to outcome.
Any inability to successfully complete clinical
development could result in additional costs to us and impair our ability to generate revenues from product sales, regulatory and
commercialization milestones and royalties. If, following submission, our BLA is not accepted for substantive review (i.e., filing)
or approved, the FDA may require that we conduct additional clinical or preclinical trials, manufacture additional validation batches
or develop additional analytical test methods before it will reconsider our application. If the FDA requires additional studies
or data, we would incur increased costs and delays in the marketing approval process, which may require us to expend more resources
than we have available. In addition, the FDA may not consider any additional required trials that we perform and complete to be
sufficient.
In addition, if (1) we are required to conduct
additional clinical trials or other testing of or generate data pertaining to vonapanitase beyond the trials and testing that we
contemplate, (2) we are unable to successfully complete clinical trials or other testing of vonapanitase or any additional product
candidates, (3) the results of these trials or tests are unfavorable, uncertain or are only modestly favorable, or (4) there are
unacceptable safety concerns associated with vonapanitase or any additional product candidates, we, in addition to incurring additional
costs, may:
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be delayed in obtaining marketing approval for vonapanitase or any additional product candidates;
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not obtain marketing approval at all;
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obtain approval for indications or patient populations that are not as broad as we intended or
desired;
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obtain approval with labeling that includes significant use or distribution restrictions or significant
safety warnings, including boxed warnings;
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be subject to additional post-marketing testing or other requirements; or
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be required to remove the product from the market after obtaining marketing approval.
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In general, the FDA requires two adequate and
well-controlled clinical trials to demonstrate the effectiveness of a product candidate. In December 2016, we announced that our
first Phase 3 clinical trial did not meet its primary endpoint of improved primary unassisted patency compared to placebo (p=0.254).
Based on our interactions with the FDA, we believe that, if the results for each of the co-primary endpoints of our second Phase
3 clinical trial show statistical significance (p≤0.05), our second Phase 3 trial together with data from previously completed
studies will provide the basis for a BLA submission for vonapanitase to the FDA. However, even with robust p-values, there is no
guarantee that the results of the second Phase 3 trial will be sufficient for a BLA submission, filing or approval, and the FDA
may require that we conduct additional trials.
We may be unable to obtain regulatory approval for vonapanitase
or any additional product candidates under applicable regulatory requirements. The denial or delay of any approvals would prevent
or delay commercialization and have a material adverse effect on our potential to generate revenue, our business and our results
of operations.
Vonapanitase and any additional product candidates
are subject to extensive governmental regulations relating to, among other things, research, clinical trials, approval, manufacturing,
recordkeeping, labeling, storage, advertising, promotion, distribution, import, export and commercialization. In order to obtain
regulatory approval for the commercial sale of any product candidate, we must demonstrate through extensive preclinical studies
and clinical trials that the product candidate is safe and effective for use in each target indication. Failure to obtain marketing
approval for a product candidate will prevent us from commercializing the product candidate. Vonapanitase is still in development
and is subject to the risks of failure inherent in drug or biologic development. We have not received approval to market any product
candidate from regulatory authorities in any jurisdiction. We have only limited experience in conducting and managing the clinical
trials, and in submitting and supporting the applications necessary to gain marketing approvals, and we expect to rely on third-parties,
including clinical research organizations, or CROs, to assist us in this process. Securing marketing approval also requires the
submission of information about the product manufacturing process to, and inspection of manufacturing facilities and clinical trial
sites by, the regulatory authorities. Vonapanitase may not be effective, may be only moderately effective or may prove to have
undesirable or unintended side effects, toxicities or other characteristics that may preclude our obtaining marketing approval
or prevent or limit commercial use. We may gain regulatory approval for vonapanitase or any additional product candidates in some
but not all of the territories available or some but not all of the target indications, resulting in limited commercial opportunity
for the product, or we may never obtain regulatory approval for vonapanitase or any additional product candidates in any jurisdiction.
The process of obtaining marketing approvals,
both in the United States and abroad, is expensive, may take many years if additional clinical trials are required, if approval
is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the
product candidates involved. Changes in marketing approval policies during the development period, changes in or the enactment
of additional statutes or regulations, or changes in regulatory review for each submitted product application, may cause delays
in the approval or rejection of an application. The FDA and foreign regulatory authorities also have substantial discretion in
the drug and biologics approval process. The number and types of preclinical studies and clinical trials that will be required
for regulatory approval varies depending on the product candidate, the disease or condition that the product candidate is designed
to address, and the regulations applicable to any particular product candidate. Approval policies, regulations or the type and
amount of clinical data necessary to gain approval may change during the course of a product candidate’s clinical development
and may vary among jurisdictions, and there may be varying interpretations of data obtained from preclinical studies or clinical
trials, either of which may cause delays or limitations in the approval or the decision not to approve an application. Regulatory
agencies can delay, limit or deny approval of a product candidate for many reasons, including:
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IRBs, the FDA or comparable foreign regulatory authorities may disagree with the design or implementation
of our clinical trials;
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we may be unable to demonstrate to the satisfaction of the FDA or comparable foreign regulatory
authorities that a product candidate is safe and effective for its proposed indications;
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an FDA Advisory Committee or other regulatory authority may recommend against approval or restrictions
on approval;
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the results of later-stage clinical trials may not meet the level of statistical or clinical significance
required by the FDA or comparable foreign regulatory authorities for approval;
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the results of later-stage clinical trials may not confirm the positive results from earlier preclinical
studies or clinical trials;
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we may be unable to demonstrate that a product candidate’s clinical and other benefits outweigh
its safety risks;
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the FDA or comparable foreign regulatory authorities may disagree with our interpretation of data
from preclinical studies or clinical trials;
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the data collected from clinical trials of vonapanitase or any additional product candidate may
not be sufficient to the satisfaction of the FDA or comparable foreign regulatory authorities to support the submission of a BLA,
or other comparable submission in foreign jurisdictions or to obtain regulatory approval in the United States or elsewhere;
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our manufacturing processes or facilities may not be adequate to support approval of our product
candidates; or
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regulatory agencies may change their approval policies or adopt new regulations in a manner rendering our clinical data insufficient
for approval.
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It is possible that neither vonapanitase nor
any product candidates we may seek to develop in the future will ever obtain the appropriate regulatory approvals necessary for
us or any future collaborators to commence product sales. We do not know whether any clinical trials will begin as planned, or
will be revised prior to or during the conduct of the study, completed on time or conducted at all. Any delay in obtaining, or
failure to obtain, required approvals would materially adversely affect our ability to generate revenue from the particular product
candidate, which likely would result in significant harm to our financial position and adversely impact our stock price.
We may face difficulty in enrolling patients for clinical
trials.
We may find it difficult to enroll patients
in our clinical trials, which could delay or prevent completion of clinical trials of vonapanitase or any additional product candidates.
Identifying and qualifying patients to participate in clinical trials of vonapanitase or any additional product candidates are
critical to our success. The timing of our clinical trials depends on the speed at which we can recruit patients to participate
in testing product candidates. The enrollment timeline for radiocephalic fistula patients is lengthy and there are a limited number
of sites from which we can enroll pre-hemodialysis or hemodialysis patients. If patients are unwilling to participate in our trials
because of negative publicity from adverse events or for other reasons, including the results of completed or competitive clinical
trials for similar patient populations, the timeline for recruiting patients, conducting trials and obtaining regulatory approval
of potential products may be delayed or prevented. These delays could result in increased costs, delays in advancing our product
development, delays in testing the effectiveness of our technology or termination of the clinical trials altogether. We may not
be able to identify, recruit and enroll a sufficient number of patients, or those with required or desired characteristics to achieve
diversity in a trial, to complete our clinical trials in a timely manner. Patient enrollment is affected by numerous factors including:
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severity of the disease under investigation;
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design of the trial protocol;
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size and nature of the patient population;
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eligibility criteria for the trial in question;
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perceived risks and benefits of the product candidate under study;
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proximity and availability of clinical trial sites for prospective patients;
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availability of competing therapies and clinical trials;
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efforts to facilitate timely enrollment in clinical trials;
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our ability to obtain and maintain subject consents;
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the risk that enrolled subjects will drop out or be withdrawn from our studies;
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patient referral practices of physicians;
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ability to monitor patients adequately during and after treatment; and
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the ability of subjects to comply with the clinical trial visit schedule and procedures.
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We may not be able to initiate or continue clinical
trials if we cannot enroll a sufficient number of eligible patients to participate in the clinical trials required by regulatory
agencies. If we have difficulty enrolling a sufficient number of patients to conduct our clinical trials as planned, we may need
to delay, limit or terminate ongoing or planned clinical trials, any of which would have an adverse effect on our business.
If we experience any of a number of possible unforeseen events
in connection with clinical trials of vonapanitase or any additional product candidates, potential marketing approval or commercialization
of vonapanitase or any additional product candidates could be delayed or prevented.
If we experience delays in clinical testing,
we will be delayed in obtaining regulatory approvals and commercializing our product candidates, our costs may increase and our
business may be harmed. We do not know whether any future clinical trials that have not started will begin as planned, whether
the design will be revised prior to or during conduct of the study, completed on schedule or conducted at all. Our product development
costs may increase if we experience delays in clinical testing or changes to clinical protocols. Significant clinical trial delays
also could shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our
competitors to bring products to market before we do, which would impair our ability to successfully commercialize our product
candidates and may harm our business, results of operations and prospects. We may experience numerous unforeseen events during,
or as a result of, clinical trials that could delay or prevent marketing approval of vonapanitase or any additional product candidates,
including:
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trials of vonapanitase or any additional product candidates may produce unfavorable or inconclusive
results;
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we may decide, or regulators may require us, to conduct additional clinical trials or abandon product
development programs;
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our third-party contractors, including those manufacturing vonapanitase or any additional product
candidates or components or ingredients for commercial use or conducting clinical trials on our behalf, may fail to comply with
regulatory requirements or meet their contractual obligations to us in a timely manner or at all;
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regulators or institutional review boards, or IRBs, may not authorize us or our investigators to
commence or continue to conduct a clinical trial at a prospective trial site;
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we may have to suspend or terminate clinical trials of vonapanitase or any additional product candidates
for various reasons, including a finding that the participants are being exposed to unacceptable health risks, undesirable side
effects or other unexpected characteristics of a product candidate;
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regulators or IRBs may require that we or our investigators suspend or terminate clinical research
for various reasons, including noncompliance with regulatory requirements or their respective standards of conduct, a finding that
the participants are being exposed to unacceptable health risks, undesirable side effects or other unexpected characteristics of
the product candidate or findings of undesirable effects caused by a chemically or mechanistically similar biologic or biologic
candidate;
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we may experience delays in reaching or fail to reach agreement on acceptable clinical trial contracts
or clinical trial protocols with prospective trial sites and/or Contract Research Organizations, or CROs;
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we may experience withdrawal of clinical trial sites from our clinical trials as a result of changing
standards of care or the ineligibility of a site to participate in our clinical trials, and may further be delayed in trying to
add clinical trial sites to our studies;
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we may experience delays in the importation and manufacture of clinical supply;
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patient enrollment in these clinical trials may be slower than we anticipate and is limited to
a select number of sites, which could cause significant delays given the prolonged enrollment period;
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participants may drop out of clinical trials of vonapanitase at a higher rate than we anticipate
and we may not be able to obtain the follow up data for the 12 month period planned in our Phase 3 trial;
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patients who enroll in a clinical trial may misrepresent their eligibility to do so or may otherwise
not comply with the clinical trial protocol, resulting in the need to drop the patients from the clinical trial or increase the
needed enrollment size for the clinical trial beyond the 600 proposed for the Phase 3 trial, all of which may extend the clinical
trial’s duration;
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the FDA or comparable foreign regulatory authorities may disagree with our clinical trial design,
implementation, or our interpretation of data from preclinical studies and clinical trials;
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FDA or comparable foreign regulatory authorities may find that our clinical trials were not conducted
in accordance with Good Clinical Practices, or GCPs;
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the FDA or comparable foreign regulatory authorities may fail to approve or subsequently find fault
with the manufacturing processes or facilities of third-party manufacturers with which we enter into agreements for clinical and
commercial supplies;
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our finished product that has been manufactured for the vonapanitase Phase 3 trials may be inadequate,
or the materials or manufactured product candidates necessary to conduct future clinical trials of vonapanitase or any additional
product candidates may be insufficient, inadequate or not available at an acceptable cost, or we may experience interruptions in
supply;
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we may lack adequate funding to continue the clinical trials; and
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the approval policies or regulations of the FDA or comparable foreign regulatory authorities may
significantly change in a manner rendering our clinical data insufficient to obtain marketing approval.
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Product development costs for us will increase
if we experience delays in testing or pursuing marketing approvals, and we may be required to obtain additional funds to complete
clinical trials and prepare for possible commercialization of vonapanitase or any additional product candidates. We do not know
whether any future clinical trials that have not yet started will begin as planned, will need to be restructured or will be completed
on schedule, or at all. Significant clinical trial delays also could shorten any periods during which we may have the exclusive
right to commercialize vonapanitase or any additional product candidates or allow our competitors to bring products to market before
we do and impair our ability to successfully commercialize vonapanitase or any additional product candidates and may harm our business
and results of operations. In addition, many of the factors that cause, or lead to, clinical trial delays may ultimately lead to
the denial of marketing approval of vonapanitase or any additional product candidates.
Any product for which we obtain FDA approval will be subject
to extensive ongoing regulatory requirements, and we may be subject to penalties if we fail to comply with regulatory requirements
or if we experience unanticipated problems with our products, when and if any of them are approved.
Any product for which we obtain marketing approval,
along with the manufacturing processes, post-approval clinical research, labeling, advertising and promotional activities for the
product, will be subject to continual requirements of, and review by, the FDA and comparable regulatory authorities. These requirements
include submissions of safety and other post-marketing information and reports, tracking, tracing, investigation, notification,
and disposition obligations under the Drug Quality and Security Act, registration and listing requirements, current good manufacturing
practices, or cGMPs, requirements relating to manufacturing, quality control, quality assurance and corresponding maintenance of
records and documents, requirements regarding the distribution of samples to physicians and recordkeeping. The FDA and comparable
foreign regulatory authorities will continue to closely monitor the safety profile of any product even after approval. If the FDA
or comparable foreign regulatory authorities become aware of new safety information after approval of any of our product candidates,
they may withdraw approval, require labeling changes or establishment of a REMS or similar risk mitigation strategy, impose significant
restrictions on a product’s indicated uses or marketing, or impose ongoing requirements for potentially costly post-approval
studies or post-market surveillance.
Even if regulatory approval of a product is
granted, the approval will be subject to limitations on the indicated uses for which the product may be marketed and may be subject
to other conditions of approval. We and our contract manufacturers will be subject to periodic unannounced inspections by the FDA
to monitor and ensure compliance with cGMPs and other regulatory requirements. In addition, approval may contain requirements for
costly post-marketing testing and surveillance to monitor the safety or efficacy of the product. Discovery after approval of previously
unknown problems with any such products, manufacturers or manufacturing processes, or failure to comply with regulatory requirements,
may result in actions such as:
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restrictions on our ability to conduct clinical trials, including full or partial clinical holds
on ongoing or planned trials;
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restrictions on a product’s manufacturing processes or facilities;
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restrictions on the marketing of a product;
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restrictions on product distribution;
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requirements to conduct post-marketing clinical trials;
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Untitled, Cyber, or Warning Letters from the FDA or similar correspondence from comparable regulatory
authorities;
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withdrawal of the products from the market;
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refusal to approve pending applications or supplements to approved applications that we submit;
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mandated modifications to labeling and promotional materials or requirements to provide corrective
information to healthcare practitioners;
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requirements to enter into a consent decree, which can include imposition of various fines, reimbursements
for inspection costs, required due dates for specific actions and penalties for noncompliance;
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debarring us pursuant to the Federal Food, Drug, and Cosmetic Act, or FDCA, excluding us from participation
in federal healthcare programs, requiring a corporate integrity agreement or debarring us from government contracts;
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the imposition of costly new manufacturing requirements or use of alternative suppliers;
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FDA or other regulatory bodies issuing safety alerts, Dear Healthcare Provider letters, press releases
or other communications containing warnings about our products;
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fines, restitution or disgorgement of profits or revenue;
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suspension or withdrawal of regulatory approvals or refusal to approve future or pending applications
or supplements;
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refusal to permit the import or export of our products;
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imposition of civil or criminal penalties.
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Accordingly, assuming we receive marketing approval
for vonapanitase or any additional product candidates, we and our contract manufacturers will continue to expend time, money and
effort in all areas of regulatory compliance, including manufacturing, distribution, product surveillance, post-marketing studies
and quality control.
Vonapanitase may cause undesirable side effects or have other
properties that could delay or prevent their regulatory approval, limit the commercial profile of approved labeling, or result
in significant negative consequences following any potential marketing approval.
As with many pharmaceutical and biological products,
treatment with vonapanitase or any additional product candidates may produce undesirable side effects or adverse reactions or events.
These adverse events may occur despite our belief, based on our preclinical and clinical trials to date, that vonapanitase has
a favorable safety profile. For instance, vonapanitase shows a high degree of structural similarity with other human serine proteases,
which are proteins that cut other proteins to activate, inactivate or degrade these other proteins, and it is theoretically possible
that if anti-vonapanitase antibodies are developed that they could cross-react with one or more of those other proteases because
of the structural similarity, and prompt an adverse reaction. However, we have not seen any evidence of such cross-reactivity in
our preclinical or clinical trials to date.
Based on our Phase 2 and Phase 3 trials, adverse
side effects that could occur with treatment with vonapanitase include fistula surgical incision pain, venous stenosis, procedural
pain, fistula thrombosis, steal syndrome and hypoesthesia. If any of these adverse events occur in rates or severity exceeding
placebo and unacceptable to regulatory authorities or IRBs, if anti-vonapanitase antibodies develop and are associated with cross-reactivity
to other proteases, or unknown serious events emerge, our clinical trials could be suspended or terminated by us, IRBs, or the
applicable regulatory authorities, and the FDA, the EMA or other foreign regulatory authorities could order us to cease further
development of, or deny approval of, vonapanitase or any additional product candidates for any or all targeted indications. The
product-related side effects could affect patient recruitment or the ability of enrolled patients to complete the trial. If we
elect or are required to delay, suspend or terminate any clinical trial of vonapanitase or any additional product candidates, the
commercial prospects of these product candidates will be harmed and our ability to generate product revenues from any of these
product candidates will be delayed or eliminated.
In addition, even if we were to obtain approval,
regulatory authorities may approve any of our product candidates for fewer or more limited indications than we request, including
more limited patient populations, may require that contraindications, warnings or precautions be included in the product labeling,
including a boxed warning, may grant approval contingent on the performance of costly post-marketing clinical trials or other post-market
requirements, or may approve a product candidate with labeling that does not include the labeling claims necessary or desirable
for the successful commercialization of that product candidate. Any of these occurrences may harm our business, financial condition
and prospects significantly.
We may not be able to maintain orphan drug designation or
obtain or maintain orphan drug exclusivity for vonapanitase.
We have obtained orphan drug designation from
the FDA for vonapanitase. In the United States, under the Orphan Drug Act, the FDA may designate a product as an orphan drug if
it is intended to treat a rare disease or condition, which is generally defined as a patient population of fewer than 200,000 individuals
annually in the United States for a preventive drug. The first NDA or BLA applicant to receive FDA approval for a particular drug
or biologic to treat a particular disease with FDA orphan drug designation is entitled to a seven-year exclusive marketing period
in the United States for that product, for that indication. During the seven-year exclusivity period, the FDA may not approve any
other applications to market the same drug or biologic for the same disease, except in limited circumstances. Orphan drug exclusivity
may be lost if the FDA determines, among other reasons, that the request for designation was materially defective or if the manufacturer
is unable to assure sufficient quantity of the product to meet the needs of patients with the rare disease or condition.
Even if we obtain orphan drug exclusivity for
vonapanitase, that exclusivity may not effectively protect the product from competition because different products can be approved
for the same condition. Even after an orphan product is approved, the FDA can subsequently approve a product containing the same
principal molecular structural features for the same condition if the FDA concludes that the later product is clinically superior
in that it is shown to be safer, more effective or makes a major contribution to patient care.
In response to a recent court decision regarding
the plain meaning of the exclusivity provision of the Orphan Drug Act and increased scrutiny by legislators, the FDA may undertake
a reevaluation of aspects of its orphan drug regulations and policies. We do not know if, when, or how the FDA may change the orphan
drug regulations and policies, and it is uncertain how any changes might affect our business. Depending on what changes the FDA
may make to its orphan drug regulations and policies, our business could be harmed.
A breakthrough therapy,
fast track product, priority review, or other designation
by the FDA for our product candidates may not lead to faster development or regulatory review or approval process, and it does
not increase the likelihood that our product candidates will receive marketing approval.
We have received a breakthrough therapy and fast track product designation for vonapanitase for improving
vascular access and decreasing the need for surgery in patients with CKD who are on hemodialysis or being prepared for hemodialysis.
As applicable, we may seek breakthrough therapy, fast track, priority review, or other designations for other uses of vonapanitase.
Breakthrough therapy and fast track product designations are designed to facilitate the clinical development and expedite the review
of drugs and biologics intended to treat a serious or life-threatening condition which demonstrate the potential to address an
unmet medical need. Priority review designation is intended to speed the FDA marketing application review timeframe for drugs and
biologics that treat a serious condition and, if approved, would provide a significant improvement in safety or effectiveness.
For drugs and biologics that have been designated as breakthrough therapy or fast track products, interaction and communication
between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development. Sponsors of
drugs and biologics designated as breakthrough therapies or fast track products may also be able to submit marketing applications
on a rolling basis, meaning that the FDA may review portions of a marketing application before the sponsor submits the complete
application to the FDA, as long as the sponsor pays the user fee upon submission of the first portion of the marketing application.
For products that receive a priority review designation, the FDA’s marketing application review goal is shortened to six
months, as opposed to ten months under standard review. This review goal is based on the date the FDA accepts the marketing application
for review (i.e., filing), which typically occurs two months after the date of submission.
Designation as a breakthrough therapy, fast
track product, priority review product, or under another program is within the discretion of the FDA. Accordingly, even if we
believe one of our product candidates meets the criteria for designation as a breakthrough therapy, fast track product, priority
review product, or other designation, the FDA may disagree and instead determine not to make such designation. In any event, the
receipt of any such designation for a product candidate may not result in a faster development process, review or approval compared
to drugs and biologics considered for approval under conventional FDA procedures and does not assure ultimate marketing approval
by the FDA. In addition, the FDA may later decide that the products no longer meet the conditions for qualification as a breakthrough
therapy, fast track product or under another designation program or decide that the time period for FDA review or approval will
not be shortened.
We may expend our limited resources to pursue a particular
product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for
which there is a greater likelihood of success.
Because we have limited financial and managerial
resources, we have focused on developing one product candidate, vonapanitase, and have focused on developing this product candidate
for specific indications that we identify as most likely to succeed, in terms of both its regulatory approval and commercialization.
As such, we are currently primarily focused on the development of vonapanitase for vascular access, and our Phase 3 trials will
be limited to the application of vonapanitase in radiocephalic fistulas.
In the future we intend to pursue additional
indications such as the application of vonapanitase in brachiocephalic fistula creation and/or patients undergoing placement of
an arteriovenous graft and/or patients with symptomatic PAD. As a result, we may forego or delay pursuit of opportunities with
other product candidates or for other indications that may prove to have greater commercial potential. Our resource allocation
decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on
current and future research and development programs and product candidates for specific indications may not yield any commercially
viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate,
we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases
in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.
Even if we obtain and maintain approval for vonapanitase or
additional product candidates from the FDA, we may never obtain approval for vonapanitase or additional product candidates outside
of the United States, which would limit our market opportunities and adversely affect our business.
Even if we obtain approval of a product candidate
in the United States from the FDA, such approval does not ensure approval of that product candidate by regulatory authorities in
other countries or jurisdictions, and approval by one foreign regulatory authority does not ensure approval by regulatory authorities
in other foreign countries or by the FDA. Sales of vonapanitase or any additional product candidates outside of the United States
will be subject to foreign regulatory requirements governing clinical trials and marketing approval. Even if the FDA grants marketing
approval for a product candidate, comparable regulatory authorities of foreign countries must also approve the manufacturing and
marketing of the product candidate in those countries. Approval procedures vary among jurisdictions and can involve requirements
and administrative review periods different from, and greater than, those in the United States, including additional preclinical
studies or clinical trials. In many countries outside the United States, a product candidate must be approved for reimbursement
before it can be approved for sale in that country. In some cases, the price that we intend to charge for our products, if approved
for sale, is also subject to approval. Moreover, the failure to obtain approval in one jurisdiction may negatively impact our ability
to obtain approval in another jurisdiction.
Based on additional data including the data
from our Phase 3 clinical trials and assuming sufficient funds become available, we plan to commence a clinical trial of vonapanitase
in Europe for patients undergoing creation of radiocephalic fistulas. Prior to enrolling our first patient in Europe, we plan to
formally seek guidance from the EMA regarding its requirements for regulatory approval. If a clinical trial of vonapanitase in
Europe is necessary for regulatory approval, we expect results from this trial to be available two to three years after the first
patient is enrolled. If results of this European trial successfully meet its primary endpoint and depending on the guidance obtained
from the EMA, we would expect to submit a Marketing Authorization Application, or MAA, following our receipt of the trial results.
Obtaining an approval is a lengthy and expensive process and the EMA has its own procedures for approval of product candidates.
Even if a product candidate is approved, the EMA may limit the indications for which the product may be marketed, require extensive
warnings on the product labeling or require expensive and time-consuming clinical trials or reporting as conditions of approval.
Regulatory authorities in countries outside of the United States and Europe also have requirements for approval of product candidates
with which we must comply prior to marketing in those countries. Obtaining foreign regulatory approvals and compliance with foreign
regulatory requirements could result in significant delays, difficulties and costs for us and could delay or prevent the introduction
of vonapanitase or any additional product candidates in those countries.
Advertising and promotion of any product candidate that obtains
approval in the United States will be heavily scrutinized by the FDA, the Department of Justice, the Department of Health and Human
Services’ Office of Inspector General, state attorneys general, members of Congress and the public.
While the FDA does not restrict physicians from
prescribing approved drugs and biologics for uses outside of the products’ approved labeling, known as off-label use, pharmaceutical
manufacturers are prohibited from promoting and marketing their products for such uses. Violations, including promotion of our
products for off-label uses, are subject to enforcement letters, inquiries, investigations, civil and criminal sanctions by the
government, corporate integrity agreements, debarment from government contracts, debarment and exclusion from participation in
federal healthcare programs. Additionally, comparable foreign regulatory authorities will heavily scrutinize advertising and promotion
of any product candidate that obtains approval outside of the United States.
In the United States, engaging in the impermissible
promotion of our products for off-label uses can also subject us to false claims litigation under federal and state statutes, which
can lead to civil and criminal penalties and fines, debarment from government contracts, exclusion from participation in federal
healthcare programs and corporate integrity agreements with governmental authorities that materially restrict the manner in which
a company promotes or distributes drug and biologic products. These false claims statutes include the federal civil False Claims
Act, which allows any individual to bring a lawsuit against a pharmaceutical company on behalf of the federal government alleging
submission of false or fraudulent claims, or causing to present such false or fraudulent claims, for payment by a federal program
such as Medicare or Medicaid. If the government decides to intervene and prevails in the lawsuit, the individual will share in
any fines or settlement funds. If the government does not intervene, the individual may proceed on his or her own. Since 2004,
these False Claims Act lawsuits against pharmaceutical companies have increased significantly in volume and breadth, leading to
several substantial civil and criminal settlements regarding certain sales practices promoting off-label product uses involving
fines that are as much as $3.0 billion.
This growth in litigation has increased the
risk that a pharmaceutical company will have to defend a false claim action, pay settlement fines or restitution, agree to comply
with burdensome reporting and compliance obligations, and be excluded from Medicare, Medicaid and other federal and state healthcare
programs. If we do not lawfully promote our approved products, we may become subject to such litigation and, if we do not successfully
defend against such actions, those actions may have a material adverse effect on our business, financial condition, results of
operations and prospects. The FDA’s policies may change and additional government regulations may be enacted that could prevent,
limit or delay marketing approval, and the sale and promotion of our product candidates. If we are slow or unable to adapt to changes
in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance,
we may lose any marketing approval that we may have obtained, which would adversely affect our business, prospects and ability
to achieve or sustain profitability.
If we are found in violation of federal or state “fraud
and abuse” laws or other healthcare laws and regulations, we may be required to pay a penalty and/or be suspended from participation
in federal or state healthcare programs, which may adversely affect our business, financial condition and results of operation.
We may also be subject to various federal and
state laws pertaining to healthcare “fraud and abuse,” including anti-kickback laws and false claims laws. Anti-kickback
laws make it illegal for a prescription drug or biologic manufacturer to solicit, offer, receive or pay any remuneration in exchange
for, or to induce, the referral of business, including the purchase or prescription of a particular drug or biologic. Other laws
that we may be subject to include the civil False Claims Act, criminal False Claims Act, the HIPAA fraud and abuse provisions,
the Civil Monetary Penalties statute, Section 1927 of the Social Security Act, the Veterans Health Care Act, the Foreign Corrupt
Practices Act, federal and state statutes and regulations pertaining to payments made to physicians and other health care providers,
the HIPAA privacy and security provisions, and other analogous state laws. Due to the breadth of the statutory provisions, it is
possible that our practices might be challenged under anti-kickback, healthcare, or other fraud and abuse laws. Moreover, recent
healthcare reform legislation has strengthened these laws. For example, the recently enacted Patient Protection and Affordable
Care Act, or ACA, among other things, amends the intent requirement of the federal anti-kickback and certain of the criminal healthcare
fraud statutes to clarify that a person or entity does not need to have actual knowledge of this statute or specific intent to
violate it. In addition, the ACA clarifies that the government may assert that a claim that includes items or services resulting
from a violation of the federal anti-kickback statute constitutes a false or fraudulent claim for purposes of the civil False Claims
Act. False claims laws prohibit anyone from knowingly presenting, or causing to be presented for payment, to government third-party
payors (including Medicare and Medicaid) claims for reimbursed drugs, or biologics or services that are false or fraudulent, claims
for items or services not provided as claimed, or claims for medically unnecessary items or services. Liability may also arise
from false certification of compliance with laws and regulations that are conditions of payment. Our activities relating to the
sale and marketing of our products may be subject to scrutiny under these laws. Violations of fraud and abuse laws, and other healthcare
statutes are punishable by criminal and civil sanctions, including fines and civil monetary penalties, the possibility of exclusion
from federal healthcare programs (including Medicare and Medicaid) and corporate integrity agreements, which impose, among other
things, rigorous operational and monitoring requirements on companies. We may further be subject to such other actions as debarment
from government contracts and future orders under existing contracts, refusal to allow us to enter into supply contracts, including
government contracts, reputational harm, diminished profits and future earnings and the curtailment or restructuring of our operations,
any of which could adversely affect our business.
Given the significant penalties and fines that
can be imposed on companies and individuals if convicted or found liable, allegations of violations under fraud and abuse laws
often result in settlements even if the company or individual being investigated admits no wrongdoing. Settlements often include
significant civil sanctions, including fines and civil monetary penalties, and corporate integrity agreements. If the government
were to allege or convict us or our executive officers of violating these laws, our business could be harmed. In addition, private
individuals have the ability to bring similar actions under the False Claims Act. Our activities could be subject to challenge
for the reasons discussed above and due to the broad scope of these laws and the increasing attention being given to them by law
enforcement authorities. Further, an increasing number of state laws require manufacturers to make reports to states on pricing
and marketing information. Many of these laws contain ambiguities as to what is required to comply with the laws. Given the lack
of clarity in laws and their implementation, our reporting actions could be subject to the penalty provisions of the pertinent
state authorities.
Similar rigid restrictions are imposed on the
promotion and marketing of medicinal products in the European Union and other countries. Laws (including those governing promotion,
marketing and anti-kickback provisions), industry regulations and professional codes of conduct often are strictly enforced. Even
in those countries where we are not directly responsible for the promotion and marketing of our products, inappropriate activity
by our international distribution partners can have adverse implications for us.
We may not be able to comply with requirements of foreign
jurisdictions in conducting trials outside of the United States.
To date, we have not conducted any clinical
trials outside of the United States. Our ability to successfully initiate, enroll and complete a clinical trial in any foreign
country, should we attempt to do so, is subject to numerous risks unique to conducting business in foreign countries, including:
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difficulty in establishing or managing relationships with contract research organizations, or CROs,
clinical sites and investigators;
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different standards for the conduct of clinical trials;
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our inability to locate qualified local consultants, physicians and partners;
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the potential burden of complying with a variety of foreign laws, medical standards and regulatory
requirements, including the regulation of pharmaceutical and biotechnology products and treatment; and
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the acceptability of data obtained from trials conducted outside the United States to the FDA in
support of a BLA.
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Risks Related to Commercialization of Our Product
If we are unable to establish effective marketing and sales
capabilities or enter into agreements with third parties to market and sell our product candidates, if they are approved, we may
be unable to generate product revenues.
We currently do not have a commercial infrastructure
for the marketing, sale and distribution of biological products. If approved, in order to commercialize our products, we must build
our marketing, sales and distribution capabilities or make arrangements with third parties to perform these services. We may not
be successful in doing so. If vonapanitase is approved by the FDA, we plan to build a specialty sales force in the United States
of approximately 75-100 representatives, supported by reimbursement specialists and a medical affairs team. We may seek to further
penetrate the United States market in the future by expanding our sales force or through collaborations with other pharmaceutical
or biotechnology companies or third party manufacturing and sales organizations. If approved for marketing outside the United States,
we may commercialize outside the United States with our own specialty sales force and/or with a commercial partner.
As a company we have no prior experience in
the marketing, sale and distribution of biological products, and there are significant risks involved in the building and managing
of a commercial infrastructure. The establishment and development of our own sales force and related compliance plans to market
any products we may develop will be expensive and time consuming and could delay any product launch, and we may not be able to
successfully develop this capability. We, or our future collaborators, will have to compete with other companies to recruit, hire,
train, manage and retain marketing and sales personnel. In the event we are unable to develop a marketing and sales infrastructure,
we may not be able to commercialize vonapanitase or any additional product candidates, which would limit our ability to generate
product revenues. Our ability to generate product revenues would be impaired by:
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our inability to recruit, train, manage and retain adequate numbers of effective sales and marketing
personnel;
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the inability of sales personnel to obtain access to vascular surgeons or persuade adequate numbers
of vascular surgeons to use vonapanitase or any additional product candidates;
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our inability to effectively oversee a geographically dispersed sales and marketing team;
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the costs associated with training sales personnel on legal compliance matters and monitoring their
actions;
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liability for sales personnel failing to comply with the applicable legal requirements; and
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unforeseen costs and expenses associated with creating an independent sales and marketing organization.
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Although our current plan is to hire most of
our sales and marketing personnel only if vonapanitase is approved by the FDA, we will incur expenses prior to product launch in
recruiting this sales force and developing a marketing and sales infrastructure. If the commercial launch of vonapanitase is delayed
as a result of FDA requirements or other reasons, we would incur these expenses prior to being able to realize any revenue from
sales of vonapanitase. Even if we are able to effectively hire a sales force and develop a marketing and sales infrastructure,
our sales force and marketing teams may not be successful in commercializing vonapanitase or any additional product candidates.
In the event we are unable to hire a sales force
or collaborate with a third-party marketing and sales organization to commercialize any approved product candidates outside the
United States, our ability to generate product revenues may be limited. To the extent we rely on third parties to commercialize
any products for which we obtain regulatory approval, we may receive less revenues than if we commercialized these products ourselves.
In addition, we would have less control over the sales efforts of any other third parties involved in our commercialization efforts.
Even if vonapanitase or any additional product candidates
receive regulatory approval, they may fail to achieve the broad degree of physician adoption and use necessary for commercial success.
The commercial success of vonapanitase and any
product candidates that we may develop will depend upon the degree of market acceptance by physicians, patients, healthcare payors
and others in the medical community. Even if the FDA approves vonapanitase or one or more of our future product candidates, physicians
and patients may not accept and use them. Acceptance and use of any of our products will depend upon a number of factors including:
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perceptions by members of the healthcare community, including physicians, about the safety and
effectiveness of our products, and their advantages as compared to any competitive products;
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the timing of market introduction of the product candidate as well as competitive products;
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the clinical indications for which the product candidate is approved;
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any restrictions on or warnings regarding the use of the products;
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cost-effectiveness of our products relative to any competing products;
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availability of timely coverage and reimbursement for our products from government or other third-party
payors; and
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effectiveness of marketing and distribution efforts by us and any our licensees and distributors.
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Because we expect sales of vonapanitase, if
approved, to generate substantially all of our product revenues for the foreseeable future, the failure of vonapanitase to gain
market acceptance would harm our business and would require us to seek additional financing.
Vonapanitase or any additional product candidates, if approved,
may face significant competition and our failure to effectively compete may prevent us from achieving significant market penetration
and expansion.
The biotechnology and pharmaceutical industries
are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products. We face
potential competition from many different sources, including major pharmaceutical, specialty pharmaceutical, biotechnology and
medical device companies, academic institutions, governmental agencies and public and private research institutions. While we believe
that vonapanitase’s features, safety and efficacy will differentiate it from any competitive products that may become available
in the future, we expect to face potential competition from many different sources, including larger and better-funded pharmaceutical,
specialty pharmaceutical and biotechnology companies and medical device companies, as well as from academic institutions and governmental
agencies and public and private research institutions that may develop potentially competitive products or technologies.
Some of our competitors have significantly greater
financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials,
obtaining regulatory approvals, marketing and selling 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.
The key competitive factors affecting the success
of vonapanitase, if approved, are likely to be its efficacy, safety, convenience, price, and the availability of reimbursement
from government and other third-party payors. Our commercial opportunity could be reduced or eliminated if our competitors develop
and commercialize products that are safer, more effective, more convenient or less expensive than any products that we may develop.
Our competitors may also obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for
ours.
We are not aware of products approved in the
United States or Europe that would compete with vonapanitase for the improvement of secondary patency and fistula use for hemodialysis.
We are aware of companies with therapies in development including Vascular Therapies, Enceladus Pharmaceuticals, Symic Biomedical
and Aplagon, as well as companies developing vascular access technologies, including BioConnect Systems, Avenu Medical, Phraxis,
Brookhaven Medical, Laminate Medical Technologies, Stent Tek and TVA Medical. Other technologies in development include new synthetic
grafts, including those that may be developed by companies that currently compete in the graft market, such as W.L. Gore, C.R.
Bard and Maquet, as well as tissue engineered grafts, including those in development by Cytograft and Humacyte. Finally, vonapanitase’s
commercial success could be affected by the development of technologies to improve the outcomes of interventions to restore patency,
including stents, stent grafts and drug-coated balloons.
Vonapanitase, or any additional product candidates for which
we seek approval as biologic products, may face competition sooner than anticipated.
The enactment of the Biologics Price Competition
and Innovation Act of 2009, or BPCIA, as part of the ACA, created an abbreviated pathway for the approval of biosimilar and interchangeable
biological products. The abbreviated regulatory pathway establishes legal authority for the FDA to review and approve biosimilar
biologics, including the possible designation of a biosimilar as “interchangeable” based on its similarity to an existing
brand product. Under the BPCIA, an application for a biosimilar product cannot be approved by the FDA until 12 years after the
original branded product was approved under a BLA. Certain changes, however, and supplements to an approved BLA, and subsequent
applications filed by the same sponsor, manufacturer, licensor, predecessor in interest, or other related entity do not qualify
for the 12-year exclusivity period.
The BPCIA is complex and is still being interpreted
and implemented by the FDA. ACA is also facing increased scrutiny by legislators. As a result, the ultimate impact, implementation,
meaning and continued effectiveness of BPCIA are subject to uncertainty. While it is uncertain when such processes intended to
implement the BPCIA may be fully adopted by the FDA or whether any aspects of BPCIA may change, any such processes or changes could
have a material adverse effect on the future commercial prospects for our biological products.
We believe that vonapanitase, or any additional
product candidates approved as a biological product under a BLA, should qualify for the BPCIA’s 12-year period of exclusivity.
However, there is a risk that BPCIA will be repealed or amended, or the FDA will not consider vonapanitase or any additional product
candidates to be reference products for competing products, potentially creating the opportunity for generic competition sooner
than anticipated.
Additionally, this period of regulatory exclusivity
does not currently apply to companies pursuing regulatory approval via their own traditional BLA, rather than via the abbreviated
pathway. Moreover, the extent to which a biosimilar, once approved, will be substituted for any one of our reference products in
a way that is similar to traditional generic substitution for non-biological products is not yet clear, and will depend on a number
of marketplace and regulatory factors that are still developing. It is possible that payers will give reimbursement preference
to biosimilars even over reference biologics absent a determination of interchangeability.
If the government or other third-party payors fail to provide
adequate and timely coverage and payment rates for vonapanitase or any additional product candidates or if surgeons or hospitals
choose not to use vonapanitase, our revenue and prospects for profitability will be limited.
In both domestic and foreign markets, sales
of our future products will depend substantially upon the availability of timely coverage and reimbursement from government and
other third-party payors. The majority of incident and prevalent hemodialysis patients have Medicare coverage, while other patients
have other third-party payors, including other government health programs such as Medicaid, managed care providers, private health
insurers and other organizations. Coverage decisions may depend upon clinical and economic standards that disfavor new drug and
biologic products when more established or lower cost therapeutic alternatives are already available or subsequently become available.
Vonapanitase or any additional product candidates, if approved, may face competition from other therapies, biologics, and drugs
for limited financial resources. We may need to conduct post-marketing studies in order to demonstrate the cost-effectiveness of
any future products to the satisfaction of outpatient clinics, hospitals, other target customers and their third-party payors.
These post-marketing studies might require us to commit a significant amount of management time and financial and other resources.
Our future products might not ultimately be considered cost-effective. Adequate third-party coverage and reimbursement might not
be available to enable us to maintain price levels sufficient to realize an appropriate return on investment in product development.
Third-party payors, whether foreign or domestic,
or governmental or commercial, are developing increasingly sophisticated methods of controlling healthcare costs. Assuming coverage
is approved, the resulting reimbursement payment rates might not be adequate to allow us to establish or maintain a market share
sufficient to realize a sufficient return on our investments. If reimbursement is not available, or is available only to limited
levels, our product candidates may be competitively disadvantaged, and we, or our collaborators, may not be able to successfully
commercialize our product candidates. Alternatively, securing favorable reimbursement terms may require us to compromise pricing
and prevent us from realizing an adequate margin over cost. In addition, in the United States, no uniform policy of coverage and
reimbursement for drug and biologic products exists among third-party payors. Therefore, coverage and reimbursement for drug and
biologic products can differ significantly from payor to payor. Further, we believe that future coverage and reimbursement will
likely be subject to increased restrictions both in the United States and in international markets. Third-party coverage and reimbursement
for our products or product candidates for which we receive regulatory approval may not be available or adequate in either the
United States or international markets, which could have a negative effect on our business, results of operations, financial condition
and prospects.
Government programs impose price controls on
pharmaceutical and biological products and penalties for increasing commercial prices at rates that exceed the government inflation
index, which may limit the commercial price we charge and our realization on sales. Further, the net reimbursement for drug and
biologic products may be subject to additional reductions if there are changes to laws that presently restrict imports of drugs
and biologics from countries where they may be sold at lower prices than in the United States. An inability to promptly obtain
coverage and adequate payment rates from both government-funded and private payors for any our product candidates for which we
obtain marketing approval could have a material adverse effect on our operating results, our ability to raise capital needed to
commercialize products and our overall financial condition.
Risks Related to Dependence on Third Parties
We and our contract manufacturers are subject to significant
regulation with respect to manufacturing our product candidates. The manufacturing facilities on which we rely may not continue
to meet regulatory requirements and have limited capacity.
We currently have a relationship with only one
supplier, Lonza, for the manufacturing of the API for vonapanitase for clinical testing purposes, and intend to continue to use
Lonza as our sole or primary supplier of the API for vonapanitase in the future. We have used two companies, Jubilant HollisterStier
and Patheon Manufacturing Services Inc. (formerly DSM Pharmaceuticals), to vial and make our vonapanitase finished product. We
also expect to rely upon third parties to produce materials required for the commercial production of vonapanitase or any additional
product candidates if we succeed in obtaining the necessary regulatory approvals. This may increase the risk that we will not have
sufficient quantities of our product candidates to conduct our clinical trials or such quantities at an acceptable cost, which
could result in the delay, prevention, or impairment of clinical development and commercialization of our product candidates.
All entities involved in the preparation of
drugs or biologics for clinical trials or commercial sale, including our existing contract manufacturers, are subject to extensive
regulation. Ingredients of a finished therapeutic biologic product approved for commercial sale or used in clinical trials must
be manufactured in accordance with cGMPs and equivalent foreign standards. These regulations govern manufacturing processes and
procedures (including record-keeping) and the implementation and operation of quality systems to control and assure the quality
of investigational products and products approved for sale. Poor control of production processes can lead to the introduction of
adventitious agents or other contaminants, or to inadvertent changes in the properties or stability of product candidate that may
not be detectable in final product testing. We or our contract manufacturers must supply all necessary documentation in support
of a BLA on a timely basis and must adhere to the FDA’s cGMPs regulations enforced by the FDA through its facilities inspection
program. Any failure by our third-party manufacturers to comply with cGMPs, or failure to scale-up and validate manufacturing processes,
including any failure to deliver sufficient quantities of product candidates in a timely manner for the process validation required
in connection with a BLA submission, could lead to a delay in, or failure to obtain, regulatory approval of vonapanitase or any
additional product candidates. For example, on November 27, 2013, our third-party supplier of finished biological product, Jubilant
HollisterStier, received a Warning Letter from the FDA alleging that the company was not complying with cGMPs. We received a letter
from the FDA on February 13, 2014, stating that the Warning Letter does not impact the batch of finished product we are using for
our Phase 3 clinical trials. However, if Jubilant HollisterStier or any other third-party supplier does not have an acceptable
cGMP compliance status at the time of review by the FDA of any BLA we might submit, approval of the BLA would be delayed. This
third party supplier or other third parties could encounter similar difficulties that could impede our clinical trials, approval
or commercialization.
Our facilities and quality systems and the facilities
and quality systems of some or all of our third-party contractors must also pass a pre-approval inspection for compliance with
the applicable regulations as a condition of regulatory approval of vonapanitase or any additional product candidates. In addition,
the regulatory authorities may, at any time, audit or inspect a manufacturing facility involved with the preparation of our product
candidate or the associated quality systems for compliance with the regulations applicable to the activities being conducted. If
these facilities and quality systems do not pass a pre-approval plant inspection from the FDA or a comparable foreign authority,
approval of our product candidate by the FDA or the equivalent approvals in other jurisdictions will not be granted until the regulatory
authority is satisfied that the facility complies with applicable regulations.
Regulatory authorities also may, at any time
following approval of a product for sale, audit our manufacturing facilities or those of our third-party contractors. If any such
inspection or audit identifies a failure to comply with applicable regulations or if a violation of our product specifications
or applicable regulations occurs independent of such an inspection or audit, we or the relevant regulatory authority may require
remedial measures that may be costly and/or time-consuming for us or a third party to implement and that may include the temporary
or permanent suspension of a clinical trial or commercial sales or the temporary or permanent closure of a facility. Any such remedial
measures imposed upon us or third parties with whom we contract could materially harm our business.
If we or any of our third-party manufacturers
fail to maintain regulatory compliance, the FDA can impose regulatory sanctions including, among other things, refusal to approve
a pending application for a new drug or biologic product or revocation of a pre-existing approval. If any such event occurs, our
business, financial condition and results of operations may be materially harmed.
Currency fluctuations in the Swiss Franc and changes in exchange
rates could adversely affect our business by increasing our costs and cause our profitability to decline.
Our contract with Lonza for the manufacturing
of the API is denominated in Swiss Francs. Therefore, fluctuations in the exchange rate for Swiss Francs may affect our operating
results. On January 15, 2015, the Swiss National Bank announced an edit to its policy of fixing the Swiss Franc and Euro exchange
rate, which caused volatility in the currency markets for Swiss Francs and an immediate increase in their value, making our contractual
payments to Lonza more expensive based on the current exchange rates. In the second quarter of 2015, we entered into forward foreign
currency contracts to purchase Swiss Francs to reduce our foreign currency exposure under our contract with Lonza, all of which
have been settled and are no longer outstanding. We have purchased Swiss Francs to mitigate our exposure to fluctuations in the
U.S. dollar value of forecasted transactions denominated in Swiss Francs. In the future we may purchase additional forward foreign
currency contracts to hedge certain forecasted transactions, including those with Lonza, and reduce exposures to foreign currency
fluctuations. Any use of these derivative instruments would be intended to mitigate a portion of the exposure of these risks with
the intent to reduce our risk or cost, but generally would not fully offset any change in operating results as a consequence of
fluctuations in foreign currencies. Any significant foreign exchange rate fluctuations could adversely affect our financial condition
and results of operations and any use of derivative instruments may not offset such fluctuations and could exacerbate their impact
on our financial condition and results of operations.
We rely on third parties to conduct some or all aspects of
our product manufacturing, protocol development, research, and preclinical and clinical testing, and plan to continue to rely on
such third parties if we receive marketing approvals. These third parties may not perform satisfactorily.
We do not currently, and do not expect in the
future, to independently conduct all aspects of our product manufacturing, protocol development, research and monitoring and management
of our clinical programs. Vonapanitase API is produced by our contract manufacturer, Lonza. Vonapanitase finished product is produced
by our contract fill/finish provider, Jubilant HollisterStier. Release testing and stability for API and finished product is performed
by PPD, Inc. We currently rely, and expect to continue to rely, on third parties with respect to these items for our continued
and future clinical studies as well as for commercialization, if we receive regulatory marketing approval. While we will have agreements
governing their activities, we will have limited influence over their actual day-to-day performance. Nevertheless, we will be responsible
for ensuring that the manufacturing is conducted in accordance with regulatory requirements such as cGMPs. Our reliance on the
third parties does not relieve us of our regulatory responsibilities.
Any of these third parties may terminate their
engagements with us under the terms of our agreements upon notice to us. If we need to enter into alternative arrangements, our
product candidate development and eventual commercialization activities may be delayed. Our reliance on these third parties for
research and development activities, and eventual commercial supply, reduces our day-to-day control over these activities but does
not relieve us of our responsibility to ensure compliance with all required legal, regulatory and scientific standards and any
applicable trial protocols. For example, for vonapanitase or any additional product candidates that we develop and commercialize
on our own, we will remain responsible for ensuring that the product is manufactured in accordance with cGMPs, each of our clinical
trials is conducted in accordance with GCPs and its protocol and is analyzed in accordance with its statistical analysis plan for
the clinical trial.
If these third parties do not successfully carry
out their contractual duties, meet expected deadlines or conduct our studies in accordance with regulatory requirements or our
protocols, we may be delayed in completing, or unable to complete, the clinical trials required to support future approval of vonapanitase
or any additional product candidates, and, if ultimately approved for marketing, may not be able to produce a sufficient amount
of commercial supply.
We rely on our manufacturers to purchase from
third-party suppliers the materials necessary to produce our product candidate, vonapanitase, for our clinical trials, and eventual
commercial supply, if we receive regulatory approval. There are a small number of suppliers for certain raw materials that we use
to manufacture vonapanitase. These suppliers may not sell these raw materials to our manufacturers at the times we need them or
on commercially reasonable terms. We do not have any control over the process or timing of the acquisition of these raw materials
by our manufacturers. Moreover, we currently do not have any agreements for the commercial production of these raw materials. Although
the API and the finished product for each of our Phase 3 trials has already been manufactured and is held in storage, we will need
supply of finished product as part of the process validation and for any stability or other tests in connection with a BLA submission
and also to conduct additional clinical trials, for example for additional vonapanitase indications. We will further require finished
product for commercialization if we receive regulatory approval. Any significant delay in the supply of vonapanitase’s ingredients
due to the need to replace a third-party manufacturer could considerably delay completion of our clinical trials, product testing
and potential regulatory approval of vonapanitase or any additional product candidate, and commercialization as we believe that
replacing Lonza as the manufacturer of our API would take one to two years and replacement of any of our other manufacturers may
take a substantial amount of time. If our manufacturers or we are unable to purchase these raw materials after regulatory approval
has been obtained for our product candidate, our ability to commercially launch and/or generate revenues from the sale of any approved
product would be impaired. Reliance on third-party manufacturers entails exposure to risks to which we would not be subject if
we manufactured the product candidate ourselves, including:
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inability to negotiate manufacturing agreements with third parties under commercially reasonable
terms;
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reduced day-to-day control over the manufacturing process for our product candidates as a result
of using third-party manufacturers for all aspects of manufacturing activities;
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reduced control over the protection of our trade secrets and know-how from misappropriation or
inadvertent disclosure;
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termination or nonrenewal of manufacturing agreements with third parties in a manner or at a time
that may be costly or damaging to us or result in delays in the development or commercialization of our product candidates; and
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disruptions to the operations of our third-party manufacturers or suppliers caused by conditions
unrelated to our business or operations, including the bankruptcy of the manufacturer or supplier.
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Any of these events could lead to delays in
the development of vonapanitase or any additional product candidates, including delays in our clinical trials, or failure to obtain
regulatory approval for our product candidates, or it could impact our ability to successfully commercialize vonapanitase or any
additional product candidates. Some of these events could be the basis for FDA or other regulatory action, including Warning Letters,
injunction, recall, seizure or total or partial suspension of production. Any of these events could have a material adverse effect
on our business.
We rely on third parties to conduct, supervise and monitor
our clinical trials. If these third parties do not successfully carry out their contractual duties or meet expected deadlines,
we may not be able to obtain regulatory approval for, or commercialize, vonapanitase or any additional product candidates and our
business could be substantially harmed.
We rely on CROs and clinical trial sites to
ensure our clinical trials are conducted properly and on time. While we will have agreements governing their activities, we will
have limited influence over their actual day-to-day performance. Nevertheless, we will be responsible for ensuring that each of
our clinical trials is conducted in accordance with the applicable protocol, and legal, regulatory and scientific standards and
recognize that our reliance on the CROs does not relieve us of our regulatory responsibilities.
We and our CROs are required to comply with
the FDA’s GCPs for conducting, recording and reporting the results of clinical trials to assure that the data and reported
results are credible and accurate and that the rights, integrity and confidentiality of clinical trial participants are protected.
The FDA and comparable foreign regulatory authorities enforce these GCPs through periodic inspections of trial sponsors, principal
investigators and clinical trial sites. If we or our CROs fail to comply with applicable GCPs, the clinical data generated in our
future clinical trials may be deemed unreliable and the FDA, the EMA, or other foreign regulatory authorities may require us to
perform additional clinical trials before approving any marketing applications. In addition, we are required to report certain
financial interests of our third-party investigators if these relationships provide for a financial interest in the outcome of
the study because of the way the payment was arranged (e.g., a royalty) or because the investigator has a proprietary interest
in the product (e.g., a patent) or because the investigator has an equity interest in the sponsor of the covered study exceeding
certain financial thresholds. The FDA or comparable foreign regulatory authorities may question the integrity of the data from
those clinical trials conducted by principal investigators who previously served or currently serve as scientific advisors or consultants
to us from time to time and receive cash compensation in connection with such services.’
Upon inspection, the FDA may determine that
our clinical trials did not comply with GCPs. In addition, our future clinical trials will require a sufficient number of test
subjects to evaluate the safety and efficacy of vonapanitase or any additional product candidates. Accordingly, if our CROs fail
to comply with these regulations or fail to recruit a sufficient number of patients, we may be required to repeat such clinical
trials, which would delay the regulatory approval process.
Our CROs are not our employees, and we are therefore
unable to monitor on a day-to-day basis whether or not they devote sufficient time and resources to our clinical and preclinical
programs. These CROs may also have relationships with other commercial entities, including our competitors, for whom they may also
be conducting clinical trials or other product development activities that could harm our competitive position. If our CROs do
not successfully carry out their contractual duties or obligations, fail to meet expected deadlines, or if the quality or accuracy
of the clinical data they obtain is compromised due to the failure to adhere to our clinical protocols or regulatory requirements,
or for any other reasons, our clinical trials may be extended, delayed or terminated, and we may not be able to obtain regulatory
approval for, or successfully commercialize, vonapanitase or any additional product candidates. If any such event were to occur,
we may be subject to regulatory enforcement actions, our financial results and the commercial prospects for vonapanitase or any
additional product candidates would be harmed, our costs could increase, and our ability to generate revenues could be delayed.
If any of our relationships with these third-party
CROs terminates, we may not be able to enter into arrangements with alternate CROs or to do so on commercially reasonable terms.
Further, switching or adding additional CROs involves additional costs and requires management time and focus. In addition, a transition
period may be required when a new CRO commences work. As a result, delays may occur, which could materially impact our ability
to meet our desired clinical development timelines. Though we carefully manage our relationships with our CROs, there can be no
assurance that we will not encounter challenges or delays in the future or that these delays or challenges will not have a material
adverse impact on our business, financial condition and prospects.
We also rely on other third parties to store
and distribute our products for the clinical trials that we conduct. Any performance failure on the part of our distributors could
delay clinical development or marketing approval of vonapanitase or any additional product candidates or commercialization of our
product, if approved, producing additional losses and depriving us of potential product revenue.
We may seek to form partnerships in the future with respect
to vonapanitase or any additional product candidates, and we may not realize the benefits of such partnerships.
We may form partnerships, create joint ventures
or collaborations or enter into licensing arrangements with third parties for the development and commercialization of vonapanitase
or any additional product candidates. We face significant competition in seeking appropriate strategic partners and the negotiation
process is time-consuming and complex. Any delays in entering into new strategic partnership agreements related to our product
candidates could delay the development and commercialization of our product candidates and reduce their competitiveness even if
they reach the market. Moreover, we may not be successful in our efforts to establish a strategic partnership or other collaborative
arrangement for any additional product candidates. For example, potential partners may consider that our research and development
pipeline is insufficiently developed to justify a collaborative effort, or that vonapanitase or any additional product candidates
and programs do not have the requisite commercial or clinical potential in the target population. Even if we are successful in
establishing such a strategic partnership or collaboration, we cannot be certain that, following such a strategic transaction or
license, we will be able to progress the development and commercialization of the applicable product candidates as envisioned,
or that we will achieve the revenues that would justify such transaction.
Risks Related to Our Intellectual Property
If our efforts to protect our intellectual property related
to vonapanitase or any additional product candidates are not adequate, we may not be able to compete effectively in our market.
We rely upon a combination of patents, patent
applications, know-how and confidentiality agreements to protect the intellectual property related to our only product candidate,
vonapanitase, and will use a similar strategy to protect any additional product candidates. The patent position of biotechnology
companies is generally uncertain because it involves complex legal and factual considerations. The standards applied by the United
States Patent and Trademark Office, or USPTO, and foreign patent offices in granting patents are not always applied uniformly or
predictably. For example, there is no uniform worldwide policy regarding patentable subject matter or the scope of claims allowable
in biotechnology patents. The patent applications that we own may fail to result in issued patents with claims that cover vonapanitase
or any additional product candidates in the United States or in other countries. There is no assurance that all potentially relevant
prior art relating to our patents and patent applications has been found, and prior art that is not before the patent examiners,
as well as prior art that is before the patent examiners, could be used by a third party to invalidate a patent or could be relied
on to prevent a patent from issuing from a pending patent application. Even if patents do successfully issue and even if these
patents cover vonapanitase or any additional product candidates, third parties may challenge their validity, enforceability or
scope, which may result in our patents being narrowed or invalidated.
Furthermore, even if they are unchallenged,
our patents and patent applications may not adequately provide exclusivity for vonapanitase or any additional product candidates,
prevent others from designing around our patents with similar products that are outside the scope of our patents, or prevent others
from operating in jurisdictions in which we did not pursue patent protection. Any of these outcomes could impair our ability to
prevent competition from third parties, which may have an adverse impact on our business.
If patent applications we hold with respect
to vonapanitase or any additional product candidates fail to issue, if their breadth or strength of protection is threatened, or
if they fail to provide meaningful exclusivity for vonapanitase or any additional product candidates, it could dissuade companies
from collaborating with us. As of March 31, 2017 we own 33 issued patents and own 25 pending patent applications, most of which
cover aspects of vonapanitase or its use. We cannot offer any assurances about which, if any, of the pending patent applications
will issue as patents, the breadth of any such patents or any of our currently issued patents, or whether any issued patents will
be challenged by third parties or will be found invalid and unenforceable if challenged. Any successful challenge to these patent
applications, or patents that may issue from them, or to currently issued patents owned by us, could deprive us of rights necessary
for the successful commercialization of vonapanitase or any other product candidate that we may develop. Since patent applications
in the United States and most other countries are confidential for a period of time after filing, and some remain so until issued,
we cannot be certain that we were the first to file a patent application relating to any particular aspect of a product candidate.
Furthermore, if third parties have filed such patent applications, an interference proceeding in the United States can be initiated
by these third parties, or by the USPTO itself, to determine who was the first to invent any of the subject matter covered by the
patent claims of our patents and patent applications.
In the United States, for patent applications
filed prior to March 16, 2013, assuming the other requirements for patentability are met, the first to invent is entitled to the
patent, while outside the United States, the first to file a patent application is entitled to the patent. Our currently pending
utility patent applications are examined under the system in place before March 16, 2013. Third parties are allowed to submit prior
art prior to the issuance of a patent by the USPTO, and may become involved in reexamination,
inter partes
review or interference
proceedings challenging our patent rights. An adverse determination in any such submission, proceeding or litigation could reduce
the scope of, or invalidate, our patent rights, which could adversely affect our competitive position with respect to third parties.
In addition, patents have a limited lifespan.
In most countries, the statutory term of a patent is 20 years from the earliest domestic priority date claimed. In the United States,
for applications filed after June 7, 1995, the statutory term of a patent is 20 years from earliest non-provisional priority date
claimed. Various extensions of patent protection may be available in particular countries; however, in all circumstances, the life
of a patent, and the protection it affords, has a limited term. If we encounter delays in obtaining regulatory approvals, the period
of time during which we could market a product under patent protection could be reduced. We expect to seek extensions of patent
protection where these are available in any countries where we are prosecuting patents. Such possible extensions include those
permitted under the Drug Price Competition and Patent Term Restoration Act of 1984 in the United States, which permits up to five
years’ extension of patent protection and no more than fourteen years following product approval for a single patent that
covers an FDA-approved drug or biologic that contains an active ingredient or salt or ester of the active ingredient that has not
previously been marketed. The scope of protection available during an extension of a patent claiming a product is limited to the
approved product itself for approved uses, and the scope of protection available during an extension of a patent claiming a method
of using a product is limited to the uses claimed in the patent and approved for the product. The actual length of the extension
is calculated by adding one half of the time between the IND effective date and a company's initial submission of a marketing application,
plus the entire time between the submission of the marketing application and the FDA's approval of the application. However, the
applicable authorities, including the FDA and the USPTO in the United States, and any equivalent regulatory authority in other
countries, may not agree with our assessment of whether such extensions are available, and may refuse to grant extensions to our
patents, or may grant more limited extensions than we request. If this occurs, our competitors may be able to take advantage of
our investment in development and clinical trials by referencing our clinical and preclinical data, and then may be able to launch
their product earlier than might otherwise be the case.
Any loss of, or failure to obtain, patent protection
could have a material adverse impact on our business. We may be unable to prevent competitors from entering the market with a product
that is similar to or the same as our products.
Confidentiality agreements with employees and third parties
may not prevent unauthorized disclosure of proprietary information.
We seek to protect our proprietary technology
and processes, in part, by entering into confidentiality agreements with our employees, consultants, scientific advisors and contractors.
We also seek to preserve the integrity and confidentiality of our data and know-how by maintaining physical security of our premises
and physical and electronic security of our information technology systems. Nonetheless, despite these precautions, agreements
or security measures may be breached, and we may not have adequate remedies for any breach. In addition, our know-how may otherwise
become known or be independently discovered by competitors. To the extent that our consultants, contractors or collaborators use
intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how
and inventions.
Enforcing a claim that a third party illegally
obtained and is using any of our know-how is expensive and time consuming, and the outcome is unpredictable. In addition, courts
outside the United States sometimes are less willing than United States courts to protect know-how. Misappropriation or unauthorized
disclosure of our know-how could impair our competitive position and may have a material adverse effect on our business.
We may become involved in lawsuits to protect or enforce our
intellectual property, which could be expensive, time consuming and unsuccessful, and which may lead to a finding that our patents
are invalid and/or unenforceable.
Competitors may infringe our patents or misappropriate
or otherwise violate our intellectual property rights. To counter infringement or unauthorized use, litigation may be necessary
to enforce or defend our intellectual property rights, to protect our know-how and/or to determine the validity and scope of our
own intellectual property rights. Intellectual property litigation can be expensive and time consuming. Many of our current and
potential competitors have the ability to dedicate substantially greater resources to litigate intellectual property rights than
we can. Accordingly, despite our efforts, we may not be able to prevent third parties from infringing or misappropriating our intellectual
property. Litigation could result in substantial costs and diversion of management resources, which could harm our business and
financial results. In addition, in an infringement proceeding, a court may decide that our patents are invalid or unenforceable,
and may refuse to stop the other party from using the technology at issue, including on the grounds that our patents are invalid
or unenforceable or do not cover the technology in question. An adverse result in any litigation proceeding could put one or more
of our patents at risk of being invalidated, held unenforceable or interpreted narrowly. Furthermore, because of the substantial
amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential
information could be compromised by disclosure during this type of litigation.
Third-party claims of intellectual property infringement or
misappropriation may prevent or delay our development and commercialization efforts.
Our commercial success depends in part on our
ability to develop, manufacture, market and sell vonapanitase or any additional product candidates, and to use proprietary technologies
without infringing the patents and proprietary rights of third parties. There is a substantial amount of litigation and adversarial
proceedings, both within and outside the United States, involving patent and other intellectual property rights in the biotechnology
and pharmaceutical industries, including patent infringement lawsuits, interferences, oppositions, reexamination, and
inter
partes
review proceedings before the USPTO and corresponding foreign patent offices. Third parties own patent rights both within
and outside the United States in the fields in which we are developing and may develop vonapanitase or any additional product candidates.
As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that vonapanitase or
any additional product candidates may be subject to claims of infringement of the patent rights of third parties.
Third parties may assert that we are employing
their proprietary technology without authorization. There may be third-party patents or patent applications with claims that may
cover vonapanitase or any additional product candidates and/or the use, manufacture, sale and/or offer for sale of vonapanitase
or any additional product candidates. We are aware of European Patent No. EP 1 012 307 B1, or the '307 patent, which claims, among
other things, autocatalytically cleavable zymogenic precursor of a serine protease wherein a naturally occurring non-autocatalytic
cleavage site is replaced in the zymogenic precursor by an autocatalytic cleavage site. The '307 patent expires on August 12, 2018.
We currently estimate that the soonest that we will market vonapanitase is after this date.
In some cases, we may have failed to identify
relevant third-party patents or patent applications. For example, applications filed before November 29, 2000, and certain applications
filed after that date that will not be filed outside the United States remain confidential until patents issue. Except for the
preceding exceptions, patent applications in the United States and elsewhere are generally published but, only after a waiting
period of approximately 18 months after the earliest filing. Therefore, patent applications covering vonapanitase or future product
candidates could have been filed by others without our knowledge. Additionally, pending patent applications which have been published
can, subject to certain limitations, be later amended in a manner that could cover vonapanitase or any additional product candidates
and/or the use, manufacture, sale and/or offer for sale of vonapanitase or any additional product candidates.
If any valid and enforceable third-party patents
were held by a court of competent jurisdiction to cover vonapanitase or any additional product candidates and/or their use, manufacture,
sale, and/or offer for sale, the holders of any of these patents may be able to block our ability to develop and commercialize
the applicable product candidate until the patent expired or unless we obtain a license. Licenses may not be available on acceptable
terms, if at all. Even if we were able to obtain a license, the rights may 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.
Some of our early research of recombinant expression
of vonapanitase, but not the corresponding development work, utilized some technology under license from a third party. The third
party may contend that we use the licensed technology for our commercial recombinant expression of vonapanitase. Litigation may
be necessary to defend against such a claim. Even if we are successful in defending against such a claim, litigation could result
in substantial costs and be a distraction to management. If we are not successful in defending against such a claim, in addition
to paying monetary damages, we may have to reconfigure the vonapanitase expression system, which would materially adversely affect
our commercial development efforts.
Parties making claims against us may obtain
injunctive or other equitable relief, which could effectively block our ability to commercialize vonapanitase or any additional
product candidates. We may face a claim of misappropriation if a third party believes that we inappropriately obtained and used
trade secrets of that third party. If we are found to have misappropriated a third party’s trade secrets, we may be prevented
from further using such trade secrets, limiting our ability to develop vonapanitase or any additional product candidates, and we
may be required to pay damages.
Defending against claims of patent infringement
or misappropriation of trade secrets could be costly and time consuming, regardless of the outcome. Thus, even if we were to ultimately
prevail, or to settle at an early stage, any litigation could burden us with substantial unanticipated costs. In addition, litigation
or threatened litigation could result in significant demands on the time and attention of our management team, distracting them
from the pursuit of other company business. In the event of a successful claim of infringement against us, we may have to pay substantial
damages, including treble damages and attorneys’ fees for willful infringement, pay royalties, redesign our infringing products
or obtain one or more licenses from third parties, which may be impossible or require substantial time and monetary expenditure.
During the course of any patent or other intellectual
property litigation, there could be public announcements of the results of hearings, rulings on motions, and other interim proceedings
in the litigation. If securities analysts or investors regard these announcements as negative, the perceived value of our products,
programs, or intellectual property could be diminished. Accordingly, the market price of our Common Stock may decline.
If we are unable to adequately protect our proprietary technology,
or obtain and maintain issued patents which are sufficient to protect our current product candidate, vonapanitase, or any additional
product candidates, others could compete against us more directly, which would have a material adverse impact on our business,
results of operations, financial condition and prospects.
We strive to protect and enhance the proprietary
technologies that we believe are important to our business, including seeking patents intended to cover our products and compositions,
their methods of use and any other inventions that are important to the development of our business. We also rely on know-how to
protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.
Our success will depend significantly on our
ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how
related to our business, defend and enforce our current patents and any future patents that may issue, preserve the confidentiality
of our know-how and operate without infringing the valid and enforceable patents and proprietary rights of third parties. We also
rely on know-how and in-licensing opportunities to develop, strengthen and maintain the proprietary position of vonapanitase or
any additional product candidates.
We cannot provide any assurances that any of
our pending patent applications will mature into issued patents and, if they do, that such patents or our currently issued patents
will include claims with a scope sufficient to protect vonapanitase or any additional product candidates or otherwise provide any
competitive advantage. For example, one of our patents that may provide coverage for vonapanitase only covers particular formulations.
As a result, this patent would not prevent third-party competitors from creating, making and marketing alternative formulations
that fall outside the scope of our patent claims. There can be no assurance that any such alternative formulations will not be
equally effective.
Moreover, other parties have developed technologies
that may be related or competitive to our approach, and may have filed or may file patent applications and may have received or
may receive patents that may overlap or conflict with our patent applications, either by claiming the same methods or formulations
or by claiming subject matter that could dominate our patent position. These third party patent positions may limit or even eliminate
our ability to obtain patent protection for certain inventions.
The patent positions of biotechnology and pharmaceutical
companies, including our patent position, involve complex legal and factual questions, and, therefore, the issuance, scope, validity
and enforceability of any patent claims that we may obtain cannot be predicted with certainty. Patents, if issued, may be challenged,
deemed unenforceable, invalidated, or circumvented. United States patents and patent applications may also be subject to interference
proceedings,
ex parte
reexamination, or
inter partes
review proceedings, and challenges in district court. Patents
may be subjected to opposition, revocation proceedings, or comparable proceedings lodged in various foreign, both national and
regional, patent offices. These proceedings could result in either loss of the patent or denial of the patent application or loss
or reduction in the scope of one or more of the claims of the patent or patent application. In addition, such proceedings may be
costly. Thus, any patents that we may own or exclusively license may not provide any protection against competitors. Furthermore,
an adverse decision in an interference proceeding can result in a third party receiving the patent right sought by us, which in
turn could affect our ability to develop, market or otherwise commercialize vonapanitase or any additional product candidates.
Furthermore, though a patent is presumed valid
and enforceable, its issuance is not conclusive as to its validity or its enforceability and it may not provide us with adequate
proprietary protection or competitive advantages against competitors with similar products. Even if a patent issues and is held
to be valid and enforceable, competitors may be able to design around our patents, such as using pre-existing or newly developed
technology. Other parties may develop and obtain patent protection for more effective technologies, designs or methods. We may
not be able to prevent the unauthorized disclosure or use of our technical knowledge or know-how by consultants, vendors, former
employees and current employees. The laws of some foreign countries do not protect our proprietary rights to the same extent as
the laws of the United States, and we may encounter significant problems in protecting our proprietary rights in these countries.
If these developments were to occur, they could have a material adverse effect on our sales.
In addition, proceedings to enforce or defend
our patents, if and when issued, could put our patents at risk of being invalidated, held unenforceable, or interpreted narrowly.
These proceedings could also provoke third parties to assert claims against us, including that some or all of the claims in one
or more of our patents are invalid or otherwise unenforceable. If any of our patents, if and when issued, covering vonapanitase
or any additional product candidates, are invalidated or found unenforceable, our financial position and results of operations
would be materially and adversely impacted. In addition, if a court found that valid, enforceable patents held by third parties
covered vonapanitase, or any additional product candidates, our financial position and results of operations would also be materially
and adversely impacted.
The degree of future protection for our proprietary
rights is uncertain, and we cannot ensure that:
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any of our patents or pending patent applications, if issued, will include claims having a scope
sufficient to protect vonapanitase or any additional product candidates;
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any of our pending patent applications will issue as patents at all;
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we will be able to successfully commercialize product candidates, if approved, before our relevant
patents expire;
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we were the first to make the inventions covered by each of our patents and pending patent applications;
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we were the first to file patent applications for these inventions;
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others will not develop similar or alternative technologies that do not infringe our patents;
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others will not use pre-existing technology to effectively compete against us;
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any of our patents will be found ultimately to be valid and enforceable;
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any patents issued to us will provide a basis for an exclusive market for our commercially viable
products, will provide us with any competitive advantages or will not be challenged by third parties;
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we will develop additional proprietary technologies or product candidates that are separately patentable;
or
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that our commercial activities or products will not infringe the patents or proprietary rights
of others.
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We rely upon unpatented know-how to maintain
our competitive position, which we seek to protect, in part, by confidentiality agreements with our employees and our collaborators
and consultants. It is possible that technology relevant to our business will be independently developed by a person that is not
a party to such an agreement. Furthermore, if the employees and consultants who are parties to these agreements breach or violate
the terms of these agreements, we may not have adequate remedies for any such breach or violation, and our confidential know-how
could become known to others through such breaches or violations. Further, our know-how could otherwise become known or be independently
discovered by our competitors. Further, the term of confidentiality requirements for current and terminated agreements with some
of our consultants, contract manufacturing or research organizations and other third parties is finite.
We may be subject to claims challenging the inventorship or
ownership of our patents and other intellectual property.
We enter into confidentiality and intellectual
property assignment agreements with our employees, consultants, outside scientific collaborators, sponsored researchers and other
advisors. These agreements generally provide that inventions conceived by the party in the course of rendering services to us will
be our exclusive property. However, these agreements may not be honored and may not effectively assign intellectual property rights
to us. For example, even if we have a consulting agreement in place with an academic advisor pursuant to which the academic advisor
is required to assign any inventions developed in connection with providing services to us, the academic advisor may not have the
right to assign these inventions to us, as it may conflict with his or her obligations to assign all intellectual property to his
or her employing institution.
Litigation may be necessary to defend against
these and other claims challenging inventorship or ownership of inventions. If we are unsuccessful in defending against any of
these claims, in addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership
of, or right to use, valuable intellectual property. Such an outcome could have a material adverse effect on our business. Even
if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management
and other employees.
Obtaining and maintaining our patent protection depends on
compliance with various procedural, document submission, fee payment and other requirements imposed by governmental patent agencies,
and our patent protection could be reduced or eliminated for non-compliance with these requirements.
The USPTO and various foreign governmental patent
agencies require compliance with a number of procedural, documentary, fee payment and other provisions during the patent process.
There are situations in which noncompliance can result in abandonment or lapse of a patent or patent application, resulting in
partial or complete loss of patent rights in the relevant jurisdiction. In such an event, competitors might be able to enter the
market earlier than would otherwise have been the case.
Issued patents covering vonapanitase or covering any additional
product candidates could be found invalid or unenforceable if challenged in court.
If we initiated legal proceedings against a
third party to enforce a patent, if and when issued, covering vonapanitase or any additional product candidate, the defendant could
counterclaim that the patent covering our product candidate is invalid and/or unenforceable. In patent litigation in the United
States, defendant counterclaims alleging invalidity and/or unenforceability are commonplace. Grounds for a validity challenge include
alleged failures to meet any of several statutory requirements, including lack of novelty, obviousness or non-enablement. Grounds
for unenforceability assertions include allegations that someone connected with prosecution of the patent withheld relevant information
from the USPTO, or made a misleading statement, during prosecution. Third parties may also raise similar claims before administrative
bodies in the United States or abroad, even outside the context of litigation. These mechanisms include reexamination and
inter
partes
review in the United States and equivalent proceedings in foreign jurisdictions,
e.g.
, opposition proceedings.
These proceedings could result in revocation or amendment of our patents in such a way that they no longer cover, for example,
vonapanitase or competitive products. The outcome following legal assertions of invalidity and unenforceability is unpredictable.
With respect to validity, for example, we cannot be certain that there is no invalidating prior art, including prior art of which
we and the patent examiner were unaware during prosecution. 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 the applicable product candidate. A
loss of patent protection would have a material adverse impact on our business.
We will not seek to protect our intellectual property rights
in all jurisdictions throughout the world, and we may not be able to adequately enforce our intellectual property rights even in
the jurisdictions where we seek protection.
Filing, prosecuting and defending patents on
product candidates in all countries and jurisdictions throughout the world would be prohibitively expensive, and our intellectual
property rights in some countries outside the United States could be less extensive than those in the United States, assuming that
rights are obtained in the United States. In addition, the laws of some foreign countries do not protect intellectual property
rights to the same extent as federal and state 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, or from selling or importing products made using our
inventions in and into the United States or other jurisdictions.
Competitors may use our technologies in jurisdictions
where we do not pursue and obtain patent protection to develop their own products and further, may export otherwise infringing
products to territories where we have patent protection, but enforcement is not as strong as that in the United States. 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. Even if we pursue and obtain issued patents in particular jurisdictions, our patent claims or other intellectual
property rights may not be effective or sufficient to prevent third parties from so competing.
The laws of some foreign countries do not protect
intellectual property rights to the same extent as the laws of the United States. Many companies have encountered significant problems
in protecting and defending intellectual property rights in certain foreign jurisdictions. The legal systems of some countries,
particularly developing countries, do not favor the enforcement of patents and other intellectual property protection, especially
those relating to biotechnology. This could make it difficult for us to stop the infringement of our patents, if obtained, or the
misappropriation of our other intellectual property rights. For example, many foreign countries have compulsory licensing laws
under which a patent owner must grant licenses to third parties. In addition, many countries limit the enforceability of patents
against third parties, including government agencies or government contractors. In these countries, patents may provide limited
or no benefit. Patent protection must ultimately be sought on a country-by-country basis, which is an expensive and time-consuming
process with uncertain outcomes. Accordingly, we may choose not to seek patent protection in certain countries, and we will not
have the benefit of patent protection in such countries.
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 biopharmaceuticals, 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, could put 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. 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 develop
or license.
Some of our intellectual property may have been discovered
through government funded programs and thus may be subject to federal regulations such as government “march-in” rights,
certain reporting requirements, and a preference for United States industry. Compliance with these regulations may limit our exclusive
rights, subject us to expenditure of resources with respect to reporting requirements, and limit our ability to contract with foreign
manufacturers.
Some of our intellectual property rights may
have been generated through the use of United States government funding and therefore are subject to certain federal regulations.
For example, our patents relating to some therapeutic uses of vonapanitase and associated systems and kits that include a catheter,
which we refer to as the “therapy family,” arose from research funded by the United States government. As a result,
the United States government has certain rights to this intellectual property pursuant to the Bayh-Dole Act of 1980, or Bayh-Dole
Act. These United States government rights in certain inventions developed under a government-funded program include a non-exclusive,
non-transferable, irrevocable worldwide license to use inventions for any governmental purpose. In addition, the United States
government has the right to require us to grant exclusive, partially exclusive, or non-exclusive licenses to any of these inventions
to a third party if it determines that: (i) adequate steps have not been taken to commercialize the invention; (ii) government
action is necessary to meet public health or safety needs; or (iii) government action is necessary to meet requirements for public
use under federal regulations, also referred to as “march-in rights.” The United States government also has the right
to take title to these inventions if we, or the applicable licensor, fail to disclose the invention to the government and fail
to file an application to register the intellectual property within specified time limits. In addition, the United States government
may acquire title to these inventions in any country in which a patent application is not filed within specified time limits. Intellectual
property generated under a government funded program is also subject to certain reporting requirements, compliance with which may
require us or the applicable licensor to expend substantial resources. In addition, the United States government requires that
any products embodying the subject invention or produced through the use of the subject invention be manufactured substantially
in the United States. The manufacturing preference requirement can be waived if the owner of the intellectual property can show
that reasonable but unsuccessful efforts have been made to grant licenses on similar terms to potential licensees that would be
likely to manufacture substantially in the United States or that under the circumstances domestic manufacture is not commercially
feasible. This preference for United States manufacturers may limit our ability to contract with foreign product manufacturers
for products covered by the applicable intellectual property.
We currently do not plan to apply for additional
United States government funding, but if we do, and we discover compounds or drug or biological candidates as a result of such
funding, intellectual property rights to these discoveries may be subject to the applicable provisions of the Bayh-Dole Act.
If we do not obtain additional protection under the Hatch-Waxman
Amendments and similar foreign legislation by extending the patent protection for vonapanitase, our business may be materially
harmed.
Depending upon the timing, duration and specifics
of the first FDA marketing approval of vonapanitase and, if applicable, any additional product candidates, a United States patent
that we own or license may be eligible for limited patent term restoration under the Drug Price Competition and Patent Term Restoration
Act of 1984, referred to as the Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit extension of one patent that covers
an FDA-approved drug or biologic that contains an active ingredient or salt or ester of the active ingredient that has not previously
been marketed for up to five years and no more than fourteen years after product approval for patent term lost during product development
and the FDA regulatory review process. The length of the extension is calculated by adding one half of the time between the IND
effective date and a company's initial submission of a marketing application, plus the entire time between the submission of the
marketing application and the FDA's approval of the application. During this period of extension, the scope of protection is limited
to the approved product for approved uses (for patents claiming a product) and any use claimed by the patent and approved for the
product (for patents claiming a method of using a product).
Although we plan on seeking patent term restoration
for our products, it may not be granted if, for example, we fail to apply within applicable deadlines, fail to apply prior to expiration
of relevant patents or otherwise fail to satisfy applicable requirements. Moreover, the applicable time period or the scope of
patent protection afforded could be less than we request. If we are unable to obtain patent term restoration or the term of any
such patent restoration is less than we request, our competitors may be able to enter the market and compete against us sooner
than we anticipate, and our ability to generate revenues could be materially adversely affected.
Changes in United States patent law could diminish the value
of patents in general, thereby impairing our ability to protect our products.
As is the case with other biotechnology companies,
our success is heavily dependent on intellectual property, particularly patents. Obtaining and enforcing patents in the biotechnology
industry involve both technological and legal complexity, and is therefore costly, time-consuming and inherently uncertain. In
addition, the United States has recently enacted and is currently implementing wide-ranging patent reform legislation, the Leahy-Smith
America Invents Act, or America Invents Act. The America Invents Act includes a number of significant changes to United States
patent law. These include provisions that affect the way patent applications will be prosecuted, provides expanded opportunities
for post-grant administrative review of patents before the USPTO, and may also affect patent litigation. It is not yet clear what,
if any, impact the America Invents Act will have on the operation of our business. However, the America Invents Act and its implementation
could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense
of any patents that may issue from our patent applications, all of which could have a material adverse effect on our business and
financial condition.
In addition, recent United States Supreme Court
rulings have narrowed the scope of patent protection available in certain circumstances and weakened the rights of patent owners
in certain situations. The full impact of these decisions is not yet known. For example, on March 20, 2012 in
Mayo Collaborative
Services v. Prometheus Laboratories, Inc.
, the Court held that several claims drawn to measuring drug metabolite levels from
patient samples and correlating them to drug doses were not patent-eligible subject matter. The decision appears to impact diagnostics
patents that merely apply a law of nature via a series of routine steps and it has created uncertainty around the ability to obtain
patent protection for certain inventions. Additionally, on June 13, 2013 in
Association for Molecular Pathology v. Myriad Genetics,
Inc.,
the Court held that claims to isolated genomic DNA are not patent-eligible, but claims to complementary DNA molecules
are patent-eligible because they are not a natural product. The effect of the decision on patents for other isolated natural products
is uncertain. However, on March 4, 2014, the USPTO issued a memorandum to patent examiners providing guidance for examining claims
that recite laws of nature, natural phenomena or natural products under the
Myriad
and
Prometheus
decisions. This
guidance did not limit the application of
Myriad
to DNA, but, rather, applied the decision to other natural products.
In addition to increasing uncertainty with regard
to our ability to obtain future patents, this combination of events has created uncertainty with respect to the value of patents,
once obtained. Depending on these and other decisions by the United States 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 current or future patents.
We may be subject to damages resulting from claims that we
or our employees have wrongfully used or disclosed alleged trade secrets of their former employers.
Our employees have been previously employed
at other biotechnology or pharmaceutical companies, including our competitors or potential competitors, or at universities or academic
medical centers. We also engage advisors and consultants who are concurrently employed at universities or who perform services
for other entities. Although we are not aware of any claims currently pending against us, we may be subject to claims that we or
our employees, advisors or consultants have inadvertently or otherwise used or disclosed intellectual property, including trade
secrets or other proprietary information, of a former employer or other third party. We may in the future also be subject to claims
that an employee, advisor or consultant performed work for us that conflicts with that person’s obligations to a third party,
such as an employer, and thus, that the third party has an ownership interest in the intellectual property arising out of work
performed for us. Litigation may be necessary to defend against these claims. Even if we are successful in defending against these
claims, litigation could result in substantial costs and be a distraction to management. If we are unsuccessful in defending against
such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel. A loss of
key personnel or their work product could hamper or prevent our ability to commercialize vonapanitase or any additional product
candidates, which would materially adversely affect our commercial development efforts.
Numerous factors may limit any potential competitive advantage
provided by our intellectual property rights.
The degree of future protection afforded by
our intellectual property rights is uncertain because intellectual property rights have limitations, and may not adequately protect
our business, provide a barrier to entry against our competitors or potential competitors, or permit us to maintain our competitive
advantage. Moreover, if a third party has intellectual property rights that cover the practice of our technology, we may not be
able to exercise or extract value from our intellectual property rights fully or at all. The following examples are illustrative:
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we might not have been the first to make the inventions covered by a patent or pending patent application
that we own;
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we might not have been the first to file patent applications covering an invention;
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others may independently develop similar or alternative technologies without infringing our intellectual
property rights;
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third parties may compete with us in jurisdictions where we do not pursue and obtain patent protection;
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pending patent applications that we own may not lead to issued patents;
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patents that we own may not provide us with any competitive advantages, or may be held invalid
or unenforceable;
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third parties may assert an ownership interest in our intellectual property;
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we may not develop or in-license additional proprietary technologies that are patentable; and
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the patents or proprietary rights of others may have an adverse effect on our business.
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Should any of these events occur, they could significantly harm
our business and results of operations.
Risks Related to Our Business and Industry
If we fail to attract and keep senior management and key scientific
personnel, we may be unable to successfully develop our products, conduct our clinical trials and commercialize our product candidates.
Our future growth and success depend on our
ability to recruit, retain, manage and motivate our employees. We are highly dependent on our senior management team, in particular,
Timothy Noyes, our President and Chief Executive Officer, Steven Burke, our Senior Vice President and Chief Medical Officer, George
Eldridge, our Senior Vice President, Chief Financial Officer, Treasurer and Assistant Secretary, Scott Toner, our Senior Vice President
of Marketing, and Daniel Gottlieb, our Vice President, Corporate Development, as well as the other principal members of our management
and scientific teams. Although we have formal employment agreements with our executive officers, these agreements do not prevent
them from terminating their employment with us at any time. The loss of the services of any member of our senior management or
scientific team or the inability to hire or retain experienced management personnel could adversely affect our ability to execute
our business plan and harm our operating results.
Because of the specialized scientific and managerial
nature of our business, we rely heavily on our ability to attract and retain qualified scientific, technical and managerial personnel.
We do not currently carry “key person” insurance on the lives of members of executive management. The competition for
qualified personnel in the pharmaceutical field is intense. Due to this intense competition, we may be unable to continue to attract
and retain qualified personnel necessary for the development of our business or to recruit suitable replacement personnel. In addition,
we rely on consultants and advisors, including scientific and clinical advisors, to assist us in formulating our research and development
and commercialization strategy including, F. Nicholas Franano, our scientific founder. Our consultants and advisors may be employed
by employers other than us and may have commitments under consulting or advisory contracts with other entities that may limit their
availability to us.
We will need to significantly increase the size of our organization,
and we may experience difficulties in managing growth.
We are currently a small company and in order
to commercialize our potential products, we will need to increase our operations and expand our use of our third-party contractors.
We plan to continue to build our compliance, financial and operating infrastructure to ensure the maintenance of a well-managed
company including hiring additional staff within our regulatory and clinical groups as we move into later stages of our Phase 3
development. We intend to recruit an in-house commercial organization in the United States focused on promoting vonapanitase, if
it is approved. We currently do not have a sales and marketing capability and therefore intend to recruit a specialty sales force
of approximately 75-100 representatives in anticipation of vonapanitase's approval. We estimate it will take three to six months
to recruit this specialty sales force. We will need to expand our employment base when we are in the full commercial stages of
our current potential product's life cycle.
Future growth will impose significant added
responsibilities on members of management, including the need to identify, recruit, maintain and integrate additional employees.
In addition, to meet our obligations as a public company, we will need to increase our general and administrative capabilities.
Our management, personnel and systems currently in place may not be adequate to support this future growth. Our future financial
performance and our ability to commercialize our potential products and to compete effectively will depend, in part, on our ability
to manage any future growth effectively. To that end, we must be able to:
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manage our clinical trials and the regulatory process effectively;
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manage the manufacturing of product candidates and potential products for clinical and commercial
use;
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integrate current and additional management, administrative, financial and sales and marketing
personnel;
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develop a marketing and sales infrastructure;
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hire new personnel necessary to effectively commercialize vonapanitase and any additional product
candidates;
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develop our administrative, accounting and management information systems and controls; and
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hire and train additional qualified personnel.
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Product candidates that we may acquire or develop
in the future may be intended for patient populations that are large. In order to continue development and marketing of these product
candidates, if approved, we would need to significantly expand our operations. Our staff, financial resources, systems, procedures
or controls may be inadequate to support our operations and our management may be unable to manage successfully future market opportunities
or our relationships with customers and other third parties.
Our disclosure controls and procedures may not prevent or
detect all errors or acts of fraud.
Upon completion of our Initial Public Offering,
or IPO, we became subject to the periodic reporting requirements of the Securities Exchange Act of 1934, as amended, or the Exchange
Act. Our disclosure controls and procedures are designed to reasonably assure that information required to be disclosed by us in
reports we file or submit under the Exchange Act is accumulated and communicated to management, and recorded, processed, summarized
and reported within the time periods specified in the rules and forms of the SEC. We believe that any disclosure controls and procedures
or internal controls and procedures, no matter how well conceived and operated, can provide only reasonable, not absolute, assurance
that the objectives of the control system are met.
These inherent limitations include the realities
that judgments in decision-making can be faulty, and that breakdowns can occur because of simple error or mistake. Additionally,
controls can be circumvented by the individual acts of some persons, by collusion of two or more people or by an unauthorized override
of the controls. Accordingly, because of the inherent limitations in our control system, misstatements due to error or fraud may
occur and not be detected.
If product liability lawsuits are successfully brought against
us, our insurance may be inadequate and we may incur substantial liability.
We face an inherent risk of product liability
claims as a result of the clinical testing of vonapanitase or any additional product candidates. We will face an even greater risk
if we commercially sell vonapanitase or any additional product candidate that we develop. We maintain primary product liability
insurance and excess product liability insurance that cover our clinical trials, and we plan to maintain insurance against product
liability lawsuits for commercial sale of our potential products. Historically, the potential liability associated with product
liability lawsuits for pharmaceutical products has been unpredictable. Although we believe that our current insurance is a reasonable
estimate of our potential liability and represents a commercially reasonable balancing of the level of coverage as compared to
the cost of the insurance, we may be subject to claims in connection with our clinical trials and, in the future, commercial use
of our potential products, for which our insurance coverage may not be adequate, and the cost of any product liability litigation
or other proceeding, even if resolved in our favor, could be substantial.
For example, we may be sued if any product we
develop allegedly causes injury or is found to be otherwise unsuitable during clinical 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 or a breach of warranties. Large judgments have been awarded in class
action lawsuits based on drugs or biologics that had unanticipated adverse effects. 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 vonapanitase or any additional product candidates. Regardless of the merits or eventual
outcome, liability claims may result in:
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reduced resources of our management to pursue our business strategy;
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decreased demand for our product candidates or products that we may develop;
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injury to our reputation and significant negative media attention;
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withdrawal of clinical trial participants;
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termination of clinical trial sites or entire trial programs;
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initiation of investigations by regulators;
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product recalls, withdrawals or labeling, marketing or promotional restrictions;
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significant costs to defend resulting litigation;
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diversion of management and scientific resources from our business operations;
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substantial monetary awards to trial participants or patients;
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the inability to commercialize any products that we may develop.
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We currently have a $5 million product liability
insurance coverage in connection with our clinical trials and we will need to increase our insurance coverage if and when we begin
selling vonapanitase or any additional product candidates if and when they receive marketing approval. However, the product liability
insurance we will need to obtain in connection with the commercial sales of vonapanitase or any additional product candidates if
and when they receive regulatory approval may be unavailable in meaningful amounts or at a reasonable cost. In addition, insurance
coverage is becoming increasingly expensive. If we are unable to obtain or maintain sufficient insurance coverage at an acceptable
cost or to otherwise protect against potential product liability claims, it could prevent or inhibit the development and commercial
production and sale of vonapanitase or any additional product candidates if and when they obtain regulatory approval, which could
materially adversely affect our business, financial condition, results of operations, cash flows and prospects.
Additionally, we do not carry insurance for
all categories of risk that our business may encounter. Some of the policies we currently maintain include general liability, employment
practices liability, property, auto, workers’ compensation, products liability and directors’ and officers’ insurance.
We do not know, however, if we will be able to maintain insurance with adequate levels of coverage. Any significant uninsured liability
may require us to pay substantial amounts, which would materially adversely affect our financial position, cash flows and results
of operations.
If we engage in acquisitions in the future, we will incur
a variety of costs and we may never realize the anticipated benefits of such acquisitions.
We may attempt to acquire businesses, technologies,
services, products or product candidates in the future that we believe are a strategic fit with our business. We have no present
agreement regarding any material acquisitions. If we do undertake any acquisitions, however, the process of integrating an acquired
business, technology, service, products or product candidates into our business may result in unforeseen operating difficulties
and expenditures, including diversion of resources and management’s attention from our core business. In addition, we may
fail to retain key executives and employees of the companies we acquire, which may reduce the value of the acquisition or give
rise to additional integration costs. Future acquisitions could result in additional issuances of equity securities that would
dilute the ownership of existing stockholders. Future acquisitions could also result in the incurrence of debt, actual or contingent
liabilities or the amortization of expenses related to other intangible assets, any of which could adversely affect our operating
results. In addition, we may fail to realize the anticipated benefits of any acquisition.
We currently have our API produced for us by a contract manufacturer
exclusively in one manufacturing facility and if this or any future facility, any facility we use for storage of the finished product
or our equipment were damaged or destroyed, our ability to continue to operate our business would be materially harmed.
Our executive offices are located in Waltham,
Massachusetts, and our API is manufactured at Lonza’s facility located in Visp, Switzerland. We expect that Lonza plans to
utilize this facility in the future to support commercial production if our product candidate is approved. We have manufactured
our entire finished product for the ongoing Phase 3 clinical trial of vonapanitase and currently store the finished product in
only one location. Extended delays in our Phase 3 clinical trial causing us to need to manufacture new clinical supply would cause
a significant disruption in our operations and cause us to incur unexpected costs to manufacture new finished product. We are vulnerable
to natural disasters, such as severe storms and other events that could disrupt our operations. We do not carry insurance for natural
disasters and we may not carry sufficient business interruption insurance to compensate us for losses that may occur. If the current
manufacturing facility or any future facility, stored product or equipment were damaged or destroyed, or if we experience a significant
disruption in our operations for any reason, our ability to continue to operate our business would be materially harmed.
If supply is interrupted, there could be a significant
disruption in our clinical development and commercial supply. If the supply is interrupted after approval of the BLA, an alternative
manufacturer would need to be qualified through a BLA supplement which could result in further delay. The regulatory agencies may
also require additional studies if a new manufacturer is relied upon for commercial production. Switching manufacturers may involve
substantial costs and would likely result in a delay in our desired clinical and commercial timelines.
These factors could cause the delay of clinical
trials, regulatory submissions, required approvals or commercialization of vonapanitase or any additional product candidates, cause
us to incur higher costs and prevent us from commercializing our products successfully. Furthermore, if our suppliers fail to meet
contractual requirements, and we are unable to secure one or more replacement suppliers capable of production at a substantially
equivalent cost, our clinical trials may be delayed or we could lose potential revenue.
Our business and operations would suffer in the event of system
failures or security breaches.
Despite the implementation of security measures,
our internal computer systems, and those of our CROs and other third parties on which we rely, are vulnerable to damage from computer
viruses, unauthorized access, cyber attacks, natural disasters, terrorism, war and telecommunication and electrical failures. If
issues were to arise and cause interruptions in our operations, it could result in a material disruption of our drug and biologic
development programs. For example, the loss of clinical trial data from completed or 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 were to result 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 vonapanitase or any additional
product candidates could be delayed. We may also be vulnerable to cyber attacks by hackers, or other malfeasance. This type of
breach of our cybersecurity may compromise our confidential information and/or our financial information and detrimentally impact
our business or result in legal proceedings.
Our employees may engage in misconduct or other improper activities,
including noncompliance with regulatory standards and requirements and insider trading, which could significantly harm our business.
We are exposed to the risk of employee fraud
or other misconduct. Misconduct by employees could include intentional failures to comply with the regulations of the FDA and foreign
regulators, provide accurate information to the FDA and foreign regulators, comply with healthcare fraud and abuse laws and regulations
in the United States and abroad, and report financial information or data accurately or disclose unauthorized activities to us.
In particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations
intended to prevent fraud, misconduct, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict
or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive programs and other
business arrangements. Employee misconduct could 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 a Code of Business Conduct and Ethics,
but it is not always possible to identify and deter employee misconduct, 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 comply with these laws or regulations. If any actions are instituted against
us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on
our business, including the imposition of significant fines or other sanctions.
We have broad discretion in our use of our cash and cash equivalents
and may not use them effectively.
Our management has broad discretion to use our
cash and cash equivalents to fund our operations and could spend these funds in ways that do not improve our results of operations
or enhance the value of our Common Stock. The failure of our management to apply these funds effectively could result in financial
losses that could have a material adverse effect on our business, cause the price of our Common Stock to decline and delay the
development of our product candidates. Pending their use to fund our operations, we may invest our cash and cash equivalents in
a manner that does not produce income or that loses value.
Recent federal legislation may increase the difficulty and
cost for us to commercialize vonapanitase and may affect the prices we may obtain, and impair our ability to profitably sell vonapanitase,
if approved.
In the United States and some foreign jurisdictions,
there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could
prevent or delay marketing approval for vonapanitase, restrict or regulate post-approval activities and affect our ability to profitably
sell vonapanitase, if approved. Legislative and regulatory proposals have been made to expand post-approval requirements and restrict
sales and promotional activities for pharmaceutical products. We do not know whether additional legislative changes will be enacted,
or whether the FDA regulations, targets or interpretations will be changed, or what the impact of such changes on the marketing
approvals of vonapanitase, if any, may be. In addition, increased scrutiny by the United States Congress of the FDA’s approval
process may significantly delay or prevent marketing approval, as well as subject us to more stringent product labeling and post-marketing
testing and other requirements.
In the United States, the pharmaceutical industry
has been significantly affected by legislative initiatives. For example, the Medicare Prescription Drug, Improvement, and Modernization
Act of 2003, or the MMA, changed the way Medicare covers and pays for pharmaceutical products. The legislation expanded Medicare
coverage for drug and biologic purchases by the elderly and introduced a new reimbursement methodology based on average sales prices
for drugs and biologics. Cost reduction initiatives and other provisions of this legislation could decrease the coverage of, or
the reimbursement rate that we receive for, vonapanitase, if approved, and could seriously harm our business. While the MMA applies
only to reimbursement of drugs and biologics under the Medicare program, private payors often follow Medicare coverage policy and
payment limitations in setting their own reimbursement rates, and any reduction in reimbursement that results from the MMA may
result in a similar reduction in payments from non-governmental payors.
In March 2010, President Obama signed the Patient
Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act of 2010 or, collectively,
the ACA, which substantially changes the way healthcare will be financed by both governmental and private insurers, and significantly
impacts the pharmaceutical industry. Among the provisions of the ACA of importance to our business, including, without limitation,
our ability to commercialize, and the prices we may obtain for, vonapanitase, if approved for sale, are the following:
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an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription
drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs;
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increases in the statutory minimum rebates a manufacturer must pay as a condition to having a drug
or biologic available for coverage under the Medicaid program;
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expansion of healthcare fraud and abuse laws, including the federal civil False Claims Act and
the federal Anti-Kickback Statute, and the addition of new government investigative powers and enhanced penalties for non-compliance;
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extension of a manufacturer’s Medicaid rebate liability to covered drugs and biologics dispensed
to individuals who are enrolled in Medicaid managed care organizations;
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expansion of eligibility criteria for Medicaid programs by, among other things, allowing states
to offer Medicaid coverage to additional individuals and by adding new eligibility categories for certain individuals with income
at or below 133% of the federal poverty level beginning in 2014, thereby potentially increasing a manufacturer’s Medicaid
rebate liability;
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expansion of the entities eligible for discounts under the Public Health Service pharmaceutical
pricing program;
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new requirements under the federal Open Payments program and its implementing regulations;
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a new requirement to annually report drug and biologic samples that manufacturers and distributors
provide to physicians;
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a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct
comparative clinical effectiveness research, along with funding for such research; and
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a special Medicare Part B payment rate for biosimilars that favors them over the reference biological
product.
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In addition, other legislative changes have
been proposed and adopted since the ACA was enacted. These changes include aggregate reductions to Medicare payments to providers
of up to 2% per fiscal year, which went into effect in April 2013. In January 2013 the American Taxpayer Relief Act of 2012 was
signed into law, which, among other things, reduced Medicare payments to several types of providers and increased the statute of
limitations period for the government to recover overpayments to providers from three to five years. The full impact on our business
of the ACA and other new laws is uncertain but may result in additional reductions in Medicare and other healthcare funding. Nor
is it clear whether other legislative changes will be adopted, if any, or how such changes would affect the demand for vonapanitase,
if approved.
Governments outside the United States tend to impose strict
price controls, which may adversely affect our revenues, if any.
In international markets, reimbursement and
health care payment systems vary significantly by country, and many countries have instituted price ceilings on specific products
and therapies. In some countries, particularly the countries of the European Union, the pricing of prescription pharmaceuticals
is subject to governmental control. In these countries, pricing negotiations with governmental authorities can take considerable
time after the receipt of marketing approval for a product. To obtain coverage and reimbursement or pricing approval in some countries,
we may be required to conduct a clinical trial that compares the cost-effectiveness of our product candidate to other available
therapies. There can be no assurance that our products will be considered cost-effective by third-party payors, that an adequate
level of reimbursement will be available or that the third-party payors’ reimbursement policies will not adversely affect
our ability to sell our products profitably. If reimbursement of our products is unavailable or limited in scope or amount, or
if pricing is set at unsatisfactory levels, our business could be harmed, possibly materially.
Risks Related to Our Common Stock
We are an “emerging growth company” and as a result
of the reduced disclosure and governance requirements applicable to emerging growth companies, our Common Stock may be less attractive
to investors.
We are an “emerging growth company,”
or EGC, as defined in the JOBS Act, and we intend to take advantage of certain exemptions from various reporting requirements that
are applicable to other public companies that are not EGCs, including: not being required to comply with the auditor attestation
requirements of Section 404 of the Sarbanes-Oxley Act, reduced disclosure obligations regarding executive compensation in our periodic
reports and proxy statements, and exemptions from the requirements of holding a nonbinding advisory vote on executive compensation
and stockholder approval of any golden parachute payments not previously approved.
We may take advantage of these reporting exemptions
until we are no longer an EGC. We will remain an EGC until the earlier of (1) the last day of the fiscal year (a) following the
fifth anniversary of the completion of our IPO, (b) in which we have total annual gross revenue of at least $1 billion, or (c)
in which we are deemed to be a large accelerated filer, which means the market value of our Common Stock that is held by non-affiliates
exceeds $700 million as of the prior June 30th, and (2) the date on which we have issued more than $1 billion in non-convertible
debt during the prior three-year period.
We cannot predict whether investors will find
our Common Stock less attractive if we rely on these exemptions. If some investors find our Common Stock less attractive as a result,
there may be a less active trading market for our Common Stock and our stock price may be more volatile. In addition, the JOBS
Act provides that an EGC can take advantage of an extended transition period for complying with new or revised accounting standards.
This allows an EGC to delay the adoption of these accounting standards until they would otherwise apply to private companies. We
have irrevocably elected not to avail ourselves of this exemption and, therefore, we will be subject to the same new or revised
accounting standards as other public companies that are not EGCs.
Even after we no longer qualify as an EGC, we
may still qualify as a “smaller reporting company” which would allow us to take advantage of many of the same exemptions
from disclosure requirements, including not being required to comply with the auditor attestation requirements of Section 404 of
the Sarbanes-Oxley Act and reduced disclosure obligations regarding executive compensation in our periodic reports and proxy statements.
We cannot predict if investors will find our Common Stock less attractive because we will rely on these exemptions. If some investors
find our Common Stock less attractive as a result, there may be a less active trading market for our Common Stock and our stock
price may be more volatile.
The market price for our Common Stock may be volatile, which
could contribute to the loss of your investment.
Fluctuations in the price of our Common Stock
could contribute to the loss of all or part of your investment. Prior to our IPO, there was no public market for our Common Stock.
We are now listed on NASDAQ, but we cannot predict the extent to which investor interest in our Company will lead to the development
of or sustain an active trading market on NASDAQ or otherwise or how liquid that market might become. If an active trading market
for our Common Stock does not develop or is not sustained, the market price and liquidity of our Common Stock will be materially
and adversely affected and it may be difficult for stockholders to sell their shares of Common Stock at prices that are attractive
to them, or at all. Further, an inactive market may also impair our ability to raise capital by selling shares of our Common Stock.
If an active market for our Common Stock develops
and continues, the trading price of our Common Stock is likely to be highly volatile and could be subject to wide fluctuations
in response to various factors, some of which are beyond our control. Any of the factors listed below could have a material adverse
effect the price of our Common Stock and stockholders may also be unable to sell their shares of Common Stock at prices that are
attractive to them due to fluctuations in the market price of our Common Stock. In such circumstances the trading price of our
Common Stock may not recover and may experience a further decline.
Factors affecting the trading price of our Common Stock
may include:
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our failure to develop and commercialize vonapanitase or any additional product candidates;
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actual or anticipated fluctuations in our quarterly financial results or the quarterly financial
results of companies perceived to be similar to us;
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changes in the market’s expectations about our operating results;
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adverse results or delays in preclinical studies or clinical trials;
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our decision to initiate a clinical trial, not to initiate a clinical trial or to terminate an
existing clinical trial;
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adverse regulatory decisions, including failure to receive regulatory approval for vonapanitase
or any additional product candidates;
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success of competitive products;
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adverse developments concerning our collaborations and our manufacturers;
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inability to obtain adequate product supply for any product candidate for clinical trials or commercial
sale or inability to do so at acceptable prices;
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the termination of a collaboration or the inability to establish additional collaborations;
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unanticipated serious safety concerns related to the use of any of vonapanitase or any additional
product candidates;
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our ability to effectively manage our growth;
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the size and growth, if any, of the targeted market;
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our operating results failing to meet the expectation of securities analysts or investors in a
particular period or failure of securities analysts to publish reports about us or our business;
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changes in financial estimates and recommendations by securities analysts concerning our company,
our market opportunity, or the biotechnology and pharmaceutical industries in general;
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operating and stock price performance of other companies that investors deem comparable to us;
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overall performance of the equity markets;
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announcements by us or our competitors of acquisitions, new product candidates or programs, significant
contracts, commercial relationships or capital commitments;
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our ability to successfully market vonapanitase or any additional product candidates;
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changes in laws and regulations affecting our business, including but not limited to clinical trial
requirements for approvals;
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disputes or other developments relating to proprietary rights, including patents, litigation matters
and our ability to obtain patent protection for vonapanitase or any additional product candidates;
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commencement of, or involvement in, litigation involving our company, our general industry, or
both;
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changes in our capital structure, such as future issuances of securities or the incurrence of additional
debt;
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the volume of shares of our Common Stock available for public sale;
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additions or departures of key scientific or management personnel;
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any major change in our board or management;
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changes in accounting practices;
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ineffectiveness of our internal control over financial reporting;
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sales of substantial amounts of Common Stock by our directors, executive officers or significant
stockholders or the perception that such sales could occur; and
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general economic and political conditions such as recessions, interest rates, fuel prices, international
currency fluctuations and acts of war or terrorism.
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Broad market and industry factors may materially
harm the market price of our Common Stock irrespective of our operating performance. The stock market in general, and NASDAQ and
the market for biotechnology companies in particular, have experienced extreme price and volume fluctuations that have often been
unrelated or disproportionate to the operating performance of the particular companies affected. The trading prices and valuations
of these stocks, and of ours, may not be predictable. A loss of investor confidence in the market for technology or software stocks
or the stocks of other companies which investors perceive to be similar to us, the opportunities in the digital simulation market
or the stock market in general, could depress our stock price regardless of our business, prospects, financial conditions or results
of operations.
Actual or potential sales of our Common Stock by our employees,
including our executive officers, pursuant to pre-arranged stock trading plans could cause our stock price to fall or prevent it
from increasing for numerous reasons, and actual or potential sales by such persons could be viewed negatively by other investors.
In accordance with the guidelines specified
under Rule 10b5-1 of the Exchange Act and our policies regarding stock transactions, a number of our employees, including executive
officers, have adopted and may continue to adopt stock trading plans pursuant to which they have arranged to sell shares of our
Common Stock from time to time in the future. Generally, sales under such plans by our executive officers and directors require
public filings. Actual or potential sales of our Common Stock by such persons could cause the price of our Common Stock to fall
or prevent it from increasing for numerous reasons. For example, a substantial number of shares of our Common Stock becoming available
(or being perceived to become available) for sale in the public market could cause the market price of our Common Stock to fall
or prevent it from increasing. Also, actual or potential sales by such persons could be viewed negatively by other investors.
The issuance of additional sales of our Common Stock, or the
perception that such issuances may occur, including through our “At-The-Market” offering, could cause the market price
of our Common Stock to fall
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We have entered into a Sales Agreement with
Cowen and Company, LLC, or Cowen, for the offer and sale of up to $40 million in aggregate amount of our Common Stock from
time to time through Cowen, as our sales agent, pursuant to a Registration Statement on Form S-3 which became effective on
January 12, 2016. We filed a prospectus supplement on March 16, 2017 because we are currently subject to General Instruction I.B.6
of Form S-3, which limits the amounts that we may sell under the Registration Statement. Cowen is not required to sell any specific
number or dollar amount of shares of our Common Stock but will use its reasonable efforts, as our agent and subject to the terms
of the Sales Agreement, to sell that number of shares upon our request. Sales of the shares, if any, may be made by any means permitted
by law and deemed to be an “at-the-market” offering as defined in Rule 415 of the Securities Act of 1933, as amended,
or the Securities Act, and will generally be made by means of brokers' transactions on the NASDAQ Global Market or otherwise at
market prices prevailing at the time of sale, or as otherwise agreed with Cowen.
We may terminate the Sales Agreement at any
time or it will terminate once proceeds of $40 million have been raised. For the three months ended March 31, 2017, we sold
93,512 shares of common stock under our At-The-Market, or ATM, program for aggregate gross proceeds of $0.2 million. Whether we
choose to affect future sales under our ATM program will depend upon a variety of factors, including, among others, market conditions
and the trading price of our Common Stock relative to other sources of capital. The issuance from time to time of these new shares
of Common Stock through our ATM program or in any other equity offering, or the perception that such sales may occur, could have
the effect of depressing the market price of our Common Stock.
Our issuance of Common Stock under our “At-The-Market”
offering program may be dilutive, and there may be future dilution of our Common Stock.
After giving effect to the issuance of Common
Stock under our ATM offering program and the receipt of the expected net proceeds and the use of those proceeds, there may be a
dilutive effect on our estimated earnings per share and funds from operations per share in years during which an offering is ongoing.
The actual amount of potential dilution cannot be determined at this time and will be based on numerous factors. Additionally,
we are not restricted by our organizational documents, contractual arrangements or otherwise from issuing additional Common Stock
or preferred stock, including any securities that are convertible into or exchangeable or exercisable for, or that represent the
right to receive, Common Stock or preferred stock or any substantially similar securities in the future. The market price of our
Common Stock could decline as a result of issuances of a large number of shares of our Common Stock after this offering or the
perception that such issuances could occur.
Our management will have broad discretion with respect to
the use of the proceeds resulting from the issuance of Common Stock under our “At-The-Market” offering program.
Our management has significant flexibility in
applying the net proceeds we expect to receive from the issuance of Common Stock under our ATM program. We intend to use the net
proceeds from this offering for general corporate purposes, which may include repaying debt. However, because the net proceeds
are not required to be allocated to any specific investment or transaction, investors cannot determine at the time of issuance
the value or propriety of our application of the net proceeds, and investors may not agree with our decisions. In addition, our
use of the net proceeds from the offering may not yield a significant return or any return at all. The failure by our management
to apply these funds effectively could have an adverse effect on our financial condition, results of operations or the trading
price of our Common Stock.
Raising additional funds through debt or equity financing
could be dilutive and may cause the market price of our Common Stock to decline.
Until such time, if ever, as we can generate
substantial product revenues, we expect to finance our cash needs through a combination of equity offerings and debt financings,
and potentially through strategic partnerships with third parties. To the extent that additional capital is raised through the
sale of equity or convertible debt securities, the issuance of those securities could result in substantial dilution for our current
stockholders and the terms may include liquidation or other preferences that adversely affect the rights of our current stockholders.
Furthermore, the issuance of additional securities, whether equity or debt, by us, or the possibility of such issuance, may cause
the market price of our Common Stock to decline and existing stockholders may not agree with our financing plans or the terms of
such financings. Moreover, the incurrence of debt financing could result in a substantial portion of our operating cash flow being
dedicated to the payment of principal and interest on such indebtedness and could impose restrictions on our operations, 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. Additional funding may
not be available to us on acceptable terms, or at all.
If securities analysts do not publish research or reports
about our business or if they downgrade our stock, the price of our Common Stock could decline.
The trading market for our Common Stock will
rely in part on the research and reports that industry or financial analysts publish about us, our business, our markets and our
competitors. We do not control these analysts. If securities analysts do not cover our Common Stock, the lack of research coverage
may adversely affect the market price of our Common Stock. Furthermore, if one or more of the analysts who do cover us downgrade
our stock or if those analysts issue other unfavorable commentary about us or our business, our stock price would likely decline.
If one or more of these analysts cease coverage of us or fails to regularly publish reports on us, we could lose visibility in
the market and interest in our stock could decrease, which in turn could cause our stock price or trading volume to decline and
may also impair our ability to expand our business with existing customers and attract new customers.
The concentration of our capital stock ownership with insiders
will likely limit your ability to influence corporate matters.
As of March 31, 2017, our executive officers,
directors, current 5% or greater stockholders, and their respective affiliates together beneficially own or control, in aggregate,
more than 50% of the shares of our outstanding Common Stock. As a result, these executive officers, directors and principal stockholders,
acting together, will have substantial influence over most matters that require approval by our stockholders, including the election
of directors, any merger, consolidation or sale of all or substantially all or of our assets or any other significant corporate
transaction. Corporate action might be taken even if other stockholders oppose such action. These stockholders may delay or prevent
a change of control or otherwise discourage a potential acquirer from attempting to obtain control of our company, even if such
change of control would benefit our other stockholders. This concentration of stock ownership may adversely affect investors’
perception of our corporate governance or delay, prevent or cause a change in control of our company, any of which could adversely
affect the market price of our Common Stock.
Future sales and issuances of our Common Stock or rights to
purchase Common Stock, including pursuant to our equity incentive plans, could result in additional dilution of the percentage
ownership of our stockholders and could cause our stock price to fall.
We have filed a registration statement permitting
shares of Common Stock issued in the future, pursuant to our employee benefit plans, to be freely resold by plan participants in
the public market, subject to applicable lock-up agreements, applicable vesting schedules and, for shares held by directors, executive
officers and other affiliates, volume limitations under Rule 144 for shares. Our 2014 Employee Incentive Plan and 2014 Employee
Stock Purchase Plan also contain a provision for the annual increase of the number of shares reserved for issuance under such plan,
which shares we also intend to register in the future as such annual increase occurs. If the shares we may issue from time to time
under our employee benefit plans are sold, or if it is perceived that they will be sold, by the award recipient in the public market,
the trading price of our Common Stock could decline.
We expect that significant additional capital
will be needed in the future to continue our planned operations, including conducting clinical trials, commercialization efforts,
expanded research and development activities and costs associated with operating a public company. To raise capital, we may sell
Common Stock, convertible securities or other equity securities in one or more transactions at prices and in a manner we determine
from time to time. If we sell Common Stock, convertible securities or other equity securities in more than one transaction, investors
may be materially diluted by subsequent sales. Such sales may also result in material dilution to our existing stockholders, and
new investors could gain rights, preferences and privileges senior to the holders of our Common Stock.
We will incur significant increased costs as a result of operating
as a public company, and our management will be required to devote substantial time to new compliance initiatives.
As a newly public company, we have incurred
and will continue to incur significant legal, accounting and other expenses that we did not incur as a private company. In addition,
the Sarbanes-Oxley Act, and rules of the SEC and those of NASDAQ impose various requirements on public companies including requiring
establishment and maintenance of effective disclosure and financial controls. Our management and other personnel devote a substantial
amount of time to these compliance initiatives. Moreover, these rules and regulations have increased and will continue to increase
our legal and financial compliance costs and will make some activities more time-consuming and costly.
The Sarbanes-Oxley Act requires, among other
things, that we maintain effective internal control over financial reporting and disclosure controls and procedures. In particular,
we must perform system and process evaluation and testing of our internal control over financial reporting to allow management
to report on the effectiveness of our internal control over financial reporting, as required by Section 404 of the Sarbanes-Oxley
Act. In addition, we will be required to have our independent registered public accounting firm attest to the effectiveness of
our internal control over financial reporting the later of our second annual report on Form 10-K or the first annual report on
Form 10-K following the date on which we are no longer an EGC. Our compliance with Section 404 of the Sarbanes-Oxley Act will require
that we incur substantial accounting expense and expend significant management efforts. We currently do not have an internal audit
group, and we will need to hire additional accounting and financial staff with appropriate public company experience and technical
accounting knowledge. If we are not able to comply with the requirements of Section 404 in a timely manner, or if we or our independent
registered public accounting firm identify deficiencies in our internal control over financial reporting that are deemed to be
material weaknesses, the market price of our stock could decline and we could be subject to sanctions or investigations by NASDAQ,
the SEC or other regulatory authorities, which would require additional financial and management resources.
Our ability to successfully implement our business
plan and comply with Section 404 requires us to be able to prepare timely and accurate financial statements. We expect that we
will need to continue to improve existing, and implement new operational and financial systems, procedures and controls to manage
our business effectively. Any delay in the implementation of, or disruption in the transition to, new or enhanced systems, procedures
or controls, may cause our operations to suffer and we may be unable to conclude that our internal control over financial reporting
is effective and to obtain an unqualified report on internal controls from our auditors as required under Section 404 of the Sarbanes-Oxley
Act. This, in turn, could have an adverse impact on trading prices for our Common Stock, and could adversely affect our ability
to access the capital markets.
We do not expect to pay any cash dividends for the foreseeable
future.
You should not rely on an investment in our
Common Stock to provide dividend income. We do not anticipate that we will pay any cash dividends to holders of our Common Stock
in the foreseeable future. Instead, we plan to retain any earnings to maintain and expand our operations. Accordingly, investors
must rely on sales of their Common Stock after price appreciation, which may never occur, as the only way to realize any return
on their investment. As a result, investors seeking cash dividends should not purchase our Common Stock.
Our ability to use our net operating loss carryovers and certain
other tax attributes may be limited.
As described above under “—Risks
Related to Our Financial Condition and Need for Additional Capital,” we have incurred net losses since our inception and
anticipate that we will continue to incur significant losses for the foreseeable future. Under the Internal Revenue Code, as amended
(the “Code”), a corporation is generally allowed a deduction for net operating losses, or NOLs, carried over from a
prior taxable year. Under that provision, we can carry forward our NOLs to offset our future taxable income, if any, until such
NOLs are used or expire. The same is true of other unused tax attributes, such as tax credits.
If a corporation undergoes an “ownership
change,” generally defined as a greater than 50% change (by value) in its equity ownership over a three-year period, Sections
382 and 383 of the Code, limit the corporation’s ability to use carryovers of its pre-change NOLs, credits and certain other
tax attributes to reduce its tax liability for periods after the ownership change. We completed an analysis to determine if there
were changes in ownership for tax years through 2015, as defined by Section 382 of the Internal Revenue Code that would limit our
ability to utilize certain net operating loss and tax credit carryforwards and it was determined there was no change in ownership.
We are in the process of completing an analysis to determine if there were changes in ownership for tax years through 2016, as
defined by Section 382. To the extent the Company undergoes a change in ownership, as defined by Section 382, utilization of our
net operating losses and tax credits carryforwards may become limited. If this were to occur, this could result in increased U.S.
federal income tax liability for us if we generate taxable income in a future period. Limitations on the use of NOLs and other
tax attributes could also increase our state tax liability. The use of our tax attributes will also be limited to the extent that
we do not generate positive taxable income in future tax periods.
We could be subject to securities class action litigation.
In the past, securities class action litigation
has often been brought against a company following a decline in the market price of its securities. This risk is especially relevant
for us because biotechnology companies have experienced significant stock price volatility in recent years. If we face such litigation,
it could result in substantial costs and a diversion of management’s attention and resources, which could harm our business.
Provisions in our amended and restated certificate of incorporation,
our amended and restated bylaws and Delaware law may have anti- takeover effects that could discourage an acquisition of us by
others, even if an acquisition would be beneficial to our stockholders, and may prevent attempts by our stockholders to replace
or remove our current management.
Our amended and restated certificate of incorporation,
amended and restated bylaws and Delaware law contain provisions that may have the effect of delaying or preventing a change in
control of us or changes in our management. Our amended and restated certificate of incorporation and bylaws include provisions
that:
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authorize “blank check” preferred stock, which could be issued by our Board of Directors
without stockholder approval and may contain voting, liquidation, dividend and other rights superior to our Common Stock;
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create a classified Board of Directors whose members serve staggered three-year terms;
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specify that special meetings of our stockholders can be called only by our Board of Directors;
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prohibit stockholder action by written consent;
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establish an advance notice procedure for stockholder approvals to be brought before an annual
meeting of our stockholders, including proposed nominations of persons for election to our Board of Directors;
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provide that our directors may be removed only for cause;
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provide that vacancies on our Board of Directors may be filled only by a majority of directors
then in office, even though less than a quorum;
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specify that no stockholder is permitted to cumulate votes at any election of directors;
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expressly authorize our Board of Directors to modify, alter or repeal our amended and restated
bylaws; and
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require supermajority votes of the holders of our Common Stock to amend specified provisions of
our amended and restated certificate of incorporation and amended and restated bylaws.
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These provisions, alone or together, could delay
or prevent hostile takeovers and changes in control or changes in our management.
In addition, because we are incorporated in
the State of Delaware, we are governed by the provisions of Section 203 of the Delaware General Corporation Law, which limits the
ability of stockholders owning in excess of 15% of our outstanding voting stock to merge or combine with us.
Any provision of our amended and restated certificate
of incorporation or amended and restated bylaws or Delaware law that has the effect of delaying or deterring a change in control
could limit the opportunity for our stockholders to receive a premium for their shares of our Common Stock, and could also affect
the price that some investors are willing to pay for our Common Stock.
Our amended and restated certificate of incorporation
designates the Court of Chancery of the State of Delaware and federal court within the State of Delaware as the exclusive forum
for certain types of actions and proceedings that may be initiated by our stockholders, which could limit our stockholders’
ability to obtain a favorable judicial forum for disputes with us or our directors, officers or employees.
Our amended and restated certificate of incorporation
provides that, subject to limited exceptions, the Court of Chancery of the State of Delaware and federal court within the State
of Delaware will be exclusive forums for (1) any derivative action or proceeding brought on our behalf, (2) any action asserting
a claim of breach of a fiduciary duty owed by any of our directors, officers or other employees to us or our stockholders, (3)
any action asserting a claim against us arising pursuant to any provision of the Delaware General Corporation Law, our amended
and restated certificate of incorporation or our amended and restated bylaws, or (4) any other action asserting a claim against
us that is governed by the internal affairs doctrine. Any person or entity purchasing or otherwise acquiring any interest in shares
of our capital stock shall be deemed to have notice of and to have consented to the provisions of our amended and restated certificate
of incorporation described above. This choice of forum provision may limit a stockholder’s ability to bring a claim in a
judicial forum that it finds favorable for disputes with us or our directors, officers or other employees, which may discourage
such lawsuits against us and our directors, officers and employees. Alternatively, if a court were to find these provisions of
our amended and restated certificate of incorporation inapplicable to, or unenforceable in respect of, one or more of the specified
types of actions or proceedings, we may incur additional costs associated with resolving such matters in other jurisdictions, which
could adversely affect our business and financial condition.