ITEM 1A. RISK FACTORS
Investment in our
common stock involves significant risk. You should carefully consider the information described in the following risk factors,
together with the other information appearing elsewhere in this Annual Report on Form 10-K, before making an investment decision
regarding our common stock. If any of the events or circumstances described in these risks actually occur, our business, financial
condition, results of operations and future growth prospects would likely be materially and adversely affected. In these circumstances,
the market price of our common stock could decline, and you may lose all or a part of your investment in our common stock. Moreover,
the risks described below are not the only ones that we face.
Summary Risk Factors
Our business is subject
to a number of risks, including risks that may prevent us from achieving our business objectives or may adversely affect our business,
clinical and commercialization activities, the manufacturing of our product candidates, intellectual property, third-party relationships,
competition factors, product and environmental liability, and common stock. These risks are discussed more fully below and include,
but are not limited to, risks related to:
Risks Related to Our Business
· the COVID-19 pandemic, including its impact on our business and operations;
· the Company has incurred significant losses and may never be profitable;
Risks Related to Clinical and Commercialization
Activities
Risks Related to the Manufacturing
of our Product Candidates
Risks Related to Our Intellectual
Property
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Risks Related to Our Relationships
with Third Parties
Risks Related to Competitive Factors
· our products will likely face intense competition;
Risks Related to Product and Environmental
Liability
· our products may expose us to potential product liability;
Risks Related to Our Common Stock
· we expect that our stock price will continue to fluctuate significantly; and
Risks Related to Our Business
We need substantial additional funding
before we can complete the development of our product candidates. If we are unable to obtain such additional capital, we will be
forced to delay, reduce or eliminate our product development and clinical programs and may not have the capital required to otherwise
operate our business.
Developing biopharmaceutical
products, including conducting preclinical studies and clinical trials and establishing manufacturing capabilities, is expensive.
As of December 31, 2020, we had cash and cash equivalents totaling approximately $32.7 million. We have not generated any
revenues from the commercial sale of products. We will not be able to generate any product revenues until, and only if, we receive
approval to sell our drug candidates from the FDA or other regulatory authorities.
From inception, we
have financed our operations through public and private sales of our equity securities, grants from the National Institutes of
Health, or NIH, and the Department of Defense, or DoD, and a loan commitment and grant award from the California Institute for
Regenerative Medicine, or CIRM. As we have not generated any revenue from commercial sales to date and we do not expect to generate
revenue for several years, if ever, we will need to raise substantial additional capital in order to fund our general corporate
activities and to fund our research and development, including our ongoing clinical trials and plans for new clinical trials and
product development.
We may seek to raise
additional funds through various potential sources, such as equity and debt financings, or through strategic collaborations and
license agreements. We can give no assurances that we will be able to secure such additional sources of funds to support our operations
or, if such funds are available to us, that such additional financing will be sufficient to meet our needs. Moreover, to the extent
that we raise additional funds by issuing equity securities, our stockholders may experience additional significant dilution, and
debt financing, if available, may involve restrictive covenants. To the extent that we raise additional funds through collaboration
and licensing arrangements, it may be necessary to relinquish some rights to our technologies or our product candidates, or grant
licenses on terms that may not be favorable to us.
If we are unable to
raise sufficient funds to support our current and planned operations, we may elect to discontinue certain of our ongoing activities
or programs. The inability to raise additional funds could also prevent us from taking advantage of opportunities to pursue promising
new or existing programs in the future.
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Our forecasts regarding
our beliefs in the sufficiency of our financial resources to support our current and planned operations are forward-looking statements
and involve significant risks and uncertainties, and actual results could vary as a result of a number of factors, including the
factors discussed elsewhere in this “Risk Factors” section. We have based these estimates on assumptions that may prove
to be wrong, and we could utilize our available capital resources sooner than we currently expect. Our future funding requirements
will depend on many factors, including, but not limited to:
· the costs of developing adequate manufacturing processes and facilities;
· the costs associated with and timing of regulatory approval;
· the effect of competing technological and market developments;
We have a history of net losses,
and we expect losses to continue for the foreseeable future. In addition, a number of factors may cause our operating results to
fluctuate on a quarterly and annual basis, which may make it difficult to predict our future performance.
We have a history of
net losses, expect to continue to incur substantial net losses for the foreseeable future, and may never achieve or maintain profitability.
Our operations to date have been primarily limited to organizing and staffing our company, developing our technology, and undertaking
preclinical studies and clinical trials of our product candidates. We have not yet obtained regulatory approval for any of our
product candidates. Specifically, our financial condition and operating results have varied significantly in the past and will
continue to fluctuate from quarter-to-quarter and year-to-year in the future due to a variety of factors, many of which are beyond
our control. Factors relating to our business that may contribute to these fluctuations include the following factors:
· delays in the commencement, enrollment, and timing of clinical testing;
· market acceptance of our product candidates;
· competition from existing products or new products that may emerge;
· our ability to maintain adequate insurance policies;
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· costs related to and outcomes of potential intellectual property litigation;
· our ability to implement additional internal systems and infrastructure;
· our ability to adequately support future growth;
The Company’s technology is
not yet proven and each of our product candidates is still in clinical or preclinical development.
The Company’s
product candidates, CAP-1002 and our exosome technologies, are in development and each requires further and, in some cases, extensive
clinical testing before it may be approved by the FDA, or another regulatory authority in a jurisdiction outside the United States,
which could take several years to complete, if ever. The Company’s failure to establish the efficacy of its technologies
would have a material adverse effect on the Company. We cannot predict with any certainty the results of such clinical testing,
including the results of any potential Phase III trial of our CAP-1002 product candidate in DMD. Additionally, we cannot predict
with any certainty if, or when, we might commence any additional clinical trials of our product candidates, whether we will be
able to secure a partner to fund and/or conduct a potential Phase III trial, or whether our current trials will yield sufficient
data to permit us to proceed with additional clinical development and ultimately submit an application for regulatory approval
of our product candidates in the United States or abroad, or whether such applications will be accepted by the appropriate regulatory
agencies. We are also unable to predict whether our preclinical studies of our exosomes products will result in a viable clinical
development program.
Our business depends
entirely on the successful development and commercialization of our product candidates. We currently have no products approved
for sale and generate no revenues from sales of any products, and we may never be able to develop a marketable product.
Our product candidates
will require additional clinical development, evaluation of clinical, preclinical and manufacturing activities, marketing approval
in multiple jurisdictions, substantial investment and significant marketing efforts before we generate any revenues from product
sales. We are not permitted to market or promote our product candidates, before we receive marketing approval from the FDA and
comparable foreign regulatory authorities, and we may never receive such marketing approvals.
The
success of our product candidates will depend on several factors, including the following:
· successful and timely completion of our clinical trials;
· timely receipt of an EUA or marketing approval for our products;
· the performance of our current and future collaborators, if any;
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· successful launch of commercial sales following any EUA or marketing approval;
· a continued acceptable safety profile following any EUA or marketing approval;
· our ability to compete with other therapies.
We do not have complete
control over many of these factors, including certain aspects of clinical development and the regulatory submission process, potential
threats to our intellectual property rights and the manufacturing, marketing, distribution and sales efforts of any future collaborator.
Accordingly, we cannot assure you that we will ever be able to generate revenue through the sale of our products. If we are not
successful in marketing or commercializing our products, or are significantly delayed in doing so, our business will be materially
harmed.
Business disruptions such as natural
disasters, widespread infectious diseases or pandemics could seriously harm our future revenues and financial condition and increase
our costs and expenses.
Our corporate headquarters
and manufacturing facilities are located in the greater Los Angeles, California area, a region known for seismic activity, as well
as being susceptible to drought and fires. A significant natural disaster, such as an earthquake, flood or fire, occurring at our
headquarters or manufacturing facilities, or at the facilities of any third-party manufacturer or vendor, could have a material
adverse effect on our business, financial condition and results of operations. In addition, outbreaks of viruses, infectious diseases
or pandemics (including, for example, the outbreak of the novel coronavirus (COVID-19)), terrorist acts or acts of war targeted
at the United States, and specifically the Los Angeles, California region, could cause damage or disruption to us, our employees,
facilities, contractors and collaborators, which could have a material adverse effect on our business, financial condition and
results of operations.
The coronavirus outbreak could adversely
impact our business.
An epidemic or pandemic
disease outbreak, including the 2019 novel coronavirus (COVID-19), could severely disrupt our operations or the operations of third
parties that we depend on, including our single third-party contract manufacturer, our CROs, clinical data management organizations,
medical institutions and clinical investigators, and have a material adverse effect on our business, results of operations, financial
condition and prospects. In December 2019, it was first reported that there had been an outbreak of a novel strain of coronavirus
(COVID-19), in China. COVID-19 has since spread globally and while cases and hospitalization are currently on the decline
in the US, there can be no assurances they will not continue at the current rate or increase in the future especially in light
of the number of variants that are emerging across the world. Governments in the United States and elsewhere have taken and
are continuing to take severe measures to slow the spread of COVID-19, including requiring that certain businesses close or conduct
only the minimum necessary operations.
As COVID-19 continues
to spread, we may experience disruptions that could severely impact our business, including:
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Additionally, disruptions
at the at FDA, the EMA and other regulators, caused by global health concerns, including the COVID-19 pandemic, including delays
in inspections of clinical trial or manufacturing sites required as part of the application review process, could result in delays
of reviews and approvals of our product candidate or our proposed clinical trials. For example, in response to the COVID-19 pandemic,
on March 10, 2020, the FDA announced its intention to postpone most inspections of foreign manufacturing facilities and products
inspections of domestic manufacturing facilities through April 2020. On March 18, 2020, the FDA announced its intention
to temporarily postpone routine surveillance inspections of domestic manufacturing facilities and provided guidance regarding the
conduct of clinical trials. On July 10, 2020, the FDA announced that it is working toward the goal of restarting on-site inspections
it deems to be “mission critical.” On August 19, 2020, the FDA published guidance clarifying how it intends to
conduct inspections during the COVID-19 pandemic, including how it plans to determine which inspections are “mission-critical.”
It is unclear how FDA’s policies and guidance will impact any inspections of our facilities, including our clinical trial
sites. Regulatory authorities outside the United States may adopt similar restrictions or other policy measures in response to
the COVID-19 pandemic.
The global outbreak
of COVID-19 continues to evolve and its ultimate impact on our business will depend on future developments, which are highly uncertain
and cannot be predicted. Any of the disruptions listed above, or other disruptions caused by new developments associated
with the COVID-19 outbreak could severely impact our business.
A breakdown or breach of our information
technology systems could subject us to liability or interrupt the operation of our business.
We are increasingly
dependent upon information technology systems and data, as well as the information technology systems and data of our third party
vendors, especially if we expand our clinical trials and therefore our databases of patient information. Our or our third party
vendors’ computer systems are potentially vulnerable to breakdown, malicious intrusion and random attack. Likewise, data
privacy or security breaches by individuals authorized to access our information technology systems or others may pose a risk that
sensitive data, including intellectual property, trade secrets or personal information belonging to us, our patients, customers
or other business partners, may be exposed to unauthorized persons or to the public. Cyber-attacks are increasing in their frequency,
sophistication and intensity. While we continue to build and improve our information systems and infrastructure and believe we
have taken appropriate security measures to minimize these risks to our data and information technology systems, we intend to defend
against and respond to data security incidents, and there can be no assurance that our efforts will prevent breakdowns or breaches
in our systems, or adequately contain and mitigate risks from a data security incident, that could adversely affect our business.
Our internal computer systems, or
those used by our CROs or other contractors or consultants, may fail or suffer security breaches.
We utilize and rely
on services of third parties to perform services in connection with our clinical trials, which services involve the collection,
use, storage and analysis of personal health information. While we receive assurances from these vendors that their services are
compliant with the Health Insurance Portability and Accountability Act, or HIPAA, and other applicable privacy and cybersecurity
laws, there can be no assurance that such third parties will comply with applicable laws or regulations. Non-compliance by such
vendors or weaknesses in their information security programs may result in liability for us which would have a material adverse
effect on our business, financial condition and results of operations.
Despite the implementation
of security measures, our internal computer systems and those of our current and future clinical research organizations, or CROs,
and other contractors and consultants are vulnerable to damage from computer viruses and unauthorized access. While we have not
experienced any such material system failure or security breach to date, if such an event were to occur and cause interruptions
in our operations, it could result in a material disruption of our development programs and our business operations. For example,
the loss of clinical trial data from completed or future 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 and commercialization of our product candidates could be delayed.
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If
we achieve our near-term product development milestones, we may not be able to manage any subsequent growth.
Should we achieve our
near-term product development milestones, of which no assurance can be given, our long-term viability will depend upon the expansion
of our operations and the effective management of our growth, which will place a significant strain on our management and on our
administrative, operational and financial resources, especially if we expand our business and operations internationally. To manage
this growth, we may need to expand our facilities, augment our operational, financial and management systems and hire and train
additional qualified personnel. If we are unable to manage our growth effectively, our business would be harmed.
Risks Related to Clinical and Commercialization
Activities
Our success depends upon the viability
of our product candidates and we cannot be certain any of them will receive regulatory approval to be commercialized.
We will need FDA approval
to market and sell any of our product candidates in the United States and approvals from FDA-equivalent regulatory authorities
in foreign jurisdictions to commercialize our product candidates in those jurisdictions. In order to obtain FDA approval of any
of our product candidates, we must submit to the FDA a new drug application, or NDA, or a biologics license application, or BLA,
demonstrating that the product candidate is safe for humans and effective for its intended use. This demonstration requires significant
research and animal testing, which are referred to as preclinical studies, as well as human testing, which are referred to as clinical
trials. Satisfaction of the FDA’s regulatory requirements typically takes many years, depends upon the type, complexity,
and novelty of the product candidate, and requires substantial resources for research, development, testing and manufacturing.
We cannot predict whether our research and clinical approaches will result in drugs that the FDA considers safe for humans and
effective for indicated uses. The FDA has substantial discretion in the drug approval process and may require us to conduct additional
preclinical and clinical testing or to perform post-marketing studies. The approval process may also be delayed by changes in government
regulation, future legislation, administrative action or changes in FDA policy that occur prior to or during our regulatory review.
Even if we comply with
all FDA requests, the FDA may ultimately reject one or more of our NDAs or BLAs, as applicable. We cannot be sure that we will
ever obtain regulatory clearance for our product candidates. Failure to obtain FDA approval of any of our product candidates will
reduce our number of potentially salable products, if any, and, therefore, corresponding product revenues, and will have a material
and adverse impact on our business.
As the results of earlier preclinical
studies or clinical trials are not necessarily predictive of future results, any product candidate we advance into clinical trials
may not have favorable results in later clinical trials or receive regulatory approval.
Even if our preclinical
studies and clinical trials are completed as planned, we cannot be certain that their results will support the claims of our product
candidates. Positive results in preclinical testing and early clinical trials do not ensure that results from later clinical trials
will also be positive, and we cannot be sure that the results of later clinical trials will replicate the results of prior clinical
trials and preclinical testing.
Our clinical trial
process may fail to demonstrate that our product candidates are safe for humans and effective for indicated uses. This failure
would cause us to abandon a product candidate and may delay development of other product candidates. Any delay in, or termination
of, our clinical trials will delay or cause us to refrain from the filing of our NDAs and/or BLAs with the FDA and, ultimately,
our ability to commercialize our product candidates and generate product revenues. In addition, our clinical trials to date involve
small patient populations. Because of the small sample size, the results of these clinical trials may not be indicative of future
results.
Despite the results
reported in earlier clinical trials for our product candidates, we do not know whether any Phase II, Phase III or other clinical
trial which we may conduct will demonstrate adequate efficacy and safety to result in regulatory approval to market our product
candidates. A number of companies in the pharmaceutical industry, including those with greater resources and experience, have suffered
significant setbacks in Phase II or Phase III clinical trials, even after seeing promising results in earlier clinical trials.
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Our
exosome technologies are based on a novel therapeutic approach which makes it difficult to predict the time
and cost of development and of subsequently obtaining regulatory approval, if at all.
Our exosome technologies
involve a relatively new therapeutic approach which will face both clinical and regulatory challenges. To date,
no products based on exosomes have been approved in the United States or the European Union. It is therefore difficult to accurately
predict the developmental challenges we may face for our exosome technologies as they proceed through preclinical studies and clinical
trials. In addition, because we have only conducted preclinical studies with our exosome technologies, we have not yet been able
to assess their safety in humans, and there may be short-term or long-term effects from treatment with our exosomes that we cannot
predict at this time. Also, animal models for the indications we may explore may not exist or may be difficult to obtain for our
preclinical studies. As a result of these factors, we are unable to predict the time and cost of development of the exosome technologies
and we cannot predict whether the application of the exosome technologies, or any similar or competitive exosome technologies,
will result in regulatory approval of any products. There can be no assurance that any development problems we experience in the
future related to our exosomes or any of our research programs will not cause significant delays or unanticipated costs,
or that such development problems can be solved. Any of these factors may prevent us from completing our preclinical studies or
any clinical trials that we may initiate or commercializing any product candidates we may develop on a timely or profitable basis,
if at all.
The clinical trial
requirements of the FDA, the European Medicines Agency, or EMA, and other regulatory authorities and the criteria these regulators
use to determine the safety and efficacy of a product candidate vary substantially according to the
type, complexity and intended use and market of the product candidate. As a result, the regulatory approval process for our exosomes
is uncertain and may be more expensive and take longer than the approval process for other product candidates. It is difficult
to determine how long it will take or how much it will cost to obtain regulatory approvals for our exosomes in either the United
States or the European Union or other regions of the world or how long it will take to commercialize our product candidates, if
at all. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product
candidate to market could decrease our ability to generate sufficient product revenue, and our business, financial condition, results
of operations and prospects may be adversely impacted.
Negative developments in the field
of exosomes could damage public perception of any product candidates that we develop, which could adversely affect our ability
to conduct our business or obtain regulatory approvals for such product candidates.
Exosome-based
vaccines and therapeutics are novel and unproven therapies which may not gain the acceptance of the public, patients or the medical
community. To date, efforts by others to leverage natural exosomes have generally demonstrated an inability to generate exosomes
with predictable biologically active properties or to manufacture exosomes at suitable scale to treat more than a small number
of patients. Our success will depend on our ability to demonstrate that our exosome technologies can overcome these challenges.
Additionally,
our success will depend upon physicians who specialize in the treatment of diseases targeted by our exosomes prescribing treatments
that involve the use of our product candidates in lieu of, or in addition to, existing treatments with which they are more familiar
and for which greater clinical data may be available. Adverse events in clinical trials of our exosomes or in clinical trials of
others developing similar products and the resulting publicity, as well as any other adverse events in the field of exosome therapeutics,
could result in a decrease in demand for any products that we may develop. These events could also result in the suspension, discontinuation,
or clinical hold of, or modification to, our clinical trials. Any future negative developments in the field of exosomes and their
use as therapies could also result in greater governmental regulation, stricter labeling requirements and potential regulatory
delays in the testing or approvals of our exosomes or other potential future product candidates. Any increased scrutiny could delay
or increase the costs of obtaining marketing approval for our exosomes or any other product candidates which we may develop in
the future.
Advancing
vaccine candidates based on our exosome platform as novel products creates significant challenges for us, including:
We may not be able to file INDs to
commence additional clinical trials on the timelines we expect, and even if we are able to do so, the FDA may not permit us to
proceed.
We hope to file additional
investigational new drug applications, or INDs, over the next several years, including with respect to our exosome technologies
in one or more indications. However, the timing of our filing of these INDs is primarily dependent on receiving further data from
our preclinical studies and having sufficient processes in place in connection with the manufacturing of the exosomes.
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We cannot be sure that
submission of an IND will result in the FDA allowing further clinical trials to begin, or that, once begun, issues will not arise
that result in the suspension or termination of such clinical trials. Any IND we submit could be denied by the FDA or the FDA could
place any future investigation of ours on clinical hold until we provide additional information, either before or after clinical
trials are initiated. Additionally, even if such regulatory authorities agree with the design and implementation of the clinical
trial set forth in an IND or clinical trial application, we cannot guarantee that such regulatory authorities will not change their
requirements in the future. Unfavorable future trial results or other factors, such as insufficient capital to continue development
of a product candidate or program, could also cause us to voluntarily withdraw an effective IND.
The Company has limited experience
in conducting late-stage clinical trials, which are complex and subject to strict regulatory oversight.
The Company has limited
late-stage clinical trial experience with respect to its product candidates. The clinical testing process is governed by stringent
regulation and is highly complex, costly, time-consuming, and uncertain as to outcome, and pharmaceutical products and products
used in the regeneration of tissue may invite particularly close scrutiny and requirements from the FDA and other regulatory bodies.
Our failure or the failure of our collaborators to conduct clinical trials successfully or our failure to capitalize on the results
of clinical trials for our product candidates would have a material adverse effect on the Company. If our clinical trials of our
product candidates or future product candidates do not sufficiently enroll or produce results necessary to support regulatory approval
in the United States or elsewhere, or if they show undesirable side effects, we will be unable to commercialize these product candidates.
To receive regulatory
approval for the commercial sale of our product candidates, we must conduct adequate and well-controlled clinical trials to demonstrate
efficacy and safety in humans. Clinical failure can occur at any stage of testing. Our clinical trials may produce negative or
inconclusive results, and we may decide, or regulators may require us, to conduct additional clinical and/or non-clinical testing.
In addition, the results of our clinical trials may show that our product candidates are ineffective or may cause undesirable side
effects, which could interrupt, delay or halt clinical trials, resulting in the denial of regulatory approval by the FDA and other
regulatory authorities. Furthermore, negative, delayed or inconclusive results may result in:
· the withdrawal of clinical trial participants;
· the termination of clinical trial sites or entire trial programs;
· costly litigation arising out of the trials;
· substantial monetary awards to patients or other claimants;
· the requirement that additional trials be conducted;
· impairment of our business reputation;
· loss of revenues; and
· the inability to commercialize our product candidates.
Delays in the commencement, enrollment,
and completion of clinical testing could result in increased costs to us and delay or limit our ability to obtain regulatory approval
for our product candidates.
Delays in the commencement,
enrollment or completion of clinical testing could significantly affect our product development costs. The current pandemic has
had an impact on the ability to conduct clinical trials due to inabilities to enroll or even get subjects to complete the trials
due to lockdowns, reluctance to travel, limitations set by trial sites and other reasons. We cannot predict how long this will
exist and while the hospitalization rates and number of cases seem to be on the decline, no assurance it will not revert to prior
critical levels. A clinical trial may be suspended or terminated by the Company, the FDA, or other regulatory authorities due to
a number of factors. The commencement and completion of clinical trials require us to identify and maintain a sufficient number
of trial sites, many of which may already be engaged in other clinical trial programs for the same indication as our product candidates
or may otherwise be resource constrained. We may be required to withdraw from a clinical trial as a result of changing standards
of care, or we may become ineligible to participate in clinical studies. We do not know whether planned clinical trials will begin
on time or be completed on schedule, if at all. The commencement, enrollment and completion of clinical trials can be delayed for
a number of reasons, including, but not limited to, delays related to:
· findings in preclinical studies;
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· obtaining regulatory clearance to commence a clinical trial;
· the impact of COVID-19 on patient screening and patient enrollment;
· addressing any conflicts with new or existing laws or regulations;
· the need to add new clinical trial sites;
· collecting, analyzing and reporting final data from the clinical trials;
· meeting logistical requirements for the delivery of investigational product.
If we are required
to conduct additional clinical trials or other testing of our product candidates beyond those that we currently contemplate, we
or our development partners, if any, may be delayed in obtaining, or may not be able to obtain or maintain, clinical or marketing
approval for these product candidates. We may not be able to obtain approval for indications that are as broad as intended, or
we may be able to obtain approval only for indications that are entirely different from those indications for which we sought approval.
Changes in regulatory
requirements and guidance may occur, and we may need to amend clinical trial protocols to reflect these changes with appropriate
regulatory authorities. Amendments may require us to resubmit our clinical trial protocols to IRBs for re-examination, which may
impact the costs, timing, or successful completion of a clinical trial. If we experience delays in the completion of, or if we
terminate, our clinical trials, the commercial prospects for our product candidates will be harmed, and our ability to generate
product revenues will be delayed or will not be realized. 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 a product candidate.
Even if we are able to ultimately commercialize our product candidates, other therapies for the same or similar indications may
have been introduced to the market and already established a competitive advantage. Any delays in obtaining regulatory approvals
may:
· impose costly procedures on us; or
· diminish any competitive advantages that we may otherwise enjoy.
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We may experience numerous
unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing approval
or commercialize our product candidates, including:
If we are required
to conduct additional clinical trials or other testing of our product candidates beyond those that we currently contemplate, if
we are unable to successfully complete clinical trials of our product candidates or other testing, if the results of these trials
or tests are not positive or are insufficiently positive to support marketing approval, or if there are safety concerns, we may:
· incur unplanned costs;
· obtain marketing approval in some countries and not in others;
· be subject to additional post-marketing testing requirements; or
· have the drug removed from the market after obtaining marketing approval.
Our drug development
costs will also increase if we experience delays in testing or marketing approvals. We do not know whether clinical trials will
begin as planned, will need to be restructured or will be completed on schedule, or at all. Furthermore, we rely on third-party
CROs and clinical trial sites to ensure the proper and timely conduct of our clinical trials, and while we have agreements governing
their committed activities, we have limited influence over their actual performance. 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 drugs to market before we do and impair our ability to successfully commercialize our product candidates and may harm
our business and results of operations.
The outcome of preclinical testing
and early clinical trials may not be predictive of the success of later clinical trials, interim results of a clinical trial do
not necessarily predict final results, and the results of our clinical trials may not satisfy the requirements of the FDA or comparable
foreign regulatory authorities.
We currently have no
products approved for sale and we cannot guarantee that we will ever have marketable drugs. Clinical failure can occur at any stage
of clinical development. Clinical trials may produce negative or inconclusive results, and we or any future collaborators may decide,
or regulators may require us, to conduct additional clinical trials or preclinical studies. We will be required to demonstrate
with substantial evidence through adequate and well-controlled clinical trials that our product candidates are safe and effective
for use in treating specific conditions in order to obtain marketing approvals for their commercial sale. Success in preclinical
studies and early-stage clinical trials does not mean that future larger registration clinical trials will be successful because
product candidates in later-stage clinical trials may fail to demonstrate safety and efficacy to the satisfaction of the FDA and
non-U.S. regulatory authorities despite having progressed through preclinical studies and early-stage clinical trials. Product
candidates that have shown promising results in preclinical studies and early-stage clinical trials may still suffer significant
setbacks in subsequent registration clinical trials. Additionally, the outcome of preclinical studies and early-stage clinical
trials may not be predictive of the success of later-stage clinical trials.
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From time to time,
we may publish or report interim or preliminary data from our clinical trials, once initiated. Interim or preliminary data from
clinical trials that we may conduct may not be indicative of the final results of the trial and 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.
Interim or preliminary data also remain subject to audit and verification procedures that may result in the final data being materially
different from the interim or preliminary data. As a result, interim or preliminary data should be viewed with caution until the
final data are available.
In addition, the design
of a clinical trial can determine whether its results will support approval of a drug and flaws in the design of a clinical trial
may not become apparent until the clinical trial is well advanced. We have limited experience in designing clinical trials and
may be unable to design and conduct a clinical trial to support marketing approval. Further, if our product candidates are found
to be unsafe or lack efficacy, we will not be able to obtain marketing approval for them and our business would be harmed. A number
of companies in the pharmaceutical industry, including those with greater resources and experience than us, have suffered significant
setbacks in advanced clinical trials, even after obtaining promising results in preclinical studies and earlier clinical trials.
In some instances,
there can be significant variability in safety and efficacy results between different clinical trials of the same product candidate
due to numerous factors, including changes in trial protocols, differences in size and type of the patient populations, differences
in and adherence to the dosing regimen and other trial protocols and the rate of dropout among clinical trial participants. We
do not know whether any clinical trials we may conduct will demonstrate consistent or adequate efficacy and safety sufficient to
obtain marketing approval to market our product candidates.
In the event that an
adverse safety issue, clinical hold or other adverse finding occurs in one or more of our clinical trials, once initiated, such
event could adversely affect our other clinical trials using the same product candidate. Moreover, there is a relatively limited
safety data set for product candidates using an exosome platform. An adverse safety issue or other adverse finding in a clinical
trial conducted by a third party with a product candidate similar to ours could adversely affect our clinical trials.
Further, our product
candidates may not be approved even if they achieve their primary endpoints in Phase 3 clinical trials or registration trials.
The FDA or comparable foreign regulatory authorities may disagree with our trial design and our interpretation of data from preclinical
studies and clinical trials. In addition, any of these regulatory authorities may change requirements for the approval of a product
candidate even after reviewing and providing comments or advice on a protocol for a pivotal clinical trial that has the potential
to result in approval by the FDA or comparable foreign regulatory authorities. In addition, any of these regulatory authorities
may also approve a product candidate for fewer or more limited indications than we request or may grant approval contingent on
the performance of costly post-marketing clinical trials. In addition, the FDA or other comparable foreign regulatory authorities
may not approve the labeling claims that we believe would be necessary or desirable for the successful commercialization of our
product candidates.
Before obtaining marketing
approvals for the commercial sale of any product candidate for a target indication, we must demonstrate with substantial evidence
gathered in preclinical studies and adequate and well-controlled clinical trials, and, with respect to approval in the United
States, to the satisfaction of the FDA and elsewhere to the satisfaction of other comparable foreign regulatory authorities, that
the product candidate is safe and effective for use for that target indication. There is no assurance that the FDA or other comparable
foreign regulatory authorities will consider our future clinical trials to be sufficient to serve as the basis for approval of
one of our product candidates for any indication. The FDA and other comparable foreign regulatory authorities retain broad discretion
in evaluating the results of our clinical trials and in determining whether the results demonstrate that a product candidate is
safe and effective. If we are required to conduct additional clinical trials of a product candidate than we expect prior to its
approval, we will need substantial additional funds and there is no assurance that the results of any such additional clinical
trials will be sufficient for approval.
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The failure to obtain required regulatory
clearances or approvals for any companion diagnostic tests that we may pursue may prevent or delay approval of any of our product
candidates. Moreover, the commercial success of any of our product candidates that require a companion diagnostic will be tied
to the receipt of any required regulatory clearances or approvals and the continued availability of such tests.
In connection with
the clinical development of our product candidates for certain indications, we may work with collaborators to develop or obtain
access to companion diagnostic tests to identify appropriate patients for our product candidates. We may rely on third parties
for the development, testing and manufacturing of these companion diagnostics, the application for and receipt of any required
regulatory clearances or approvals, and the commercial supply of these companion diagnostics. The FDA and foreign regulatory authorities
regulate companion diagnostics as medical devices that will likely be subject to clinical trials in conjunction with the clinical
trials for product candidates, and which will require separate regulatory clearance or approval prior to commercialization. This
process could include additional meetings with health authorities, such as a pre-submission meeting and the requirement to submit
an investigational device exemption. In the case of a companion diagnostic that is designated as “significant risk device,”
approval of an investigational device exemption by the FDA and IRB is required before such diagnostic is used in conjunction with
the clinical trials for a corresponding product candidate. We or our third-party collaborators may fail to obtain the required
regulatory clearances or approvals, which could prevent or delay approval of our product candidates. In addition, the commercial
success of any of our product candidates that require a companion diagnostic will be tied to and dependent upon the receipt of
required regulatory clearances or approvals and the continued ability of such third parties to make the companion diagnostic commercially
available to us on reasonable terms in the relevant geographies.
If we are required to in the future
and if we are unable to successfully develop companion diagnostic tests for our product candidates that require such tests, or
experience significant delays in doing so, we may not realize the full commercial potential of these product candidates.
We may be required
by the FDA to develop, either by ourselves or with collaborators, companion diagnostic tests for our product candidates for certain
indications. To be successful, we or our collaborators will need to address a number of scientific, technical, regulatory and logistical
challenges. We have no prior experience with medical device or diagnostic test development. If we choose to develop and seek FDA
approval for companion diagnostic tests on our own, we will require additional personnel. We may rely on third parties for the
design, development and manufacture of companion diagnostic tests for our therapeutic product candidates that require such tests.
If these parties are unable to successfully develop companion diagnostics for these therapeutic product candidates, or experience
delays in doing so, we may be unable to enroll enough patients for our current and planned clinical trials, the development of
these therapeutic product candidates may be adversely affected, these therapeutic product candidates may not obtain marketing approval,
and we may not realize the full commercial potential of any of these therapeutics that obtain marketing approval. Any failure to
successfully develop this companion diagnostic may cause or contribute to delayed enrollment of this trial, and may prevent us
from initiating or completing further clinical trials to support marketing approval for our product candidates. As a result, our
business, results of operations and financial condition could be materially harmed.
We may be unsuccessful in adapting
our COVID-19 vaccine or developing future versions of our COVID-19 vaccine to protect against variants of the SARS-CoV-2 virus
and a market for vaccines against these variants may not develop.
As the pandemic has
continued, the SARS-CoV-2 virus continues to evolve, and new strains of the virus or those that are already in circulation may
prove more transmissible or cause more severe forms of COVID-19 disease than the predominant strains to date. There is a risk that
any vaccine product candidates we develop will not be as effective in protecting against variant strains of the SARS-CoV-2 virus.
The failure to adapt our vaccine product candidate to other variants of the SARS-CoV-2 virus could lead to significant reputational
harm, in addition to adversely affecting our financial results. It is also possible that we may expend significant resources adapting
our COVID-19 vaccine to protect against variants of the SARS-CoV-2 virus, but that a market for this adapted vaccine does not develop
or demand does not align with our projections or cost expenditures.
The regulatory pathway for COVID-19
vaccines is continually evolving, and may result in unexpected or unforeseen challenges.
The speed at which
all parties are acting to create and test many therapeutics and vaccines for COVID-19 is atypical, and evolving or changing plans
or priorities within the FDA or the regulatory authorities in other jurisdictions, including changes based on new knowledge of
COVID-19 and how the disease affects the human body, and new variants of the virus, may significantly affect the regulatory timeline
for further authorizations or approvals for our COVID vaccine. We cannot anticipate or predict with certainty the timelines or
regulatory processes that may be required for the development of ourCOVID-19 vaccine, or vaccines that may be developed to fight
against variants of the SARS-CoV-2 virus.
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We may not be successful in our efforts to identify or
discover additional potential product candidates.
Our research programs may initially
show promise in identifying potential product candidates, yet fail to yield product candidates for clinical development for a number of
reasons, including:
Research programs to
identify new product candidates require substantial technical, financial and human resources. If we are unable to identify suitable
compounds for preclinical and clinical development, our business would be harmed.
Negative perception of the efficacy,
safety, or tolerability of any investigational medicines that we develop, or of other products similar to products we are developing,
such as mRNA medicines and COVID-19 vaccines, could adversely affect our ability to conduct our business, advance our investigational
medicines, or obtain regulatory approvals.
To date, COVID-19 vaccines
have only received EUAs in the United States, and FDA has not granted full approval of a BLA for any COVID-19 vaccine. Other than
these EUAs, no other mRNA medicines have been granted EUA or have been approved to date by the FDA or any other regulatory agency.
Adverse events in clinical trials of our investigational medicines or in clinical trials of others developing similar products,
including other mRNA COVID-19 vaccine, and the resulting publicity, as well as any other adverse events in the field of mRNA medicine,
or other products that are perceived to be similar to mRNA medicines, such as those related to gene therapy or gene editing, could
result in a decrease in the perceived benefit of one or more of our programs, increased regulatory scrutiny, decreased confidence
by patients and clinical trial collaborators in our investigational medicines, and less demand for any product that we may develop.
If and when they are used in clinical trials, our developmental candidates and investigational medicines could result in a greater
quantity of reportable adverse events, including suspected unexpected serious adverse reactions, other reportable negative clinical
outcomes, manufacturing reportable events or material clinical events that could lead to clinical delay or hold by the FDA or applicable
regulatory authority or other clinical delays, any of which could negatively impact the perception of one or more of our programs,
as well as our business as a whole. In addition, responses by U.S., state, or foreign governments to negative public perception
may result in new legislation or regulations that could limit our ability to develop any investigational medicines or commercialize
any approved products, obtain or maintain regulatory approval, or otherwise achieve profitability. More restrictive statutory regimes,
government regulations, or negative public opinion would have an adverse effect on our business, financial condition, results of
operations, and prospects and may delay or impair the development of our investigational medicines and commercialization of any
approved products or demand for any products we may develop.
If any of our product candidates
receives marketing approval or an EUA and we, or others, later discover that the drug is less effective than previously believed
or causes undesirable side effects that were not previously identified, our ability, or that of any future collaborators, to market
the drug could be compromised.
Clinical trials of
our product candidates must be conducted in carefully defined subsets of patients who have agreed to enter into clinical trials.
Consequently, it is possible that our clinical trials, or those of any future collaborator, may indicate an apparent positive effect
of a product candidate that is greater than the actual positive effect, if any, or alternatively fail to identify undesirable side
effects. If one or more of our product candidates receives marketing approval and we, or others, discover that the drug is less
effective than previously believed or causes undesirable side effects that were not previously identified, a number of potentially
significant negative consequences could result, including:
· the drug may become less competitive in the marketplace; and
· our reputation may suffer.
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Any of these events
could have a material and adverse effect on our operations and business and could adversely impact our stock price.
Even if any of our product candidates
receive marketing approval, they may fail to achieve the degree of market acceptance by physicians, patients, healthcare payors
and others in the medical community necessary for commercial success.
If any of our product
candidates receive marketing approval, they may nonetheless fail to gain sufficient market acceptance by physicians, patients,
healthcare payors and others in the medical community. If our product candidates do not achieve an adequate level of acceptance,
we may not generate significant revenues from sales of drugs and we may not become profitable. The degree of market acceptance
of our product candidates, if approved for commercial sale, will depend on a number of factors, including:
· the efficacy and safety of the product;
· the potential advantages of the product compared to alternative therapies;
· the prevalence and severity of any side effects;
· the strength of sales, marketing and distribution support;
We face substantial competition,
which may result in others discovering, developing or commercializing products before or more successfully than we do.
The pharmaceutical
and biotechnology industries are highly competitive and characterized by rapidly advancing technologies, evolving understanding
of disease etiology and a strong emphasis on proprietary drugs. We face competition with respect to any product candidates that
we may seek to discover and develop or commercialize in the future, from major pharmaceutical, specialty pharmaceutical and biotechnology
companies. Potential competitors also include academic institutions and governmental agencies and public and private research institutions.
Many of the companies
that we compete or may compete against in the future have significantly greater financial resources and expertise in research and
development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved
drugs than we do. Small or early-stage companies may also prove to be significant competitors, particularly through collaborative
arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified
scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well
as in acquiring technologies complementary to, or that may be necessary for, our programs.
Our commercial opportunity
could be reduced or eliminated if our competitors develop and commercialize drugs that are safer, more effective, have fewer or
less severe side effects, are more convenient or are less expensive than any drugs that we may develop. Our competitors also may
obtain FDA or other comparable foreign regulatory approval for their drugs more rapidly than we may obtain approval for ours, which
could result in our competitors establishing a strong market position before we are able to enter the market. The key competitive
factors affecting the success of all of our product candidates, if approved, are likely to be their efficacy, safety, convenience,