Item 1A. Risk Factors
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This Form 10-K contains forward-looking information based
on our current expectations. Because our business is subject to many risks and our actual results may differ materially from any
forward-looking statements made by or on behalf of us, this section includes a discussion of important factors that could affect
our business, operating results, financial condition and the trading price of our common stock. You should carefully consider
these risk factors, together with all of the other information included in this Form 10-K as well as our other publicly available
filings with the SEC.
Risks Related to Our Financial Position and Need for
Additional Capital
We are a preclinical-stage company with a limited operating
history, and have no products approved for commercial sale.
We are
a preclinical-stage biopharmaceutical company. In August 2022, we completed a business combination of Second Sight Medical Products,
Inc. (Second Sight) and Nano Precision Medical, Inc. (Nano Precision Medical), to form our current company. Following the business
combination, we are focusing primarily on the development of our proprietary NanoPortal technology and the development of miniaturized,
subdermal drug implants capable of the long-term delivery of medicine in patients with chronic diseases with high unmet medical
need. Our pipeline includes our current product candidates NPM-119, NPM-159, NPM-139 and OKV-119, which we have partnered with
Okava Pharmaceuticals, Inc. All of our product candidates are in early-stage development and none of our product candidates have
entered into clinical-stage testing, been approved for marketing, or are being marketed or commercialized.
As
a result, we have no meaningful historical operations upon which to evaluate our business and prospects and we have not yet demonstrated
an ability to successfully initiate and conduct clinical trials or obtain marketing approval for any of our product candidates
or otherwise successfully overcome the risks and uncertainties frequently encountered by companies in the biopharmaceutical industry.
We have not generated any revenues to date, and we continue to incur significant research and development and other expenses.
As a result, we have not been profitable and have incurred operating losses in every reporting period since our inception. For
the years ended 2021 and 2022, we reported net losses of $12.8 million and $13.9 million, respectively, and had an accumulated
deficit of $72.8 million as of December 31, 2022.
For the foreseeable future, we expect to
continue to incur significant and increasing losses as we expand our research and development activities, seek regulatory approvals
for our product candidates and begin to commercialize them if they are approved by the U.S. Food and Drug Administration (the
“FDA”) the European Medicines Agency (the “EMA”) or comparable foreign authorities. Even if one or more
of our product candidates complete their clinical development, achieve marketing approval and are commercialized, we may never
become profitable.
In
addition, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors and risks
frequently experienced biopharmaceutical companies in rapidly evolving fields. If one or more of our product candidates receive
marketing approval, we also may need to transition from a company with a research and development focus to a company capable of
supporting commercial activities. We have not yet demonstrated an ability to successfully overcome such risks and difficulties,
or to make such a transition.
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We
do not anticipate generating revenue from product sales for the foreseeable future and may never be profitable.
The
viability of our business depends on our ability to generate revenue from product sales. Vivani’s current pipeline is focused
on the development of our proprietary NanoPortalTM technology and the development of miniaturized, subdermal drug implants
capable of the long-term delivery of medicine in patients with chronic diseases with high unmet medical need. However, we may
never be able to develop or commercialize marketable products from our current pipeline or achieve profitability. Revenue from
the sale of any product candidate for which regulatory approval is obtained will be dependent, in part, upon the size of the markets
in the territories for which regulatory approval is obtained, the accepted price for the product, the acceptance of the product
by physicians and patients, the ability to obtain reimbursement at any price and whether we own the commercial rights for that
territory. In addition, if the market size for our product candidates is smaller than estimated, the indication or intended use
approved by regulatory authorities is narrower than expected, or the target patient population for treatment is narrowed by competition,
physician choice or treatment guidelines, we may not generate significant revenue from sales of such products, even if approved.
Even if we are able to generate revenue from the sale of any approved products, we may not become profitable. Even if we achieve
profitability in the future, such profitability may not be sustained in subsequent periods.
Our ability to generate revenue and achieve
profitability depends significantly on our ability, either independently or in collaboration with third parties, to achieve several
objectives, including:
● successful submission and acceptance of INDs or comparable applications;
● successful initiation of clinical trials;
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● identifying, assessing, and developing new product candidates;
● protecting our rights in our intellectual property portfolio;
● defending against third-party interference or infringement claims, if any;
● attracting, hiring, and retaining qualified personnel.
We may never be successful in achieving
its objectives and, even if we do, may never generate revenue that is significant or large enough to achieve or maintain profitability.
Any failure to become and remain profitable would decrease the value of our company and could impair our ability to maintain or
further our research and development efforts, raise additional necessary capital, grow our business, and continue our operations.
We will require substantial additional financing to
pursue our business objectives, which may not be available on acceptable terms, or at all. A failure to obtain this necessary
capital when needed could force us to delay, limit, reduce or terminate our product development, commercialization efforts or
other operations.
Developing
pharmaceutical products, including conducting preclinical studies and clinical trials, is a very time-consuming, expensive, and
uncertain process that takes years to complete. Our operations have consumed substantial amounts of cash, and we expect our expenses
to increase in connection with our ongoing activities, particularly as we conduct clinical trials of our product candidates. Even
if one or more of our product candidates is approved for commercial sale, we will incur significant costs associated with sales,
marketing, manufacturing, and distribution activities. Our expenses could increase beyond expectations if required by the FDA,
the European Medicines Agency (EMA) or other regulatory agencies to perform clinical trials or preclinical studies in addition
to those that we currently anticipate. Other unanticipated costs may also arise. Because the design and outcome of our planned
and anticipated clinical trials are highly uncertain, we cannot reasonably estimate the actual amount of resources and funding
that will be necessary to successfully complete the development and commercialization of any product candidate. We are not permitted
to market or promote any product candidate before it receives marketing approval from the regulatory authorities. Accordingly,
we will need to obtain substantial additional funding in order to continue our operations and pursue our business objectives.
There can be no assurance that we will
be able to raise sufficient additional capital on acceptable terms or at all. If such additional financing is not available on
satisfactory terms, or is not available in sufficient amounts, we may be required to delay, limit, or eliminate one or more of
our business objectives, and our competitiveness, and business, financial condition and results of operations may be materially
adversely affected. If we are unable to continue our business, including due to inadequate funding, you could lose your investment.
Vivani’s
future capital requirements will depend on many factors, including, but not limited to:
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● the expenses needed to attract and retain skilled personnel;
● the costs associated with being a public company;
We
may raise capital in the form of equity or debt financing, partnerships, collaborations, licensing, spin-offs or other strategic
transactions. If we raise additional capital by issuing equity securities, the ownership of our existing shareholders may be reduced,
and accordingly these shareholders may experience substantial dilution. We may also issue equity securities that provide for rights,
preferences, and privileges senior to those of its common stock. If we raise funding through debt instruments or facilities, lenders
may require us to pledge some or all of our assets as collateral. We may also be required to observe financial, operational and
other covenants that constrain our business and operations. If we enter into partnerships, collaborations, licensing or other
strategic transactions, we may be required to grant rights to third parties, including rights to develop and market product candidates,
that we would otherwise have retained.
Our ability to utilize
its net operating loss (NOL) carry-forwards and certain other tax attributes may be limited.
Under Section 382 of the Code, 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), the corporation’s ability to use its pre-change NOL carry-forwards and other pre-change tax attributes
to offset its post-change income may be limited. We have not completed a study to assess whether any ownership changes, as defined
by Section 382 of the Code, have occurred. Past, current and future ownership changes may limit our ability to utilize remaining
tax attributes.
As
of December 31, 2022, our parent which comprises the Legacy SSMP business, and our subsidiary, Nano Precision Medical, each
had the following carry-forwards available to offset future taxable income and income taxes (in thousands):
NPM SSMP
Federal R&D tax credit carry-forward, begin expiring in 2026 $ 1,586 $ 20
State R&D carry-forward, begin expiring in 2026 $ 1,973 $ 4,989
Since
Legacy SSMP and NPM file separate tax returns, the carry-forwards of one filer are not available to offset the taxable income or
income taxes of the other filer.
Furthermore, under recently enacted U.S. tax legislation, although the treatment of tax losses
generated in taxable years ending before December 31, 2017, has generally not changed, tax losses generated in taxable years beginning
after December 31, 2017 may only be utilized to offset 80 % of taxable income annually. This change may require us to pay federal
income taxes in future years despite generating a loss for federal income tax purposes in prior years.
Risks Related to Product Development, Clinical Testing
and Commercialization
We
are dependent on the successful development, regulatory approval and commercialization of one or more of our product candidates,
there can be no assurance that we may achieve any of these objectives.
We have spent significant time, money and
effort on the licensing and development of our core assets, including NPM-119 (exenatide implant) in preclinical stage development,
NPM-139 and NPM-159 (undisclosed drug molecules) in initial feasibility testing with our proprietary NanoPortal implant technology.
To date, we have not commenced clinical testing of any of our product candidates. All of our product candidates will require additional
development, including clinical trials as well as further preclinical studies to evaluate their safety, tolerability and pharmacokinetics,
and to optimize their formulation. Our product candidates may require significant additional testing before advancing to pivotal
clinical trials that are designed to generate sufficient safety and efficacy data to support a marketing application. Even if we
conduct and complete such testing of our product candidates, there can be no assurance that we will obtain marketing approval for
one or more of these candidates. Positive results obtained during early development do not necessarily mean later development will
succeed or that regulatory approvals will be obtained. Our drug development efforts may not lead to commercially-viable products
for any number of reasons, including because our product candidates fail to demonstrate safety and efficacy to the satisfaction
of applicable regulatory authorities to support marketing approval, or because we have inadequate financial or other resources
to advance our product candidates through development and approval processes. If any of our product candidates fail to demonstrate
sufficient safety or efficacy data at any time to support their continued development, or we encounter other challenges in the
development of our product candidates, we would experience potentially significant delays in, or be required to abandon, development
of the product candidate.
We
do not anticipate that any of our product candidates will be eligible to receive regulatory approval from the FDA, the EMA or
comparable foreign authorities and begin commercialization for a number of years, if ever. Even if we ultimately receive regulatory
approval for any of these product candidates, we may be unable to commercialize them successfully for a variety of reasons, either
independently or in collaboration with third parties. These include, for example, the availability of alternative treatments,
lack of cost-effectiveness, the cost of manufacturing the product on a commercial scale and competition with other drugs. The
success of our product candidates may also be limited by the prevalence and severity of any adverse side effects or the willingness
of patients and healthcare providers to use or administer our drug implants. If we fail to develop, obtain approval for and commercialize
one or more of our product candidates, our business would be materially and adversely impacted.
Clinical development involves a lengthy and expensive
process with uncertain outcomes. We may incur additional costs and experience delays in developing our product candidates, and
our clinical development efforts may not yield favorable results.
To receive
regulatory approval for our product candidates, adequate and well-controlled clinical trials must be conducted to demonstrate safety
and efficacy in humans to the satisfaction of the FDA, the EMA, and comparable foreign authorities. We have not yet conducted clinical
trials for our current product candidates and clinical testing of such product candidates may not yield results to support continued
development or seeking regulatory approval. The development process is expensive, can take many years and has an uncertain outcome.
Failure can occur at any stage of the process. We may experience numerous unforeseen events during, or as a result of, the development
process that could delay or prevent development and approval of our product candidates, including the following:
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● clinical trials may produce negative or inconclusive results;
● costs of development may be greater than anticipated;
Even
if we experience success in early development for any product candidate, that experience may not be replicated in later development
or with respect to any other product candidates. For example, in our industry, product candidates in later-stage clinical trials
routinely fail to demonstrate adequate safety and efficacy despite having progressed through initial clinical trials or preclinical
testing.
Even
if our clinical trials generate data that we believe are promising, such data may not be sufficient to support seeking marketing
approval by the FDA, the EMA, or comparable foreign authorities. Further, data generated during development can be interpreted
in different ways, and the FDA, the EMA or comparable foreign authorities may interpret such data in different ways than we do.
If we fail to generate data that adequately demonstrate the safety and efficacy of our product candidates to support marketing
approval from regulatory authorities, we will not be able to market and commercialize these product candidates.
From
time to time, in addition to or as an alternative to raising capital through equity or debt offerings, we may seek to selectively
and opportunistically enter into collaborations with third parties to assist in the development and potential future commercialization
of some or all of our product candidates. However, there can be no assurance that we will be able to establish such collaborations
on acceptable terms, if at all, or it may take longer than expected to establish new collaborations. Even if we enter into one
or more of such collaborations, the risks associated with the development of product candidates still remain, and there can be
no assurance that our potential collaborators will successfully develop, seek approval for and commercialize any of our product
candidates.
Vivani’s product
candidates may have serious adverse, undesirable or unacceptable side effects that could delay, pause or terminate our clinical
trials, or prevent us from obtaining regulatory approval for or commercialize such product candidates. If such side effects
are identified during the development of our product candidates or following approval, if any, we may need to abandon our development
of such product candidates, the commercial profile of any approved label may be limited, or we may be subject to other significant
negative consequences following marketing approval, if any.
Undesirable
side effects observed in preclinical studies or clinical trials of our product candidates could interrupt, delay, or halt their
development and could result in the denial of regulatory approval by the FDA, the EMA, or comparable foreign authorities for any
or all targeted indications or adversely affect the marketability of any such product candidates that receive regulatory approval.
Our
product candidates may exhibit adverse effects in preclinical toxicology studies and adverse interactions with other drugs. Our
product candidates may require a risk management program that could include patient and healthcare provider education, usage guidelines,
appropriate promotional activities, a post-marketing observational study, and ongoing safety and reporting mechanisms, among other
requirements. Prescribing could be limited to physician specialists or physicians trained in the use of the drug or could be limited
to a more restricted patient population. Any risk management program required for approval of our product candidates could potentially
have an adverse effect on our business, financial condition, and results of operations.
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Undesirable side effects involving our
product candidates may have other significant adverse implications on our business, financial condition, and results of operations.
For example:
● we may be subject to product liability or shareholder litigation.
In addition,
even if any of our product candidates receive marketing approval and we or others later identify undesirable side effects caused
by such products (or any other similar products) after such approval, a number of potentially significant negative consequences
could result, including:
● we may decide to recall or remove such products from the marketplace;
● our reputation may suffer.
Any
of these events could prevent us from achieving or maintaining market acceptance of the affected product and could substantially
increase the costs and expenses of commercializing the product, which in turn could delay or prevent us from generating significant
revenues from the sale of the product.
Our efforts to identify and develop product candidates
beyond those in our current pipeline may not succeed, and any product candidates that we select for clinical development may not
actually begin clinical trials.
We intend
to expand our current pipeline of core assets by advancing drug implants from future and ongoing feasibility programs into preclinical
and clinical development. However, the process of identifying and developing drug implants is expensive, time-consuming, and unpredictable.
Data from our current preclinical programs may not support the clinical development of its lead compounds or other compounds from
these programs, and we may not identify any additional drug compounds suitable for recommendation for clinical development. Moreover,
any drug compounds that we select for clinical development may not generate sufficient safety and efficacy data that would support
advancement into clinical trials or to continue clinical trials that are ongoing. Such findings would potentially impede our ability
to maintain or expand our development pipeline. Our ability to identify new drug implants and advance them into preclinical and
clinical development also depends upon our ability to fund our research and development operations, and there can be no assurance
that additional funding will be available on acceptable terms, or at all.
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We could experience delays in the commencement or
completion of clinical trials, which could result in increased costs or otherwise impair our research and development efforts.
Delays in the commencement or completion
of clinical trials could significantly impact our drug development costs and otherwise impair our research and development efforts.
We do not know whether planned clinical trials will begin on time or be completed on schedule, if at all. The commencement of
clinical trials can be delayed for a variety of reasons, including, but not limited to, delays related to:
● obtaining regulatory approval to commence one or more clinical trials;
In addition, once a clinical trial has
begun, it may be suspended or terminated by us or our collaborators, institutional review boards, or, if applicable, data safety
monitoring boards charged with overseeing our clinical trials, the FDA, the EMA, or comparable foreign authorities due to a number
of factors, including:
● unforeseen safety issues; or
● lack of adequate funding to continue the clinical trial.
If we experience delays in the completion
or termination of any clinical trial of our product candidates, the development of product candidates will be impaired. In addition,
any delays in completing our clinical trials will increase our costs and slow down our product candidate development process and
our anticipated timelines for seeking marketing approval. Such delays could also allow our competitors to obtain marketing approval
for their own product candidates before we do or may shorten the patent protection period during which we may have the exclusive
right to commercialize our product, if approved. Any of these occurrences may harm our business, financial condition, and prospects
significantly. In addition, many of the factors that cause, or lead to, a delay in the commencement or completion of clinical
trials may also ultimately lead to the denial of regulatory approval of our product candidates.
Results
of preclinical trials may not be predictive of the results of later-stage clinical trials, and many product candidates fail to
achieve regulatory approval despite showing initial promise in early-stage testing.
The
results of preclinical studies of product candidates may not be predictive of the results of clinical trials, and results from
early-stage clinical testing may not be replicated in later-stage clinical trials. Product candidates in later stages of clinical
trials may fail to show the desired safety and efficacy results despite having progressed through preclinical studies and initial
clinical trials. Many companies in the biopharmaceutical industry have suffered significant setbacks in advanced clinical trials
due to adverse safety profiles or lack of efficacy, notwithstanding promising results in earlier studies. We may experience similar
setbacks in our development programs for these or other reasons.
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As product candidates are developed through
preclinical, early-stage clinical and late-stage clinical trials towards approval and commercialization, it is customary that
various aspects of the development program, such as manufacturing and methods of administration, are altered along the way in
an effort to optimize processes and results. While these types of changes are common and are intended to optimize the product
candidates for late-stage clinical trials, approval and commercialization, such changes carry the risk that they will not achieve
these intended objectives.
Any of these changes could make the results
of our planned clinical trials or other future clinical trials less predictable and could cause our product candidates to perform
differently, including causing toxicities, which could delay completion of our clinical trials, delay approval of our product
candidates, and/or jeopardize our ability to commence product sales and generate revenues.
Interim, topline
and preliminary data from our clinical trials that we announce or publish from time to time may change as more patient data become
available and are subject to audit and verification procedures that could result in material changes in the final data.
From
time to time, we may publicly disclose interim, topline or preliminary data from our clinical trials, which is based on a preliminary
analysis of then-available data, and the results and related findings and conclusions are subject to change following a more comprehensive
review of the data related to the particular study or trial. We also make assumptions, estimations, calculations and conclusions
as part of our analyses of data, and we may not have received or had the opportunity to fully and carefully evaluate all data.
As a result, the topline results that we report may differ from future results of the same studies, or different conclusions or
considerations may qualify such results, once additional data have been received and fully evaluated. Topline data also remain
subject to audit and verification procedures that may result in the final data being materially different from the preliminary
data we previously published. As a result, topline data should be viewed with caution until the final data are available. From
time to time, we may also disclose interim data from our clinical studies. Interim data from clinical trials that we may complete
are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment continues and more
patient data become available. Adverse differences between preliminary or interim data and final data could significantly harm
our business prospects. Further, others, including regulatory authorities, may not accept or agree with our assumptions, estimates,
calculations, conclusions or analyses or may interpret or weigh the importance of data differently, which could impact the value
of the particular program, the approvability or commercialization of the particular product candidate or product and our company
in general. In addition, the information we choose to publicly disclose regarding a particular study or clinical trial is based
on what is typically extensive information, and you or others may not agree with what we determine is the material or otherwise
appropriate information to include in our disclosure, and any information we determine not to disclose may ultimately be deemed
significant with respect to future decisions, conclusions, views, activities or otherwise regarding a particular drug, drug candidate
or our business. If the topline data that we report differ from actual results, or if others, including regulatory authorities,
disagree with the conclusions reached, our ability to obtain approval for, and commercialize, our product candidates may be harmed,
which could harm our business, operating results, prospects or financial condition.
We may experience delays in the enrollment of patients
in our clinical trials, which would adversely affect our ability to initiate, conduct and complete such trials on our anticipated
timelines.
Identifying
and qualifying patients to participate in our clinical trials is critical to our success. Patient enrollment depends on many factors,
including:
● safety profile, to date, of the therapeutic candidate under study;
● perceived risks and benefits of our approach to treatment of indication;
● the proximity of patients to clinical sites;
● the availability of competing clinical trials;
● our ability to obtain and maintain patient informed consents.
Even
once enrolled we must retain a sufficient number of patients to complete any of our trials.
If we fail to enroll and maintain the
number of patients for which the clinical trial was designed, the statistical power of that clinical trial may be reduced, which
may impair the significance of such results and cause regulatory authorities to require additional testing. Additionally, enrollment
delays in our clinical trials may result in increased development costs for our product candidates, delay our development timelines
or force us to abandon one or more of our programs altogether.
We may experience difficulty identifying, training
and/or certifying an adequate number of healthcare professionals to properly implant and, when appropriate, explant our drug implants
candidates, which may impair our ability to conduct our clinical trials.
Our drug implant candidates require properly
trained healthcare professionals, which may include doctors, nurse practitioners and nurses, for sub-dermal placement into patients.
These healthcare professionals would also be responsible for removal and replacement of a new drug implant. There can be no assurance
that sufficient numbers of trained and/or certified healthcare professionals will be available or that the training or certification
requirements will not be more burdensome than anticipated. Both factors could lead to difficulties in conducting our clinical
trials and impair our development efforts for our product candidates.
If our competitors have product candidates that are
approved faster, marketed more effectively, are better tolerated, have a more favorable safety profile, or are demonstrated to
be more effective than our own, our commercial opportunity may be reduced or eliminated.
The biopharmaceutical industry is characterized
by rapidly advancing technologies, intense competition, and a strong emphasis on proprietary products. While we believe that our
technology, knowledge, experience, and scientific resources enable us to compete in our industry, we face competition from many
different sources, including commercial biopharmaceutical enterprises, academic institutions, government agencies and private
and public research institutions. Any product candidates that we develop and, if approved, commercialize will compete with existing
therapies and new therapies that may become available in the future.
Many
of our competitors have significantly greater financial resources and expertise in research and development, manufacturing, preclinical
studies, clinical trials, regulatory approvals, and marketing approved products. Some of our competitors with the GLP-1 receptor
agonist drug class include companies such as Novo Nordisk, AstraZeneca, and Eli Lilly. Smaller or early-stage companies may also
prove to be significant competitors, particularly through collaborative arrangements with large and established companies. Our
competitors may succeed in developing technologies and therapies that are more effective, better tolerated or less costly than
those of our own, or that would render our product candidates obsolete and noncompetitive. Even if we obtain regulatory approval
for any of our product candidates, our competitors may succeed in obtaining regulatory approvals for their products earlier than
we do. We will also face competition from these third parties in recruiting and retaining qualified scientific and management
personnel, in establishing clinical trial sites and patient registration for clinical trials, and in acquiring and in-licensing
technologies and products complementary to our programs or advantageous to our business.
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We believe that the key competitive factors
affecting the viability of product candidates, if approved, are likely to be their efficacy, safety, tolerability, frequency and
route of administration, convenience and price, the level of branded and generic competition and the availability of coverage
and reimbursement from government and other third-party payors.
Multiple
GLP-1 receptor agonist products have been proven effective to reduce cardiovascular morbidity and mortality, including Trulicity
(dulaglutide), Ozempic (semaglutide injection), and Victoza (liraglutide), Medical Guidelines may recommend preferential use of
GLP-1 receptor agonists that have positive cardiovascular morbidity and mortality data in the products approved labeling. Since
Bydureon, the NPM-119 reference drug, did not demonstrate a reduction in cardiovascular morbidity and mortality, NPM-119 will not
have this claim in the approved product label unless we generate positive cardiovascular outcomes data with NPM-119. The lack of
a cardiovascular outcomes benefit in the NPM-119 label may decrease its market potential, if approved.
If the FDA or other
applicable regulatory authorities approve generic products that compete with any of our product candidates, the sales of our product
candidates, if approved, could be adversely affected.
Once
an NDA, including a Section 505(b)(2) application, is approved, the product covered becomes a “listed drug” which can
be cited by potential competitors in support of approval of an abbreviated new drug application, or ANDA. FDA regulations and other
applicable regulations and policies provide incentives to manufacturers to create modified versions of a drug to facilitate the
approval of an ANDA or other application for similar substitutes. If these manufacturers demonstrate that their product has the
same active ingredient(s), dosage form, strength, route of administration, and conditions of use, or labeling, as our product candidate,
they might only be required to conduct a relatively inexpensive study to show that their generic product is absorbed in the body
at the same rate and to the same extent as, or is bioequivalent to, our product candidate (and in some cases even this limited
bioequivalence testing can be waived by the FDA). Competition from generic equivalents to our product candidates could substantially
limit our ability to generate revenues and therefore to obtain a return on the investments we have made in our product candidates.
We are subject to a multitude of manufacturing risks,
any of which could substantially increase our costs and limit supply of our product candidates.
The process of manufacturing our product
candidates is complex, highly regulated, and subject to numerous risks. For example, the process of manufacturing our product
candidates is susceptible to product loss due to contamination, equipment failure or improper installation or operation of equipment,
or vendor or operator error. Even minor deviations from normal manufacturing processes for any of our product candidates could
result in reduced production yields, product defects, and other supply disruptions. If microbial, viral, or other contaminations
are discovered in our product candidates or in the manufacturing facilities in which our product candidates are made, such manufacturing
facilities may need to be closed for an extended period to investigate and remedy the contamination. In addition, the manufacturing
facilities in which its product candidates are made could be adversely affected by equipment failures, labor shortages, natural
disasters, power failures and numerous other factors.
In addition, any adverse developments
affecting manufacturing operations for our product candidates may result in shipment delays, inventory shortages, lot failures,
withdrawals or recalls, or other interruptions in the supply of our product candidates. We also may need to take inventory write-offs
and incur other charges and expenses for product candidates that fail to meet specifications, undertake costly remediation efforts,
or seek costlier manufacturing alternatives.
The commercial success of our product candidates,
if approved, depends upon their market acceptance among physicians, patients, healthcare payors, and the medical community.
Even if our product candidates obtain
regulatory approval, they may not gain market acceptance among physicians, patients, healthcare payors and the medical community.
The degree of market acceptance of any of our product candidates, if approved, will depend on several factors, including:
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● our ability to provide acceptable evidence of safety and efficacy;
● relative convenience and ease of administration;
● the prevalence and severity of any adverse side effects;
● restrictions on use in combination with other products;
● availability of alternative treatments;
● effectiveness of our sales and marketing strategy;
● our ability to obtain sufficient third-party coverage or reimbursement; and
● potential product liability claims.
In
addition, the potential market opportunity for our product candidates is difficult to estimate. Our estimates of the potential
market opportunity for our product candidates include several key assumptions based on our industry knowledge, industry publications,
third-party research reports and other surveys. Independent sources have not verified all of our assumptions. If any of these
assumptions proves to be inaccurate, then the actual market for our product candidates could be smaller than our estimates of
their potential market opportunity. If the actual market for our product candidates is smaller than we expect, the market potential
for our product candidates may be limited. If we fail to achieve market acceptance of our product candidates, the viability of
our business may be limited.
If we fail to obtain and sustain an adequate level
of reimbursement by third-party payors for our product candidates, if approved, potential future sales would be materially adversely
affected.
Even
if our product candidates receive marketing approval, there will be no viable commercial market without reimbursement from third-party
payors. Reimbursement policies may be affected by future healthcare reform measures. We cannot be certain that reimbursement will
be available for our product candidates. Additionally, even if there is a viable commercial market, if the level of reimbursement
is below our expectations, our anticipated revenue and gross margins will be adversely affected.
Third-party payors, such as government
or private healthcare insurers, carefully review and increasingly question and challenge the coverage of and the prices charged
for drugs. Reimbursement rates from private health insurance companies vary depending on the company, the insurance plan, and
other factors. Reimbursement rates may be based on reimbursement levels already set for lower cost drugs and may be incorporated
into existing payments for other services. There is a current trend in the U.S. healthcare industry toward cost containment.
Large public and private payors,
managed care organizations, group purchasing organizations and similar organizations are exerting increasing influence on
decisions regarding the use of, and reimbursement levels for, particular treatments. Such third-party payors,
including Medicare, may question the coverage of, and challenge the prices charged for, medical products and services, and
many third-party payors limit coverage of or reimbursement for newly approved healthcare products. Third-party payors may
also limit the covered indications. Cost-control initiatives could decrease the price that we might establish for products,
which could result in product revenues being lower than anticipated. If we are unable to show a significant benefit over
existing therapies, Medicare, Medicaid, and private payors may not be willing to provide reimbursement for our product
candidates, if approved, which would significantly reduce the likelihood of such product candidates gaining market
acceptance.
We
expect that private insurers will consider the efficacy, cost-effectiveness, safety, and tolerability of our product candidates
in determining whether to approve reimbursement for such product candidates and at what level. Obtaining these approvals can be
a time consuming and expensive process. Our business, financial condition and results of operations would be materially adversely
affected if we do not receive adequate reimbursement of our product candidates, if approved, from private insurers on a timely
or satisfactory basis. Limitations on coverage could also be imposed at the local Medicare carrier level or by fiscal intermediaries.
Medicare Part D, which provides a pharmacy benefit to Medicare patients, does not require participating prescription drug plans
to cover all drugs within a class of products. Our business, financial condition and results of operations could be materially
adversely affected if Part D prescription drug plans were to limit access to, or deny or limit reimbursement of, our product candidates.
38
Reimbursement
systems in international markets vary significantly by country and by region, and reimbursement approvals must be obtained on
a country-by-country basis. In many countries, the product cannot be commercially launched until reimbursement is approved. In
some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial
approval is granted. The negotiation process in some countries can exceed 12 months. To obtain reimbursement or pricing approval
in some countries, we may be required to conduct a clinical trial that generates cost-effectiveness or health economics data of
our product candidates in comparison to other available therapies.
If the prices for our product candidates,
if approved, are reduced or if governmental and other third-party payors do not provide adequate coverage and reimbursement of
our products, our future revenue, cash flows and prospects for profitability will suffer.
Since
our product candidates are designed to deliver active medication for up to six months or longer, there may be additional risks
associated with the third-party payor’s willingness or desire to reimburse the full product cost at the time of purchase.
We may develop customized reimbursement practices or policies to address potential concerns from payors if appropriate. There
are no assurances that customized reimbursement practices or policies, if needed, will be effective and the potential impact on
revenues and profits is difficult to project.
Risks Related to Regulatory Approval and Other Legal
and Compliance Matters
Our product candidates
are subject to extensive regulation under the FDA, the EMA and comparable foreign authorities, and must undergo extensive clinical
testing that can be costly and time consuming, with no assurance that regulatory approval will be obtained for any of our product
candidates.
The clinical
development, manufacturing, labeling, storage, record-keeping, advertising, promotion, export, marketing, and distribution of our
product candidates are subject to extensive regulation by the FDA and other U.S. regulatory agencies, the EMA, or comparable authorities
in foreign markets. In the U.S., neither we nor any collaborators are permitted to conduct clinical testing in humans with our
product candidates unless and until clearance is received to conduct clinical investigations under an investigational new drug
application (IND) from the FDA or receive similar authorizations abroad. In addition, marketing of such product candidates may
not occur unless and until approval of a new drug application (NDA) from the FDA or similar approvals by comparable foreign regulatory
authorities are secured.
The process
of obtaining these approvals is expensive, often takes many years, and can vary substantially based upon the type, complexity and
novelty of the product candidates involved. Approval policies or regulations may change and may be influenced by the results of
other similar or competitive products, making it more difficult for us to achieve such approval in a timely manner or at all. Any
guidance that may result from recent FDA advisory panel discussions may make it more expensive to develop and commercialize such
product candidates. In addition, with respect to our current pipeline, we have not previously filed INDs or NDAs with the FDA or
filed similar applications with other foreign regulatory agencies. This lack of experience may impede our ability to obtain FDA
or other foreign regulatory agency approval in a timely manner, if at all, for our product candidates.
Despite the time and expense invested, and
even if we observe promising results from clinical testing of our product candidates, regulatory approval is never guaranteed.
In our industry, many companies have experienced significant setbacks when seeking marketing approval from regulatory agencies,
despite having generated promising data from clinical testing of their product candidates. For example, the FDA has rejected both
original and resubmitted NDAs from Intarcia Therapeutics for its exenatide implant candidate for the treatment of Type II diabetes.
Based on public correspondence from the FDA, the agency asserted that the data submitted in the applications did not show that
the product would be safe under the proposed conditions of use and that the methods used in, and the facilities and controls used
for, the manufacture, processing, or packing of the product were not shown to be adequate to preserve its identity, strength,
quality, and purity. Further correspondence disclosed additional deficiencies, including that data that did not demonstrate adequate
device reliability in regard to dose delivery. While we seek to avoid such outcomes in developing our product candidates based
on our proprietary NanoPortal technology, there can be no assurance that such product candidates will not experience similar setbacks
if and when we apply for regulatory approval. Similar results would significantly jeopardize the approvability of our product
candidates that employ the NanoPortal technology.
Any
inability to obtain these approvals would prevent us from commercializing our product candidates. The FDA, the EMA or comparable
foreign authorities can delay, limit, or deny approval of a product candidate for many reasons, including:
● a product candidate may not be deemed safe or effective;
39
With
respect to one or more of our product candidates, including NPM-119 (exenatide implant), we plan to seek regulatory approval in
the U.S. by filing an NDA under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, which is referred to as the 505(b)(2)
pathway. The 505(b)(2) pathway allows at least some of the information required for NDA approval, such as safety and efficacy information
on the active ingredient, to come from studies not conducted by or for the applicant. For NPM-119, we intend to rely on certain
information from Bydureon®and/or Bydureon
BCise®, AstraZeneca’s exenatide
extended-release injectable products. If we are unable to reference data generated for Bydureon®and/or Bydureon BCise®,
additional clinical studies, including a cardiovascular outcomes (CVOT) study, may be required and would add significant additional
costs and a significant delay in our efforts to seek and secure marketing approval. Further, if a CVOT study were conducted, there
can be no assurance that the study would generate favorable results and support U.S. registration.
Although
we have discussed our intention to use the 505(b)(2) regulatory pathway with the FDA, there can be no assurance that this pathway
will be acceptable, and there can be no assurance that the FDA will not require additional testing to support seeking approval
in the U.S. If the 505(b)2 regulatory pathway is not available, the costs of development may significantly increase and the projected
timeline to approval and launch would be significantly delayed.
Even
if a product is approved, the FDA 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 and/or reporting as conditions of approval. Regulators
of other countries and jurisdictions have their own procedures for the approval of product candidates with which we must comply
prior to marketing in those countries or jurisdictions.
Obtaining
regulatory approval for marketing of a product candidate in one country does not ensure that we will be able to obtain regulatory
approval in any other country. In addition, delays in approvals or rejections of marketing applications in the U.S. or other countries
may be based upon many factors, including regulatory requests for additional analyses, reports, data, preclinical studies and clinical
trials, regulatory questions regarding different interpretations of data and results, changes in regulatory policy during the period
of product development and the emergence of new information regarding our product candidate.
We intend to utilize
the 505(b)(2) pathway for the regulatory approval of NPM-119 and other of our product candidates. Final marketing approval of NPM-119
or any of our other product candidates by the FDA, or other regulatory authorities may be delayed, limited, or denied, any of which
would adversely affect our ability to generate operating revenues.
We intend
to pursue a regulatory pathway pursuant to Section 505(b)(2) of the Federal Food, Drug and Cosmetic Act, or FDCA, for the approval
of NPM-119 and other of our product candidates, which allows us to rely on existing clinical data for the drug. Section 505(b)(2)
was enacted as part of the Drug Price Competition and Patent Term Restoration Act of 1984, or the Hatch-Waxman Amendments, and
permits the submission of an NDA where at least some of the information required for approval comes from preclinical studies or
clinical trials not conducted by or for the applicant and for which the applicant has not obtained a right of reference. The FDA
interprets Section 505(b)(2) of the FDCA to permit the applicant to rely upon the FDA’s previous findings of safety and efficacy
for an approved product. The FDA requires submission of information needed to support any changes to a previously approved drug,
such as published data or new studies conducted by the applicant or clinical trials demonstrating safety and efficacy. The FDA
could refuse to file our NDA submissions, request additional information before accepting our submissions for filing or require
additional information to sufficiently demonstrate safety and efficacy to support approval.
If the
FDA does not agree that the 505(b)(2) regulatory pathway is appropriate or scientifically justified for our product candidates,
we may need to conduct additional clinical trials, provide additional data and information, and meet additional standards for regulatory
approval. For example, if we are unable to establish a bridge between our product candidates and the listed drug upon which we
rely to demonstrate that such reliance is justified, we may be required to show safety and efficacy through one or more additional
clinical trials. If this were to occur, the time and financial resources required to obtain FDA approval for these product candidates,
and the complications and risks associated with these product candidates, would likely substantially increase. Moreover, an inability
to pursue the 505(b)(2) regulatory pathway would likely result in new competitive products reaching the market more quickly than
our product candidates, which would likely materially adversely impact our competitive position and prospects. Even if we are allowed
to pursue the 505(b)(2) regulatory pathway, we cannot assure you that our product candidates will receive the requisite approvals
for commercialization.
Notwithstanding
the approval of many products by the FDA pursuant to 505(b)(2), over the last few years some pharmaceutical companies and others
have objected to the FDA’s interpretation of Section 505(b)(2) to allow reliance on the FDA’s prior findings of safety
and effectiveness. If the FDA changes its interpretation of Section 505(b)(2), or if the FDA’s interpretation is successfully
challenged in court, this could delay or even prevent the FDA from approving any Section 505(b)(2) application that we submit.
Moreover, the FDA adopted an interpretation of the three-year exclusivity provisions whereby a 505(b)(2) application can be blocked
by exclusivity even if does not rely on the previously-approved drug that has exclusivity (or any safety or effectiveness information
regarding that drug). Under the FDA’s interpretation, the approval of NPM-119 or other of our product candidates may be blocked
by exclusivity awarded to a previously-approved drug product that shares certain innovative features with NPM-119 or our other
product candidate, even if our 505(b)(2) application does not identify the previously-approved drug product as a listed drug or
rely upon any of its safety or efficacy data. Any failure to obtain regulatory approval of our product candidates would significantly
limit our ability to generate revenues, and any failure to obtain such approval for all of the indications and labeling claims
we deem desirable could reduce our potential revenues.
Even
if we are successful in pursuing the 505(b)(2) regulatory pathway for NPM-119, or other of our product candidates, we cannot assure
you that we will receive the requisite or timely approval for commercialization of NPM-119 or other of our product candidates.
Although the Section 505(b)(2) pathway allows us to rely in part on the FDA’s prior findings of safety or efficacy for approved
listed drugs or on published literature for which we do not have a right of reference, the FDA may determine that prior findings
by the FDA or the published literature that we believe supports the safety or efficacy of NPM-119 or other of our product candidates
is insufficient or not applicable to our application or that additional studies will need to be conducted. To the extent that we
are relying on the 505(b)(2) regulatory pathway based on the approval of a listed drug for a similar indication, the FDA may require
that we include in the labeling of NPM-119 or another of our product candidates, if approved, some or all of the safety information
that is included in the labeling of the approved listed drug. Moreover, even if any of our product candidates are approved via
the 505(b)(2) regulatory pathway, the approval may be subject to limitations on the indicated uses for which the product may be
marketed or to other conditions of approval, or may contain requirements for costly post-marketing testing and surveillance to
monitor the safety or efficacy of the product, such as a Risk Evaluation and Mitigation Strategy, or REMS, which is a risk mitigation
plan which could include medication guides, physician communication plans, or elements to assure safe use, or ETASU, such as restricted
distribution methods, patient registries and other risk minimization tools.
Additional time may
be required to obtain regulatory approval for our product candidates because they are combination products.
Some of our product candidates, including NPM-119 which is designed
as a GLP-1 implant for treatment of type 2 diabetes, are drug-device combination products which require coordination within the
FDA and similar foreign regulatory agencies for review of their device and drug components. A combination product generally is
defined as a product comprised of components from two or more regulatory categories (e.g., drug/device, device/biologic, drug/biologic).
Each component of a combination product is subject to the requirements established by the FDA for that type of component, whether
a new drug, biologic or device. In order to facilitate pre-market review of combination products, the FDA designates one of its
centers to have primary jurisdiction for the pre-market review and regulation of the overall product based upon a determination
by the FDA of the primary mode of action of the combination product. Where approval of the drug and device is sought under a single
application, there could be delays in the approval process due to the increased complexity of the review process and the lack of
a well-established review process and criteria. The EMA has a parallel review process in place for combination products, the potential
effects of which in terms of approval and timing could independently affect our ability to market our combination products in Europe.
Although the FDA and similar foreign regulatory agencies have systems in place for the review and approval of combination products
such as ours, we may experience delays in the development and commercialization of our product candidates due to regulatory timing
constraints and uncertainties in the product development and approval process.
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.