ITEM 1A. Risk Factors
Risk factors that could cause actual results to
differ from our expectations and that could negatively impact our financial condition and results of operations are discussed below and
elsewhere in this Annual Report. Additional risks and uncertainties not presently known to us or that are currently not believed
to be significant to our business may also affect our actual results and could harm our business, financial condition and results of operations. If
any of the risks or uncertainties described below or any additional risks and uncertainties actually occur, our business, results of operations
and financial condition could be materially and adversely affected.
Risks Relating to Our Business
We have a limited operating history and we may never generate revenue
or profit.
We are a clinical-stage biotechnology company that
commenced activities in January 2012. We have a limited operating history, and our business plan has not been tested. Since inception,
we have had no revenue and have incurred significant operating losses. We have financed our operations primarily through equity and debt
offerings. To generate revenue and become and remain profitable, we need to successfully complete our existing clinical trials, cultivate
partnerships with pharmaceutical companies, and develop and commercialize gedatolisib pursuant to our license agreement with Pfizer. We
must also build operational and financial infrastructure to support commercial operations, train and manage employees, and market and
sell our anticipated drug product.
We may never succeed in any of these activities and,
even if we do, we may never generate revenue that is sufficient to achieve profitability. We expect to continue to incur significant expenses
and operating losses for the foreseeable future, and the net losses we incur may fluctuate significantly from quarter to quarter. Our
failure to become and remain profitable would decrease our value and could impair our ability to raise capital, maintain or expand our
research and development efforts, expand our business, or continue our operations.
Our inability to raise additional capital on acceptable terms in
the future may limit our ability to develop and commercialize our drug candidate, gedatolisib.
We will require additional capital to finance operating
expenses and capital expenditures over the next several years if we launch gedatolisib and expand our infrastructure, commercial operations
and research and development activities. If we are not able to secure additional funding when needed, we may have to delay, reduce the
scope of or eliminate one or more research and development programs or selling and marketing initiatives. In addition, we may have to
work with a partner on one or more of our products or market development programs, which could lower the economic value of those programs
to our company.
Future financing activities could dilute the percentage ownership
of our stockholders and could cause our stock price to fall or could result in operating or other restrictions.
We may seek to raise additional capital through equity
offerings, debt financings, collaborations or licensing arrangements. Additional funding may not be available to us on acceptable terms,
or at all. If we raise funds by issuing equity securities, it will result in dilution to current stockholders. Any equity securities issued
may also provide for rights, preferences or privileges senior to those of holders of our existing securities. The incurrence of additional
indebtedness or the issuance of certain equity securities could result in increased fixed payment obligations and could also include restrictive
covenants, such as limitations on our ability to incur additional debt or issue additional equity, limitations on our ability to acquire
or license intellectual property rights, and other operating restrictions that could adversely affect our ability to conduct our business.
In the event that we enter into collaborations or licensing arrangements to raise capital, we may be required to accept unfavorable terms.
We are dependent on our ability to attract and retain key personnel.
Our operations are materially dependent upon the services
of our officers and key employees, including Brian F. Sullivan, our Chief Executive Officer, and Dr. Lance G. Laing, our Chief Science
Officer. Successful implementation of our business plan will also require the services of other consultants and additional personnel.
We cannot assure you that we will be able to attract and retain such persons as employees, independent contractors, consultants or otherwise.
If we are not able to attract individuals with the skills required for our business, or if we lose the services of either Mr. Sullivan
or Dr. Laing, we may be unable to successfully implement our business plan.
Product liability claims may damage our reputation and, if insurance
proves inadequate, these claims may harm our business.
We may be exposed to the risk of product liability
claims that is inherent in the biopharmaceutical industry. A product liability claim may damage our reputation by raising questions about
our product’s safety and efficacy and could limit our ability to sell one or more products by preventing or interfering with commercialization
of our drug candidate. In addition, product liability insurance for the biopharmaceutical industry is generally expensive to the extent
it is available at all. There can be no assurance that we will be able to obtain or maintain such insurance on acceptable terms for any
product we bring to market. Further, our product liability insurance coverage may not provide coverage or may be insufficient to reimburse
us for any or all expenses or losses we may suffer. A successful claim against us with respect to uninsured liabilities or in excess of
insurance coverage could have a material adverse effect on our business, financial condition and results of operations.
We expect to expand our development and regulatory capabilities and
potentially implement sales, marketing and distribution capabilities, and as a result, we may encounter difficulties in managing our growth,
which could disrupt our operations.
We expect to experience significant growth in the
number of our employees and the scope of our operations, particularly in the areas of drug development, regulatory affairs and, if our
product candidate receives marketing approval, sales, marketing and distribution. To manage our anticipated future growth, we must continue
to implement and improve our managerial, operational and financial systems, expand our facilities and continue to recruit and train additional
qualified personnel. Due to our limited financial and human resources, we may not be able to effectively manage the expansion of our operations
or recruit and train additional qualified personnel. The expansion of our operations may lead to significant costs and may divert our
management and business development resources. Any inability to manage growth could delay the execution of our business plans or disrupt
our operations.
Risks Related to Our Product Strategy
Our near-term revenue prospects depend on the success of our initial
drug product, gedatolisib. If we are unable to successfully complete clinical development of, obtain regulatory approval for or commercialize
gedatolisib, or if we experience delays in doing so, our business will be materially harmed.
To date, we have not yet completed any registrational
clinical trials or the development of our initial drug candidate, gedatolisib. Our future success and ability to generate revenue, which
we do not expect until 2026 or later, if ever, is dependent on our ability to successfully develop, obtain regulatory approval for and
commercialize gedatolisib for one or more intended uses. We may not have the financial resources to continue development of, or to modify
existing or enter into new collaborations for, our current or future product candidates if we experience any issues that delay or prevent
regulatory approval of, or our ability to commercialize, gedatolisib, including:
● delays in enrolling subjects in clinical trials;
● high drop-out rates of subjects from clinical trials;
● greater than anticipated clinical trial or manufacturing costs;
We were not involved in the early development of gedatolisib; therefore,
we are dependent on third parties having accurately generated, collected, interpreted and reported data from certain preclinical and clinical
trials of gedatolisib.
We had no involvement with or control over the initial
preclinical and clinical development of gedatolisib. We are dependent on third parties having conducted their research and development
in accordance with the applicable protocols and legal, regulatory and scientific standards; having accurately reported the results of
all preclinical studies and clinical trials conducted with respect to such drug product; and having correctly collected and interpreted
the data from these trials. If these activities were not compliant, accurate or correct, the clinical development, regulatory approval
or commercialization of our drug product will be delayed and may be adversely affected.
We have not yet successfully completed any registrational clinical
trials, and we may be unable to do so for any drug candidates we may develop.
We will need to successfully complete registrational
clinical trials in order to obtain the approval of the FDA or comparable foreign regulatory authorities to market our drug product. Carrying
out clinical trials, including later-stage registrational clinical trials, is a complicated process. As an organization, we have not previously
completed any registrational clinical trials. In order to do so, we are building and expanding our clinical development and regulatory
capabilities, and there is risk that we may be unable to recruit and train qualified personnel. We also expect to continue to rely on
third parties to conduct our clinical trials. If these third parties do not successfully carry out their contractual duties, meet expected
deadlines or comply with regulatory requirements, we may not be able to obtain regulatory approval of or commercialize any product candidates.
Consequently, we may be unable to successfully and efficiently execute and complete necessary clinical trials in a way that leads to submission
and approval of our drug product. We may require more time and incur greater costs than our competitors and may not succeed in obtaining
regulatory approval of any drug products that we develop. Failure to commence or complete, or delays in, our planned clinical trials,
could prevent us from or delay us in commercializing our drug products.
The successful development of our products is highly uncertain.
Our business depends on the successful development
of biopharmaceuticals, which is highly uncertain and is dependent on numerous factors, many of which are beyond our control. Product candidates
that appear promising in the early phases of development may fail to reach the market for several reasons including, among other things,
that clinical trial results may show the product candidates to be less effective than expected or to have unacceptable side effects or
toxicities; we may fail to receive the necessary regulatory approvals or there may be a delay in receiving such approvals; or the proprietary
rights of others and their competing products and technologies may prevent our product candidates from being commercialized.
The length of time necessary to complete clinical
trials and to submit an application for marketing approval for a final decision by a regulatory authority varies significantly from one
drug product to the next and from one country to the next and may be difficult to predict. We will incur significant research and development
expenses before knowing whether our products are commercially viable, and may abandon development of a specific trial, or a product candidate,
at any time for a variety of reasons. If we expend resources on products that are ultimately not commercially viable, our timing for becoming
profitable and our ability to invest in other products in our pipeline would be adversely affected.
In addition, if gedatolisib
receives marketing approval for the intended uses that we are pursuing, we will continue to be subject to significant post-approval regulatory
obligations. Compliance with these requirements is costly, and any failure to comply or other issues with our drug products post-approval
could adversely affect our business, financial condition and results of operations. In addition, there is always the risk that we, a regulatory
authority or a third party might identify previously unknown problems with a product post-approval, such as adverse events of unanticipated
severity or frequency.
If we encounter difficulties enrolling patients in any of our clinical
trials, our clinical development activities could be delayed or otherwise adversely affected.
The timely completion of clinical trials in accordance
with their protocols depends, among other things, on our ability to enroll a sufficient number of patients who remain in the trial until
its conclusion. We may experience difficulties in patient enrollment in our clinical trials for a variety of reasons, including:
● the patient eligibility and exclusion criteria defined in the protocol;
● the proximity of patients to clinical trial sites;
● the design of the clinical trial;
● perception of the safety profile of our drug products;
● our ability to obtain and maintain patient consents; and
Delays in patient enrollment may result in increased
costs or may affect the timing or outcome of our clinical trials, which could prevent completion of these trials and adversely affect
our ability to advance the development of our product candidates.
Interim, topline and preliminary data from our clinical studies that
we announce or publish from time to time may change as more data becomes 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 preliminary
or topline data from our clinical studies, 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. 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 studies that we may complete are subject
to the risk that one or more of the clinical outcomes may materially change as more patient data becomes available. Adverse differences
between preliminary or interim data and final data could significantly harm our reputation and marketing efforts.
Further, others, including healthcare providers or
payors, 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 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 our business. If the topline or interim data that
we report differ from actual results, or if others, including healthcare providers or payors, disagree with the conclusions reached, our
ability to commercialize our product candidate may be harmed, which could harm our business, operating results, prospects or financial
condition.
Clinical development involves a lengthy and expensive process, with
an uncertain outcome. We may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development
and commercialization of our product candidates.
To obtain the requisite regulatory approvals to commercialize
any drug products, we must demonstrate through extensive preclinical studies and clinical trials that such drug product is safe and effective
in humans. Clinical testing is expensive and can take many years to complete, and its outcome is inherently uncertain. We may be unable
to establish clinical endpoints that applicable regulatory authorities would consider clinically meaningful, and a clinical trial can
fail at any stage of testing.
Differences in trial design between early-stage clinical
trials and later-stage clinical trials, which involve a greater number of patients and take years to complete, make it difficult to extrapolate
the results of earlier clinical trials to later clinical trials. Moreover, clinical data are often susceptible to varying interpretations
and analyses, and many companies that have believed their product candidates performed satisfactorily in clinical trials have nonetheless
failed to obtain marketing approval of their products. Additionally, we are conducting and plan to conduct some open-label clinical trials,
where both the patient and investigator know whether the patient is receiving the investigational product candidate or either an existing
approved drug or placebo. Most typically, open-label clinical trials test only the investigational product candidate and sometimes may
do so at different dose levels. Open-label clinical trials are subject to various limitations that may exaggerate any therapeutic effect
as patients in those trials are aware when they are receiving treatment. Open-label clinical trials may be subject to a “patient
bias” where patients perceive their symptoms to have improved merely due to their awareness of receiving an experimental treatment.
In addition, open-label clinical trials may be subject to an “investigator bias” where those assessing and reviewing the outcomes
of the clinical trials are aware of which patients have received treatment and may interpret the information of the treated group more
favorably given this knowledge. Where a randomized, placebo-controlled clinical trial is designed to allow enrolled subjects to cross-over
to the treatment arm, there may be a risk of inadvertent unblinding of subjects prior to cross-over, which may limit the clinical meaningfulness
of those data and may require the conduct of additional clinical trials. As such, the results from an open-label clinical trial may not
be predictive of future clinical trial results with any of our product candidates for which we include an open-label clinical trial when
studied in a controlled environment with a placebo or active control.
Successful completion of clinical trials is a prerequisite
to submitting a new drug application, or NDA, to the FDA and similar marketing applications to comparable foreign regulatory authorities
for each drug product and, consequently, the ultimate approval and commercial marketing of any drug products. We may experience delays
in initiating or completing clinical trials, including if it takes longer than expected to activate the targeted number of clinical sites,
if the enrollment of patients is slower than anticipated or negatively affected by staffing shortages at clinical sites, or by other unanticipated
factors, or if the FDA or other regulatory authorities require us to pause one or more of our clinical trials due to unexpected safety
issues. We also may experience numerous unforeseen events during, or as a result of, any future clinical trials that we could conduct
that could delay or prevent our ability to receive marketing approval or commercialize our current product candidates or any future product
candidates.
Our costs will increase if we experience delays in
clinical testing or marketing approvals. We do not know whether our clinical trials will begin or continue as planned, will need to be
reassigned or will be completed on schedule, or at all. Significant clinical trial delays also could shorten any periods during which
we may have the exclusive right to commercialize our product candidates and may allow our competitors to bring products to market before
we do, potentially impairing our ability to successfully commercialize our product candidates and harming our business and results of
operations. Any delays in our clinical development programs may harm our business, financial condition and results of operations significantly.
We face significant competition, and our operating results will suffer
if we fail to compete effectively.
Our industry is characterized by intense competition
and rapid innovation. Our competitors may be able to develop other compounds or drugs that are able to achieve similar or better results
than our lead product candidate, gedatolisib. Our potential competitors include major multinational pharmaceutical companies, established
biotechnology companies, specialty pharmaceutical and diagnostic companies, and universities and other research institutions. Many of
our competitors have substantially greater financial, technical and other resources, such as larger research and development staff and
experienced marketing and manufacturing organizations and well-established sales forces.
Smaller or early-stage companies may also prove to
be significant competitors, particularly as they develop novel approaches to treating disease indications that gedatolisib is also focused
on treating. Established pharmaceutical companies may also invest heavily to accelerate discovery and development of novel therapeutics
or to in-license novel therapeutics that could make the product candidates that we develop obsolete. Mergers and acquisitions in the biotechnology
and pharmaceutical industries may result in even more resources being concentrated in our competitors.
Competition may increase further as a result of advances
in the commercial applicability of technologies and greater availability of capital for investment in these industries. Our competitors,
either alone or with collaboration partners, may succeed in developing, acquiring or licensing on an exclusive basis products that are
more effective, safer, more easily commercialized or less costly than our product candidates or may develop proprietary technologies or
secure patent protection that we may need for the development of our technologies and products. We believe the key competitive factors
that will affect the development and commercial success of our product candidates are efficacy, safety, tolerability, reliability, convenience
of use, price, and reimbursement.
Even if we obtain regulatory approval of drug products,
the availability and price of our competitors’ products could limit the demand and the price we are able to charge for our product
candidates. We may not be able to implement our business plan if the acceptance of our product candidates is inhibited by price competition
or the reluctance of physicians to switch from existing methods of treatment to our product candidates, or if physicians switch to other
new drug or biologic products or choose to reserve our product candidates for use in limited circumstances.
If our information technology systems or data, or those of third
parties upon which we rely, are or were compromised, we could face clinical trial delays; regulatory investigations or actions; litigation;
fines and penalties; disruptions of our business operations; reputational harm; and other adverse consequences.
Cyberattacks, malicious internet-based activity, online
and offline fraud, and other similar activities threaten the confidentiality, integrity, and availability of our sensitive information
and information technology systems, and those of the third parties upon which we rely. We rely on contract research organizations, contract
manufacturing organizations, distributors, supply chain resources, and other third-party service providers and technologies to operate
critical business systems to process sensitive information in a variety of contexts, including, without limitation, on-site systems and
cloud-based data centers, systems handling human resources, financial reporting and controls, customer relationship management, regulatory
compliance, and other infrastructure operations. We also communicate sensitive data, including patient data, electronically, and through
relationships with multiple third-party vendors and their subcontractors. These applications and data encompass a wide variety of sensitive
information, including research and development information, patient data, commercial information, and business and financial information.
Our ability to monitor these third parties’ security practices is limited, and these third parties may not have adequate security
measures in place. If we or any of our third-party service providers experience a security incident or other interruption, we could experience
adverse consequences. We cannot guarantee that third parties and infrastructure in our supply chain or our third-party partners’
supply chains have not been compromised or that they do not contain exploitable defects or bugs that could result in a breach of or disruption
to our information technology systems or the third-party information technology systems that support us and our services.
Cybersecurity threats are becoming increasingly difficult
to detect, and come from a variety of sources, including without limitation, nation-state actors and activists that create disruption
for geopolitical reasons and in conjunction with military conflicts and defense activities. This risk is heightened during times of war
and other major conflicts, including the war between Russia and Ukraine, the conflict between Israel and Hamas and the risk of a larger
regional conflict. In addition, we and the third parties upon which we rely face an evolving cybersecurity threat landscape, which includes
social-engineering attacks (including through deep fakes, which may be increasingly more difficult to identify as fake, and phishing attacks),
malicious code (such as viruses and worms), malware (including as a result of advanced persistent threat intrusions), denial-of-service
attacks, credential stuffing, credential harvesting, personnel misconduct or error, ransomware attacks, supply-chain attacks, software
bugs, server malfunctions, attacks enhanced or facilitated by artificial intelligence (“AI”), software or hardware failures,
loss of data or other information technology assets, adware, telecommunications failures, natural disasters, terrorism, and other similar
threats.
The majority of our employees and contractors work
remotely. Remote work involves risks to our information technology systems and data, as individuals utilize network connections, computers
and devices outside our premises or network, including working at home, while in transit and in public locations.
Ransomware attacks also continue to increase in prevalence
and severity and can lead to significant interruptions in our operations, ability to provide our services, loss of data and income, reputational
harm, and diversion of funds. Extortion payments may alleviate the negative impact of a ransomware attack, but we may be unwilling or
unable to make such payments due to, for example, applicable laws or regulations prohibiting such payments.
While we take steps designed to identify, prevent,
assess and mitigate vulnerabilities in our information systems and to mitigate related third-party risks, there can be no assurance that
we will be able to detect and remediate all such vulnerabilities, including on a timely basis. The threats and techniques used to exploit
vulnerabilities change frequently and are often sophisticated in nature. Therefore, we (or third parties on whom we rely) may be unable
to detect a vulnerability until after a security incident has occurred. Further, we or third parties on which we rely may face downtime
as a result of adopting new information technology systems that are designed to enhance compliance or reduce vulnerabilities.
A security incident or other interruption could result
in unauthorized, unlawful, or accidental acquisition, modification, destruction, loss, alteration, encryption, disclosure of, or access
to our sensitive information or our information technology systems, or those of the third parties upon whom we rely. This could disrupt
our clinical trials, damage our reputation, and negatively affect our ability to conduct our business in the ordinary course, including
our ability to collect, process, and prepare company financial information, provide information and educational materials through our
website, and manage the administrative aspects of our business.
We may expend significant resources or modify our
business activities (including our clinical trial activities) to try to protect against security incidents. Additionally, certain data
privacy and security obligations may require us to implement and maintain certain measures to protect our information technology systems
and sensitive information and to notify relevant stakeholders, including affected individuals, regulatory authorities and our stockholders,
of certain security incidents. The disclosure decisions are complex, may take time to determine, and may be subject to change as an investigation
progresses. Providing disclosure may be costly, and the failure to comply with such requirements could also lead to adverse consequences.
If we (or a third party upon whom we rely) experience a security incident or are perceived to have experienced a security incident, we
may face government enforcement actions (for example, investigations, fines, penalties, audits, and inspections); additional reporting
requirements and/or oversight; restrictions on processing sensitive information (including personal information); litigation (including
class claims) and mass arbitration; indemnification obligations; negative publicity; reputational harm; monetary fund diversions; interruptions
in our operations (including availability of data); financial loss; and other similar harms. Accordingly, security incidents and attendant
consequences may damage our financial position and negatively impact our ability to grow and operate our business.
Further, if the information technology systems of
the third parties upon which we rely become subject to security incidents, we may have insufficient recourse against such third parties,
and we may have to expend significant resources to mitigate the impact of such an event, and to develop and implement protections to prevent
future events of this nature from occurring. There can be no assurance that limitations of liability in our third-party contracts are
sufficient to protect us from liabilities, damages, or claims related to our data privacy and security obligations. We cannot be sure
that our insurance coverage will be adequate or sufficient to protect us from or to mitigate liabilities arising out of our data privacy
and security practices. Additionally, we cannot be sure that such coverage will continue to be available on commercially reasonable terms
or at all, or that such coverage will pay future claims.
In addition to experiencing a security incident, third
parties may gather, collect, or infer sensitive information about us from public sources, data brokers, or other means that reveals competitively
sensitive details about our organization and could be used to undermine our competitive advantage or market position. Additionally, our
sensitive information could be leaked, disclosed, or revealed as a result of or in connection with our employees’, personnel’s,
or vendors’ use of generative AI technologies.
Public health matters may materially and
adversely impact our business, including ongoing clinical trials.
The outbreak of COVID-19
and government measures taken in response demonstrated that public health matters have a significant impact on the global economy, with
healthcare systems particularly affected. Future outbreaks or variants of COVID-19, or the emergence of other pandemics or public health
disruptions, could materially and adversely impact our clinical trials, business, financial condition and results of operations. Potential
disruptions include but are not limited to:
● diversion of healthcare resources away from the conduct of clinical trials;
Artificial intelligence presents risks and challenges that can impact
our business including by posing security risks to our confidential information, proprietary information and personal data.
Issues in the use of artificial intelligence, combined
with an uncertain regulatory environment, may result in reputational harm, liability or other adverse consequences to our business operations.
As with many technological innovations, artificial intelligence presents risks and challenges that could impact our business. Our vendors
may incorporate generative artificial intelligence tools into their offerings without disclosing this use to us, and the providers of
these generative artificial intelligence tools may not meet existing or rapidly evolving regulatory or industry standards with respect
to privacy and data protection and may inhibit our or our vendors’ ability to maintain an adequate level of service and experience.
If any of our vendors experiences an actual or perceived breach or privacy or security incident because of the use of generative artificial
intelligence, we may lose valuable intellectual property and confidential information and our reputation and the public perception of
the effectiveness of our security measures could be harmed. Further, bad actors around the world use increasingly sophisticated methods,
including the use of artificial intelligence, to engage in illegal activities involving the theft and misuse of personal information,
confidential information and intellectual property. Any of these outcomes could damage our reputation, result in the loss of valuable
property and information, and adversely impact our business.
Risks Related to Product Development and Product Regulation
If we are unable to obtain approval from the FDA or comparable foreign
regulatory authorities to market our products for their intended use, we will not be able to generate revenue. For a new drug to be approved
for marketing, the FDA and other regulatory authorities must determine that the drug is safe and effective. Because all drugs can have
adverse effects, the data from our Phase 3 clinical study must demonstrate to the satisfaction of the FDA and other health authorities
that the benefits of gedatolisib in combination with palbociclib and fulvestrant, gedatolisib in combination with fulvestrant, or gedatolisib
in combination with fulvestrant plus a CDK4/6 inhibitor, outweigh its risks. Failure to demonstrate sufficient magnitude of benefit, even
if the benefit is found to be statistically significant, may not support regulatory approval.
The marketability of our products, particularly gedatolisib,
depends on securing approval from the FDA and equivalent foreign regulatory bodies. This requires rigorous pre-clinical and clinical studies,
including Phase 3 clinical trials for each intended use, that the benefits of the therapy outweigh its risks. Failure to demonstrate sufficient
magnitude of benefit, even if the benefit is found to be statistically significant, may not support regulatory approval. Satisfaction
of the FDA’s regulatory requirements typically takes many years and requires substantial resources for research, development and
testing.
If
a drug meets its primary efficacy endpoint objective in a Phase 3 clinical trial, and the drug sponsor has additional nonclinical
and clinical data required by the FDA or other regulatory authorities, the drug sponsor may submit an NDA seeking marketing
approval. Upon submission of an NDA, these health authorities perform a benefit-risk assessment that considers the strength and
quality of evidence available and takes remaining uncertainties into account. These considerations include an assessment of the
strengths and limitations of clinical trials, including design, and potential implications for assessing drug efficacy, the
magnitude of benefit and interpretation of clinical importance, the benefit attributed to the drug when studied in combination with
other therapies, and the clinical relevance of the study endpoints. We are currently conducting a Phase 3 clinical trial,
VIKTORIA-1, evaluating gedatolisib in combination with fulvestrant with or without palbociclib, in patients with HR+/HER2-
advanced breast cancer after progression on CDK4/6 therapy, conducting a Phase 3
clinical trial, VIKTORIA-2, evaluating gedatolisib in combination with a CDK4/6 inhibitor and fulvestrant as first-line treatment
for patients with endocrine treatment resistant HR+/HER2- advanced breast cancer, and
conducting a Phase 1b/2 clinical trial, CELC-G-201, evaluating gedatolisib in combination with darolutamide in patients with
metastatic castration resistant prostate cancer.
We have sought
feedback from the FDA and other regulatory authorities on the design of gedatolisib clinical trials, with the goal of addressing these
considerations in the clinical trials’ design. However, due to the complexity of clinical trials, the uncertainty of outcomes, and
the uncertainty of how the FDA and other regulatory authorities may balance benefits and risks in their review of an NDA, it may not be
practical or possible to address all benefit-risk assessment considerations in a clinical trial so that sufficient evidence is generated
to support a marketing approval, even if the primary endpoint objective is achieved in the Phase 3 stage of the trial. The FDA or other
regulatory authorities may require us to redesign or conduct additional unplanned clinical trials before granting any approval and we
may not get approval at all. Regulatory approval may also be delayed by changes in government regulation, future legislation or
administrative action or changes in FDA policy that occur prior to or during our regulatory review. We cannot predict whether our research
and clinical approaches will result in a drug that the FDA considers safe for humans and effective for indicated uses. In light of these
uncertainties, the results from clinical trials that we conduct may not support approval of gedatolisib.
If regulatory
approvals are delayed or not obtained, especially with respect to gedatolisib, it will negatively impact our ability to commercialize
our products and generate revenue and may diminish any competitive advantages that we may otherwise enjoy.
If we are required to conduct additional clinical trials or other testing of gedatolisib beyond those that we currently contemplate, if
we are unable to successfully complete clinical trials or other testing of gedatolisib, or if the results of these trials or tests are
not positive or are only modestly positive or if there are safety concerns, we may:
● be subject to changes in the way our products are administered;
● be sued; or
● experience damage to our reputation.
Additionally, if the size of the FDA group dedicated
to reviewing oncology-related submissions is reduced, further delays of any regulatory submission by Celcuity may be encountered.
Breakthrough Therapy Designation or Fast Track Designation from the
FDA may not actually lead to a faster development or regulatory review or approval process.
If a drug is intended for the treatment of a serious
or life-threatening condition and the product demonstrates the potential to address unmet medical needs for this condition, the product
sponsor may apply for Fast Track Designation. The designation offers the opportunity for frequent interactions with the FDA to discuss
the drug’s development plan and to ensure collection of appropriate data needed to support drug approval, as well as eligibility
for submission of a New Drug Application.
In addition, a drug may receive Breakthrough Therapy
Designation if it is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease
or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies
on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The benefits
of Breakthrough Therapy Designation include more intensive guidance from the FDA on an efficient development program, access to a scientific
liaison to help accelerate review time, and potential eligibility for priority review if relevant criteria are met. This designation can
expedite the development and regulatory review of an investigational medicine that is intended to treat a serious or life-threatening
condition.
Both Fast Track and Breakthrough Therapy Designations
are within the discretion of the FDA. While the FDA has granted both designations to our lead drug candidate, gedatolisib, such designations
may not result in a faster development process, review or approval compared to products considered for approval under conventional FDA
procedures, and neither designation assures ultimate approval by the FDA. In addition, the FDA may later decide that the product no longer
meets the qualification conditions and may rescind either or both such designations.
Obtaining and maintaining regulatory approval of our product candidates
in one jurisdiction does not mean that we will be successful in obtaining regulatory approval of our product candidates in other jurisdictions.
Obtaining and maintaining regulatory approval of our
product candidates in one jurisdiction does not guarantee that we will be able to obtain or maintain regulatory approval in any other
jurisdiction, while a failure or delay in obtaining regulatory approval in one jurisdiction may have a negative effect on the regulatory
approval process in others. For example, even if the FDA grants marketing approval of a product candidate, a comparable foreign regulatory
authority must also approve the manufacturing, marketing and promotion of the product candidate in those countries.
Approval procedures vary among jurisdictions and can
involve requirements and administrative review periods different from, and greater than, those in the U.S., including additional preclinical
studies or clinical trials, as clinical trials conducted in one jurisdiction may not be accepted by regulatory authorities in other jurisdictions.
In many jurisdictions outside the U.S., a product candidate must be approved for reimbursement before it can be approved for sale in that
jurisdiction. In some cases, the price that we intend to charge for our products is also subject to approval.
Obtaining foreign regulatory approvals and compliance
with foreign regulatory requirements could result in significant delays, difficulties and costs for us and could delay or prevent the
introduction of our products in certain countries. If we fail to comply with the regulatory requirements in international markets and/or
receive applicable marketing approvals, our target market will be reduced and our ability to realize the full market potential of our
product candidates will be harmed.
Even if we receive initial regulatory approvals, we will be subject
to ongoing regulatory obligations and continued regulatory review, which may result in significant additional expense, and we may be subject
to penalties if we fail to comply with regulatory requirements or experience unanticipated problems with our product candidates.
If any of our product candidates are approved, they
will be subject to ongoing regulatory requirements for manufacturing, labeling, packaging, storage, advertising, promotion, sampling,
record-keeping, conduct of post-marketing studies and submission of safety, efficacy and other post-marketing information, including both
federal and state requirements in the U.S. and requirements of comparable foreign regulatory authorities. In addition, we will be subject
to continued compliance with requirements for any clinical trials that we conduct post-approval.
Manufacturers and manufacturers’ facilities
are required to comply with extensive FDA and comparable foreign regulatory authority requirements. Accordingly, we and others with whom
we work must continue to expend time, money and effort in all areas of regulatory compliance, including manufacturing, production and
quality control.
Any regulatory approvals that we receive for our product
candidates may be subject to limitations on the approved indicated uses for which the product may be marketed or to the conditions of
approval, or contain requirements for potentially costly post-marketing testing, including Phase 4 clinical trials and surveillance to
monitor the safety and efficacy of the product candidate. Certain endpoint data we hope to include in any approved product labeling also
may not make it into such labeling, including exploratory or secondary endpoint data such as patient-reported outcome measures. The FDA
may impose consent decrees or withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems
occur after the product reaches the market. Later discovery of previously unknown problems with our product candidates, including adverse
events of unanticipated severity or frequency, or with our third-party manufacturers or manufacturing processes, or failure to comply
with regulatory requirements, may result in revisions to the approved labeling to add new safety information, imposition of post-marketing
studies or clinical trials to assess new safety risks or imposition of distribution restrictions or other restrictions under a REMS program.
Other potential consequences include, among other things:
● fines, warning letters or holds on clinical trials;
● injunctions or the imposition of civil or criminal penalties.
The FDA strictly regulates marketing, labeling, advertising
and promotion of products that are placed on the market. Products may be promoted only for the approved indications and in accordance
with the provisions of the approved label. If we are slow or unable to adapt to changes in existing requirements or adopt new requirements
or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we may have obtained and
we may not achieve or sustain profitability.
Our focus on the clinical development of gedatolisib has led us to
minimize the Company’s activities to support development of CELsignia, which will significantly delay, or potentially forestall,
further advancement of clinical development of CELsignia tests or finding appropriate pharmaceutical company partners.
The success of our CELsignia tests depends on our
ability to attract pharmaceutical company partnerships that provide revenue from the sale of CELsignia tests during clinical trials, from
milestone payments during clinical trials, from sales of our CELsignia tests as companion diagnostics or stand-alone tests thereafter,
and, potentially, from royalties on the incremental drug revenues our tests enable. Our ability to obtain such partnerships and generate
such revenue depends in part on the ability of our first CELsignia tests to demonstrate the potential incremental opportunity available
for pharmaceutical companies, as well as our ability to establish strategic partnerships or other arrangements with suitable pharmaceutical
companies. Since these activities are no longer a priority for the Company, further advancement of the clinical development of the CELsignia
platform will be substantially delayed or forestalled.
Risks Related to Intellectual Property
We depend on intellectual property licensed from third parties, including
from Pfizer for our lead product candidate, and termination of this license could result in the loss of significant rights, which would
harm our business.
We are dependent on patents, know-how and proprietary
technology, both our own and licensed from others. All patents covering gedatolisib and any combination therapies using our product candidates
are licensed from third parties. Any termination of a product license could result in the loss of significant rights and would cause material
adverse harm to our ability to commercialize our product candidates.
Disputes may also arise between us and our licensors
regarding intellectual property subject to a license agreement, including:
If disputes over intellectual property that we have
licensed prevent or impair our ability to maintain our current licensing arrangements on acceptable terms, we may be unable to successfully
develop and commercialize the affected product candidates.
We are generally also subject to all of the same risks
with respect to protection of intellectual property that we own, as we are for intellectual property that we license. If we or our licensors
fail to adequately protect this intellectual property, our ability to commercialize products could materially suffer.
If we fail to comply with our obligations under our patent license
with Pfizer, we could lose license rights that are important to our business.
We are a party to a license agreement with Pfizer
pursuant to which we in-license key patents for gedatolisib. This license imposes various diligence, milestone payment, royalty, insurance
and other obligations on us. If we fail to comply with these obligations, Pfizer may have the right to terminate the license, in which
event we would not be able to develop or market the products covered by such licensed intellectual property. Further, we cannot be certain
that the activities by these licensors were conducted in compliance with applicable laws and regulations or will result in additional
valid and enforceable patents and other intellectual property rights.
We may not be successful in obtaining or maintaining necessary rights
to develop any future product candidates on acceptable terms.
Our clinical trials and other programs currently,
and may in the future, involve additional product candidates that require the use of, or reliance on, proprietary rights held by third
parties. Accordingly, the growth of our business depends in part on our ability to acquire, in-license or use these proprietary rights.
We may be unable to acquire or in-license any compositions, methods of use, processes or other third-party intellectual property rights
from third parties that we identify as necessary or important to our business operations. We may fail to obtain any of these licenses
at a reasonable cost or on reasonable terms, if at all, which could harm our business. We may need to cease use of the compositions or
methods covered by such third-party intellectual property rights, and may need to seek to develop alternative approaches that do not infringe
on such intellectual property rights which may entail additional costs and development delays, even if we were able to develop such alternatives,
which may not be feasible. Even if we are able to obtain a license, it may be non-exclusive, thereby giving our competitors access to
the same technologies licensed to us. In that event, we may be required to expend significant time and resources to develop or license
replacement technology.
The licensing and acquisition of third-party intellectual
property rights is a competitive area, and companies that may be more established or have greater resources than we do may also be pursuing
strategies to license or acquire third-party intellectual property rights that we may consider necessary or attractive in order to commercialize
our product candidates. More established companies may have a competitive advantage over us due to their size, cash resources and greater
clinical development and commercialization capabilities. There can be no assurance that we will be able to successfully complete such
negotiations and ultimately acquire the rights to the intellectual property surrounding the additional product candidates that we may
seek to acquire.
If we are not able to prevent disclosure of our trade secrets and
other proprietary information, the value of our products could be significantly diminished.
We rely on trade secret protection to protect our
interests in proprietary know-how and in processes for which patents are difficult to obtain or enforce. We may not be able to protect
our trade secrets adequately. We have a policy of requiring our consultants, advisors and strategic partners to enter into confidentiality
agreements and our employees to enter into invention, non-disclosure and non-compete agreements. However, no assurance can be given that
we have entered into appropriate agreements with all parties that have had access to our trade secrets, know-how or other proprietary
information. There is also no assurance that such agreements will provide meaningful protection of our trade secrets, know-how or other
proprietary information in the event of any unauthorized use or disclosure of information. Furthermore, we cannot provide assurance that
any of our employees, consultants, contract personnel, or strategic partners, either accidentally or through willful misconduct, will
not cause serious damage to our programs and/or our strategy, for example by disclosing important trade secrets, know-how or proprietary
information to our competitors. It is also possible that our trade secrets, know-how or other proprietary information could be obtained
by third parties as a result of breaches of our physical or electronic security systems. Any disclosure of confidential data into the
public domain or to third parties could allow our competitors to learn our trade secrets and use the information in competition against
us. In addition, others may independently discover our trade secrets and proprietary information. Any action to enforce our rights is
likely to be time consuming and expensive, and may ultimately be unsuccessful, or may result in a remedy that is not commercially valuable.
These risks are accentuated in foreign countries where laws or law enforcement practices may not protect proprietary rights as fully as
in the United States. Any unauthorized disclosure of our trade secrets or proprietary information could harm our competitive position.
We may be subject to claims by employees claiming ownership of what
we regard as our own intellectual property.
While it is our policy to require our employees and
contractors who may be involved in the development of intellectual property to execute agreements assigning such intellectual property
to us, we may be unsuccessful in executing such an agreement with each party who in fact develops intellectual property that we regard
as our own. Our and their assignment agreements may not be self-executing or may be breached, and we may be forced to bring claims against
third parties, or defend claims they may bring against us, to determine the ownership of what we regard as our intellectual property.
If we fail in prosecuting or defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property
rights or personnel. Even if we are successful in prosecuting or defending against such claims, litigation could result in substantial
costs and be a distraction to management.
If we are unable to obtain and maintain intellectual property protection
for our product candidates, or if the scope of the intellectual property protection obtained is not sufficiently broad, our competitors
could develop and commercialize product candidates similar or identical to ours, and our ability to successfully commercialize our product
candidates may be impaired.
We have applied for patents that protect our product
candidates, and our patent portfolio currently includes, for CELsignia, six issued U.S. patents and 30 issued international patents, and,
for our drug candidate gedatolisib, 12 granted patents in the U.S. and more than 290 patents granted in foreign jurisdictions including
Australia, Canada, China, France, Germany, Spain, United Kingdom and Japan. We cannot ensure that our intellectual property position will
not be challenged or that all patents for which we have applied will be granted. We cannot know with certainty whether we were the first
to make the inventions claimed in our owned or licensed patents or pending patent applications, or that we were the first to file for
patent protection of such inventions.
The patent prosecution
process is expensive and time-consuming, and we may not be able to file, prosecute, maintain, enforce or license all necessary or desirable
patent applications at a reasonable cost or in a timely manner, or in all jurisdictions. We may choose not to seek patent protection for
certain innovations and may choose not to pursue patent protection in certain jurisdictions, and under the laws of certain jurisdictions,
patents or other intellectual property rights may be unavailable or limited in scope. Additionally, the laws and regulations governing
patents could change in unpredictable ways that would weaken our ability to obtain new patents or to enforce our existing patents and
patents that we might obtain in the future. There also may be patent reforms in foreign jurisdictions that could increase the uncertainties
and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents in those jurisdictions.
It is also possible that we will fail to identify patentable aspects of our discovery and nonclinical development output before it is
too late to obtain patent protection.
As a result of these factors, the issuance, scope,
validity, enforceability and commercial value of our patent rights are highly uncertain. Our pending and future patent applications may
not result in patents being issued that protect our product candidates, in whole or in part, or which effectively prevent others from
commercializing competitive product candidates. Moreover, given the amount of time required for the development, testing and regulatory
review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized.
As a result, our owned patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar
or identical to ours.
Third parties may initiate legal proceedings alleging that we are
infringing their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the
success of our business.
The commercial success of our products depends upon
our ability to use proprietary technologies without infringing the proprietary rights of third parties. There is considerable intellectual
property litigation in the medical technology, biotechnology and pharmaceutical industries. We may become party to, or threatened with,
future adversarial proceedings or litigation regarding intellectual property rights with respect to our products. Additionally, because
current and future employees may have been previously employed at universities or other biotechnology, diagnostic technology or pharmaceutical
companies, including our competitors or potential competitors and strategic partners, third parties may assert infringement claims against
us based on existing patents or patents that may be granted in the future, or they may allege that our employees or we have used or disclosed
intellectual property, including trade secrets or other proprietary information, of any such employee’s former employer. Litigation
may be necessary to defend against these claims.
Patent litigation could result in loss of exclusivity
or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit our
ability to stop others from using or commercializing similar or identical technology and product candidates, or limit the duration of
the patent protection of our technology and potential diagnostic tests. If we are found to infringe a third party’s intellectual
property rights, we could be required to obtain additional licenses from such third party to continue developing and marketing our applicable
products. However, we may not be able to obtain any required license on commercially reasonable terms or at all. Even if we were able
to obtain a license, it could be non-exclusive, thereby giving our competitors access to the same technologies licensed to us. We could
be forced, including by court order, to cease commercializing the infringing technology or product.
In addition, we could be found liable for monetary
damages, including treble damages and attorneys’ fees if we are found to have willfully infringed a patent. A finding of infringement
could prevent us from commercializing our products or force us to cease some of our business operations, which could materially harm our
business. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative
impact on our business.
Any lawsuits relating to infringement of intellectual property rights
necessary to defend ourselves or enforce our rights will be costly and time consuming and could be unsuccessful.
Because competition in our industry is intense, competitors
may infringe or otherwise violate our issued patents, patents of our licensors or other intellectual property. To counter infringement
or unauthorized use, we may be required to file infringement claims, which can be expensive and time consuming, and could distract our
technical and management personnel from their normal responsibilities. Any claims we assert against perceived infringers could provoke
these parties to assert counterclaims against us alleging that we infringe their patents. In addition, in a patent infringement proceeding,
a court may decide that a patent of ours is invalid or unenforceable, in whole or in part, construe the patent’s claims narrowly
or refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question.
An adverse result in any litigation proceeding could put one or more of our patents at risk of being invalidated or interpreted narrowly.
We may also elect to enter into license agreements in order to settle patent infringement claims or to resolve disputes prior to litigation,
and any such license agreements may require us to pay royalties and other fees that could be significant. Furthermore, because of the
substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential
information could be compromised by disclosure.
Risks Related to Our Reliance on Third Parties
We rely on third parties to conduct certain aspects of our preclinical
studies and clinical trials. If these third parties do not successfully carry out their contractual duties, meet expected deadlines or
comply with regulatory requirements, we may not be able to obtain regulatory approval for, or commercialize, any potential product candidates.
We depend upon third parties to execute our operational
plans and to conduct certain aspects of our preclinical studies. Additionally, we depend on third parties, including independent investigators,
to conduct our clinical trials, under agreements with universities, medical institutions, contract research organizations, or CROs, strategic
partners and others. Our reliance on third parties may affect our development timelines and increase our costs.
We have limited control over third-party clinical
investigators and limited visibility into their day-to-day activities, including with respect to their compliance with the approved clinical
protocol. Nevertheless, we are responsible for ensuring that each of our clinical trials is conducted in accordance with the applicable
protocol, legal and regulatory requirements and scientific standards. We and these third parties are required to comply with GCP requirements,
which are regulations and guidelines enforced by the FDA and comparable foreign regulatory authorities for product candidates in clinical
development. Regulatory authorities enforce these GCP requirements through periodic inspections of clinical trial sponsors, clinical investigators
and clinical trial sites. If we or any of these third parties fail to comply with applicable GCP requirements, the clinical data generated