What changed in this filing

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Item 1A. Risk Factors

2025-03-20 compared with 2024-03-14 · 266 added, 154 removed, 800 unchanged (34% of the section changed)

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Summary of Risk Factors

● Preclinical testing and clinical trials of our product candidates may not be successful.

If our NDA for the combination of avutometinib and defactinib is not approved by the FDA, we are unable to obtain marketing approval for or successfully commercialize avutometinib and defactinib, or any of our other product candidates, or if we experience significant delays in doing so, our business will be materially harmed.

● Even if avutometinib and defactinib, or any of our other product candidates, receives marketing approval, such product candidates may fail to achieve the degree of market acceptance by physicians, patients, healthcare payors and others in the medical community necessary for commercial success.

● The market opportunities for our product candidates, if approved, may be smaller than we estimate, and the FDA and other comparable foreign regulatory authorities may approve our product candidates for a more limited patient population than we anticipate.

● The approval of our product candidates as single agents or part of a combination therapy for the treatment of certain cancers may be more costly than our prior clinical trials, may take longer to achieve regulatory approval, may be associated with new, more severe or serious and unanticipated adverse events, and may have a smaller market opportunity.

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● If we experience delays or difficulties in the enrollment of patients in clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.

● Our approach to the treatment of cancer through cell death, inhibition of tumor growth, and disruption of the tumor microenvironment is relatively unproven, and we do not know whether we will be able to develop any products of significant commercial value.

● We have incurred significant losses since our inception.

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● We will need additional funding.

If we are unable to raise capital if needed, we would be forced to delay, reduce, or eliminate our product development programs or commercialization efforts, including for avutometinib.

If we are unable to raise capital if needed, we would be forced to delay, reduce, or eliminate our product development programs or commercialization efforts, including for avutometinib and defactinib.

● Raising additional capital or entering into certain licensing arrangements may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our product candidates.

● Preclinical testing and clinical trials of our product candidates may not be successful.

If we are unable to obtain marketing approval for or successfully commercialize any of our product candidates, or if we experience significant delays in doing so, our business will be materially harmed.

● We face substantial competition, which may result in others developing or commercializing products before or more successfully than we do.

● We rely in part on third parties to conduct our clinical trials and preclinical testing, and if they do not properly and successfully perform their obligations to us, we may not be able to obtain regulatory approvals for and commercialize any of our other product candidates.

● We rely on third parties to conduct investigator sponsored clinical trials of our product candidates.

Any failure by a third party to meet its obligations with respect to the clinical development of our product candidates may delay or impair our ability to obtain regulatory approval for our product candidates.

● We contract with third parties for the manufacture of our product candidates and for compound formulation research, and these third parties may not perform satisfactorily.

● If we are unable to obtain and maintain patent protection for our products, or if our licensors are unable to obtain and maintain patent protection for the products that we license from them, or if the scope of the patent protection obtained is not sufficiently broad, our competitors could develop and commercialize products similar or identical to ours, and our ability to successfully commercialize our products may be adversely affected.

commercialize products similar or identical to ours, and our ability to successfully commercialize our products may be adversely affected.

● We may not be successful in obtaining or maintaining necessary rights to product components and processes for our development pipeline through acquisitions and in-licenses.

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If Secura is unsuccessful in developing and commercializing COPIKTRA, we may not receive such payments or otherwise capitalize on the market potential of COPIKTRA.

● Our ability to receive future contingent consideration, including milestone payments and royalties, from the sale of our rights, title, and interest in COPIKTRA to Secura may be adversely affected by lower than expected COPIKTRA sales and Secura’s ability to achieve other developmental and regulatory milestones.

Risks Related to the Development of Our Product Candidates.

● We depend on GenFleet to fully perform under the GenFleet Agreement inclusive of our supply agreement with GenFleet

Risks Related to the Development of Our Product Candidates and Commercialization of our Product Candidates

Preclinical testing and clinical trials of our product candidates may not be successful.

We have invested a significant portion of our efforts and financial resources in the research and development of our product candidates, including avutometinib and defactinib, for which the FDA has accepted for review our NDA under the accelerated approval pathway for the treatment of adult patients with recurrent LGSOC, who received at least one prior systemic therapy and have a KRAS mutation.

Our ability to generate product revenues will depend heavily on the successful commercialization and development of our product candidates.

The success of our product candidates will depend on several factors, including the following:

● initiation and successful enrollment and completion of our clinical trials;

● receipt of marketing approvals from the FDA and other regulatory authorities for our current and future product candidates, including pricing approvals where required;

● establishing and maintaining commercial manufacturing capabilities or making arrangements with third-party manufacturers;

● obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our product candidates;

● establishing and maintaining commercial capabilities, including hiring and training a sales force, and launching commercial sales of the products, if and when approved, whether alone or in collaboration with others;

● acceptance of the products, if and when approved, by patients, the medical community, and third-party payors;

● securing and maintaining coverage and adequate reimbursement for our products from third party payors;

● effectively competing with other therapies;

● a continued acceptable safety and efficacy profile of the products following approval.

Many of these factors are beyond our control, including clinical development, the regulatory submission process, potential threats to our intellectual property rights and the manufacturing, marketing and sales efforts of any collaborator.

If we do not achieve one or more of these factors in a timely manner or at all, we could experience significant delays or an inability to successfully commercialize our product candidates, which would materially harm our business.

Even if avutometinib and defactinib, or any of our other product candidates, receives marketing approval, such product candidates 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 avutometinib and defactinib, or any of our other product candidates, receives marketing approval, such product candidates may nonetheless fail to gain sufficient market acceptance by physicians, patients, healthcare payors and others in the medical community.

If avutometinib and defactinib does not achieve an adequate level of acceptance, or if we are unable to increase market acceptance of avutometinib and defactinib as compared to existing or competitive products, we may not generate significant product revenues and we may not become profitable.

The degree of market acceptance of avutometinib and defactinib, or any of our other product candidates, if approved for commercial sale, will depend on a number of factors, including:

● efficacy and potential advantages compared to alternative treatments;

● convenience and ease of administration compared to alternative treatments;

● the ability to offer our product candidates for sale at competitive prices;

● the willingness of the target patient population to try new therapies and of physicians to prescribe our product candidates;

● the line of therapy for our product candidates is designated under physician treatment guidelines;

● changes in the standard of care for the targeted indications for product candidates;

● limitations or warnings, including distribution or use restrictions, contained in the approved labeling for our product candidates;

● the strength of marketing and distribution support;

● sufficient third-party coverage and reimbursement;

● the ability of the medical community to appropriately recognize and manage side effects;

● safety concerns with similar products marketed by others;

● the prevalence and severity of any side effects as a result of treatment with product candidates.

If clinical trials of our product candidates fail to demonstrate safety and efficacy to the satisfaction of regulatory authorities or do not otherwise produce positive results, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of our product candidates.

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● our product candidates may have undesirable side effects or other unexpected characteristics, causing us or our investigators, regulators or institutional review boards to suspend or terminate the trials;

● significant changes to the policies or regulations of the FDA or foreign regulatory authorities regarding the development, approval, and marketing of pharmaceutical products, including but not limited to as a result of the 2024 United States presidential election.

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 only modestly positive or if there are safety concerns, we may:

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The FDA and foreign regulatory authorities may determine that the results from our ongoing and future trials do not support regulatory approval and may require us to conduct an additional clinical trial or trials.

If these agencies take such a position, the costs of development of our product candidates could increase materially and their potential market introduction could be delayed.

If these agencies take such a position, the costs of development of our product candidates could increase materially and their potential market introduction could be delayed or abandoned.

The regulatory agencies could also require that we conduct additional clinical, nonclinical or manufacturing validation studies and submit that data before it will consider an NDA.

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If we experience delays or difficulties in the enrollment of patients in clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.

We may not be able to initiate or continue clinical trials for our product candidates if we are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or similar regulatory authorities outside the United States.

In addition, there are a number of ongoing clinical trials being conducted by other companies for product candidates treating cancer.

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Enrollment delays in our clinical trials may result in increased development costs for our product candidates, which would cause the value of our company to decline and limit our ability to obtain additional financing.

Preclinical studies and preliminary and interim data from clinical trials of our product candidates are not necessarily predictive of the results or success of ongoing or later clinical trials of our product candidates.

Preclinical studies and preliminary, initial “top-line” and interim data from clinical trials of our product candidates, or statistical analyses and projections based thereon, are not necessarily predictive of the results or success of ongoing or later clinical trials of our product candidates.

If we cannot replicate the results from our preclinical studies and clinical trials of our product candidates, we may be unable to successfully develop, obtain regulatory approval for, and commercialize our product candidates.

Preclinical studies and any positive preliminary and interim data from our clinical trials of our product candidates may not necessarily be predictive of the results of ongoing or later clinical trials.

Preclinical studies and any positive preliminary, initial “top-line,” and interim data from our clinical trials of our product candidates may not necessarily be predictive of the results of ongoing or later clinical trials.

Even if we are able to complete our planned clinical trials of our product candidates according to our current development timeline, the positive results from clinical trials of our product candidates may not be replicated in subsequent clinical trial results.

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Many companies in the pharmaceutical and biotechnology industries, including us, have suffered significant setbacks in late stage clinical trials after achieving positive results in an earlier stage of development.

If we fail to produce positive results in our planned clinical trials of any of our product candidates, the development timeline and regulatory approval and commercialization prospects for our product candidates, and, correspondingly, our business and financial prospects, would be materially adversely affected.

If we fail to

produce positive results in our planned clinical trials of any of our product candidates, the development timeline and regulatory approval and commercialization prospects for our product candidates, and, correspondingly, our business and financial prospects, would be materially adversely affected.

Our approach to the treatment of cancer through cell death, inhibition of tumor growth, and disruption of the tumor microenvironment is relatively unproven, and we do not know whether we will be able to develop any products of significant commercial value.

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While we are currently conducting clinical trials for product candidates that we believe will cause cell death, inhibition of tumor growth, and disruption of the tumor microenvironment, we may not ultimately be successful in demonstrating their efficacy, alone or in combination with other treatments.

The market opportunities for our product candidates, if approved, may be smaller than we estimate, and the FDA and other comparable foreign regulatory authorities may approve our product candidates for a more limited patient population than we anticipate.

The potential market opportunity for our product candidates is difficult to estimate precisely.

For example, the number of patients suffering from each of recurrent KRAS mutant LGSOC and recurrent KRAS wild-type LGSOC populations we are targeting near term (for KRAS mutant LGSOC) and longer term (for KRAS wild type LGSOC) is small and has not been established with precision.

Due to the rarity of our target indications, there is no comprehensive patient registry or other method of establishing with precision the actual number of patients with KRAS mutant LGSOC and KRAS wild-type LGSOC.

As a result, we have had to rely on other available sources to derive clinical prevalence estimates for our target indications.

We make estimates regarding the incidence and prevalence of target patient populations, the rate of recurrence and the median survival for particular diseases, including with respect to LGSOC, based on various third-party sources and internally generated analysis and use such estimates in making decisions regarding our drug development strategy determining indications on which to focus in preclinical or clinical trials.

Our estimates of the patient population, pricing and revenue opportunities for our product candidates, including for KRAS mutant patients with recurrent LGSOC, are based on a number of internal and third-party estimates, including, without limitation, internal forecasts of potential market penetration, the median duration of treatment from initial interim clinical data and the assumed prices at which we can commercialize our product candidates.

These estimates may be inaccurate or based on imprecise data.

If approved by the FDA, the market opportunity of our product candidates will depend on, among other things, acceptance by the medical community, patient access, drug pricing and reimbursement.

The number of patients in the addressable market may turn out to be lower than we estimate, patients may not be otherwise amenable to treatment with our drugs, or new patients may become increasingly difficult to identify or gain access to, all of which may significantly harm our business, financial condition, results of operations, and prospects.

In addition, even if we obtain approval for any of our product candidates, such approvals may be for more limited patient populations than we had anticipated, the potential market for our product candidates will be smaller than our current estimates.

Obtaining approval for only a smaller patient population of our target indications for which we anticipate seeking approval would have a materially adverse effect on our ability to achieve commercialization and generate revenues.

The approval of our product candidates as single agents or part of a combination therapy for the treatment of certain cancers may be more costly than our prior clinical trials, may take longer to achieve regulatory approval, may be associated with new, more severe or serious and unanticipated adverse events, and may have a smaller market opportunity.

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We face competition with respect to our current product candidates and will face competition with respect to any product candidates that we may seek to develop or commercialize in the future, from major pharmaceutical companies, specialty pharmaceutical companies and biotechnology companies worldwide.

There are a number of large pharmaceutical and biotechnology companies that currently market and sell products or are pursuing the development of products for the treatment of the disease indications for which we are developing our product candidates, including Novartis AG, Pfizer, Genentech, Inc., AstraZeneca PLC, Mirati, Amgen, Revolution Medicines, Inc., SpringWorks Therapeutics, Inc., BeiGene Ltd., Immuneering Corporation, Mapkure, LLC, Erasca, Inc., Relay Therapeutics, Inc.

and Kinnate Biopharma, Inc.

There are a number of large pharmaceutical and biotechnology companies that currently market and sell products or are pursuing the development of products for the treatment of the disease indications for which we are developing our product candidates, including Novartis AG, Pfizer, Genentech, Inc., AstraZeneca PLC, BMS, Amgen, Revolution Medicines, Inc., BeiGene Ltd., Quanta Therapeutics, Inc., Erasca, Inc., Roche Holding AG, Incyte Corporation and Eli Lilly and Company and others.

Some of these competitive products and therapies are based on scientific approaches that are the same as or similar to our approach, and others are based on entirely different approaches.

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Some of these drugs are branded and subject to patent protection, and others are available on a generic basis.

of these approved drugs are well established therapies and are widely accepted by physicians, patients and third-party payors.

Many of these approved drugs are well established therapies and are widely accepted by physicians, patients and third-party payors.

Insurers and other third-party payors may also encourage the use of generic products.

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Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.

Smaller and other early stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

Smaller and other early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements

with large and established companies.

These third parties compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

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Failure to obtain regulatory approval in one country may have a negative effect on the regulatory approval process in others.

Further, we and our collaboration partners are currently conducting clinical trials, and may in the future conduct additional clinical trials, outside the United States, including the Phase 1/2 clinical trial evaluating VS-7375 by GenFleet in China.

Although the FDA may accept data from clinical trials conducted outside the United States, acceptance of these data is subject to conditions imposed by the FDA.

For example, the FDA will generally not approve the application unless the data are applicable to the United States population and United States medical practice and the FDA is able to validate the data through an on-site inspection or other appropriate means.

The FDA or any comparable foreign regulatory authority may not accept data from trials conducted outside of the United States or the applicable jurisdiction, which may result in the need for additional trials that could be costly and time consuming and could result in the product candidate not receiving approval for commercialization in the applicable jurisdiction.

The foreign regulatory approval process may include all of the risks associated with obtaining FDA approval.

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We may not be able to file for regulatory approvals and may not receive necessary approvals to commercialize our products in any foreign market.

Preclinical testing and clinical trials of our product candidates may not be successful.

We have invested a significant portion of our efforts and financial resources in the research and development of our product candidates.

Our ability to generate product revenues will depend heavily on the successful commercialization and development of our product candidates.

The success of our product candidates will depend on several factors, including the following:

● initiation and successful enrollment and completion of our clinical trials;

● receipt of marketing approvals from the FDA and other regulatory authorities for our future product candidates, including pricing approvals where required;

● establishing and maintaining commercial manufacturing capabilities or making arrangements with third-party manufacturers;

● obtaining and maintaining patent and trade secret protection and regulatory exclusivity for our product candidates;

● acceptance of the products, if and when approved, by patients, the medical community, and third-party payors;

● securing and maintaining coverage and adequate reimbursement for our products from third party payors;

● effectively competing with other therapies;

● a continued acceptable safety and efficacy profile of the products following approval.

If serious adverse or unexpected side effects are identified during the development of our product candidates, we may need to abandon or limit our development of some of our product candidates.

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Avutometinib and defactinib are being administered and studied in our Phase 1, Phase 2, and Phase 3 clinical trials, and the development program continues to progress.

For both avutometinib and defactinib, the toxicities reported to date have been predictable and manageable.

For both avutometinib and defactinib, the toxicities reported to date have been predictable and appear to be manageable.

As a result of adverse events observed to date, or further safety or toxicity issues that we may experience in our clinical trials in the future, we may not receive approval to market any product candidates, which could prevent us from ever generating revenue from the sale of products or achieving profitability.

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As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential.

Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market

opportunities.

Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities.

Our spending on current and future research and development programs and product candidates for specific indications may not yield any commercially viable products.

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● the cost of development and commercialization of defactinib and avutometinib;

● the cost of development and commercialization of any of the three oncology programs if we elect to exercise any of our GenFleet Options;

● the cost of development and commercialization of any of the three oncology programs;

● other financial and strategic risks related to the agreements with Pfizer, Chugai and GenFleet.

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If one or more of these assumptions are incorrect, it could have an adverse effect on our business and operating results, and the benefits from our license agreements with Pfizer for defactinib and Chugai for avutometinib and the GenFleet Agreement may not be realized or be of the magnitude expected.

We depend on GenFleet to fully perform under the GenFleet Agreement

We depend on GenFleet to fully perform under the GenFleet Agreement inclusive of our supply agreement with GenFleet.

On August 24, 2023, we entered into the GenFleet Agreement pursuant to which we obtained three GenFleet Options that may be exercised on a program-by-program basis.

Pursuant to the GenFleet Agreement, we are reliant on GenFleet to fulfil their responsibilities including the execution of the Phase 1 clinical trials for all three oncology programs.

In December 2023, we announced the selection of a potential best-in class oral and selective KRAS G12D (ON/OFF) inhibitor VS-7375 as the lead program.

GenFleet is currently conducting a Phase 1/2 trial in China evaluating VS-7375 in patients with KRAS G12D-mutated advanced solid tumors.

In January 2025, we exercised early the GenFleet Option for the lead compound VS-7375 and expect to initiate a Phase 1/2a study in middle of 2025 in the United States.

Pursuant to the GenFleet Agreement, we are reliant on GenFleet to fulfil their responsibilities including ongoing discovery and lead optimization for the second and third programs and execution of the Phase 1 clinical trials for the second and third programs.

Accordingly, our ability to realize the anticipated benefits and success of the GenFleet Agreement is dependent upon GenFleet fulfilling their obligations.

If GenFleet does not successfully carry out their responsibilities, the benefits of the GenFleet Agreement may not be realized.

Furthermore, we have entered into a supply agreement with GenFleet pursuant to which we expect to obtain VS-7375 finished product from GenFleet for use in our planned clinical trial in the United States.

If GenFleet does not perform under the supply agreement, our ability to obtain VS-7375 and consequently our planned clinical trial in the United States investigating VS-7375 will be materially adversely impacted.

If GenFleet does not successfully carry out their responsibilities, the benefits of the GenFleet Agreement and our collaboration with GenFleet may not be realized.

Risks Related to Our Financial Position and Need for Additional Capital

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As of December 31, 2024, we had an accumulated deficit of $955.5 million.

To date, we have generated minimal product revenues and have financed our operations primarily through public and private offerings of our common stock, preferred stock, and pre-funded warrants, offerings of convertible notes, sales of our common stock pursuant to our at-the-market equity offering programs, our loan and security agreement (the “Loan Agreement”) with Oxford Finance LLC (“Oxford”), our loan and security agreement, as amended, with Hercules Capital Inc.

(“Hercules”), upfront payments under our license and collaboration agreements with Yakult, CSPC, and Sanofi, and the upfront payment under the Secura APA.

To date, we have generated minimal product revenues and have financed our operations primarily through public and private offerings of our common stock, preferred stock, warrants and pre-funded warrants, offerings of convertible notes, sales of our common stock pursuant to our at-the-market equity offering programs, our Note Purchase Agreement (the “Note Purchase Agreement”) with RGCM SA LLC, as purchaser agent, Oberland Capital Management LLC (“Oberland”) and certain funds managed by Oberland, as purchasers, (together with the other purchasers party thereto referred to as the “Note Purchase Agreement Purchasers”) our former loan and security agreement (the “Loan Agreement”) with Oxford Finance LLC (“Oxford”), our loan and security agreement, as amended, with Hercules Capital Inc.

(“Hercules”), upfront payments under our license and collaboration agreements with Yakult, CSPC, and Sanofi, and the upfront payment and milestone payments under the Secura APA.

We have devoted substantially all of our efforts to research and development.

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We anticipate that our expenses will increase substantially if and as we:

● prepare for the anticipated commercialization of avutometinib and defactinib;

● continue our ongoing clinical trials with our product candidates, including with defactinib and avutometinib;

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We will need additional funding.

If we are unable to raise capital if needed, we would be forced to delay, reduce, or eliminate our product development programs or commercialization efforts, including for avutometinib.

We expect our expenses to increase in connection with our ongoing activities, particularly as we continue the clinical development of our product candidates.

We expect our expenses to increase in connection with our ongoing activities, particularly in connection with our planned commercialization of avutometinib and defactinib and the continued clinical development of our product candidates.

We expect our cash, cash equivalents and investments at December 31, 2024 will not be sufficient to fund our current operating plan and capital expenditure requirements for the next 12 months from the issuance of these financial statements.

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Our future capital requirements will depend on many factors, including:

● the costs and timing of activities in anticipation of potential commercialization for avutometinib and defactinib and product candidates for which we expect to receive marketing approval;

● the scope, progress, and results of our ongoing and potential future clinical trials;

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● the costs, timing, and outcome of regulatory review of our product candidates (including our efforts to seek approval and fund the preparation and filing of regulatory submissions);

● revenue received from commercial sales of our product candidates, should any of our product candidates receive marketing approval;

● revenue, if any, received from commercial sales of our product candidates, including avutometinib and defactinib, should any of our product candidates receive marketing approval;

● the costs of preparing, filing, and prosecuting patent applications, maintaining and enforcing our intellectual property rights, and defending intellectual property related claims;

● our ability to establish collaborations or partnerships on favorable terms, if at all.

● receipt of milestone payments and royalties pursuant to the Secura APA including timing of such receipt.

Conducting clinical trials is a time consuming, expensive and uncertain process that takes years to complete, and we may never generate the necessary data or results required to obtain marketing approval of any of our product candidates.

Our commercial revenues will be derived from sales of products.

Although the FDA has accepted for review our NDA under the accelerated approval pathway for avutometinib in combination with defactinib for the treatment of adult patients with recurrent LGSOC who received at least one prior systemic therapy and have a KRAS mutation, the NDA may not be approved by the FDA and, even if approved, avutometinib and defactinib may not achieve commercial success.

We expect that our commercial revenues will be derived from sales of products.

Even if our product candidates gain approval, it may take several years to achieve a significant level of sales, and as a result we may need to continue to rely on additional financing to further our clinical development objectives.

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Lack of necessary funds may require us, among other things, to delay, scale back, or eliminate some or all of our planned clinical trials.

Because we continue to experience net operating losses, our ability to continue as a going concern is subject to our ability to obtain necessary capital from outside sources, including obtaining additional capital from the sale of our securities or assets, achieving milestones for additional drawdowns under our Loan Agreement or obtain loans from financial institutions, or entering into additional partnership arrangements.

There can be no assurances that we will be able to obtain such capital on favorable terms or at all.

Because we continue to experience net operating losses (“NOL”), our ability to continue as a going concern is subject to our ability to obtain necessary capital from outside sources, including obtaining additional capital from the sale of our securities or assets, achieving milestones for additional drawdowns under our Loan Agreement or obtain loans from financial institutions, or entering into additional partnership arrangements.

There can be no assurances that we will be able to obtain such capital on

favorable terms or at all.

If we are unable to raise capital when needed, we may be forced to delay, reduce or eliminate our research and development activities for our product candidates, or ultimately not be able to continue as a going concern.

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Unfavorable macroeconomic conditions and other adverse macroeconomic factors have resulted, among other matters, in tightening in the debt and equity markets, and high levels of inflation.

For example, tightening of the equity markets, makes it more difficult to raise capital at a reasonable valuation or at all.

Similarly, changes in U.S.

federal policy that affect the geopolitical landscape could give rise to circumstances outside our control that could have negative impacts on our business operations.

For example, on March 4, 2025, the U.S.

imposed a 25% tariff on imports from Canada and Mexico that do not satisfy the U.S.-Mexico-Canada Agreement rules of origin with certain exemptions and a 20% additional tariff on imports from China.

Historically, tariffs have led to increased trade and political tensions.

In response to tariffs, other countries have implemented retaliatory tariffs on U.S.

Political tensions resulting from trade policies could reduce trade volume, investment, technological exchange and other economic activities between major international economies, resulting in a material adverse effect on global economic conditions and the stability of global financial markets.

Tightening of the equity markets makes it more difficult to raise capital at a reasonable valuation or at all.

Any changes in political, trade, regulatory, and economic conditions, including U.S.

trade policies, could have a material adverse effect on our financial condition or results of operations.

In addition, the U.S.

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If inflationary pressures increase or continue for a prolonged period, it may continue to result in increased costs of labor, cost of clinical trials, and costs of manufacturing which could adversely affect our results of operations.

In addition, unrest in the banking sector has in the past and may in the future have an effect on our ability to access funds when needed.

Our ability to use our net operating loss carryforwards may be limited.

As of December 31, 2024, we had U.S.

federal and state net operating loss (“NOL”) carryforwards of approximately $473.6 million and $189.0 million, respectively.

federal and state NOL carryforwards of approximately $370.6 million and $56.7 million, respectively.

As of December 31, 2024, we also had federal and state tax credits of $2.6 million and $0.2 million, respectively, which may be used to offset future tax liabilities.

The NOL and tax credit carryforwards will expire at various dates through 2044, except for $333.4 million of federal NOL carryforwards which may be carried forward indefinitely.

Sections 382 and 383 of the Internal Revenue Code and similar provisions under state law limits the annual use of NOL carry-forwards and tax credit carryforwards, respectively, following an ownership change pursuant to section 382 of the Internal Revenue Code and similar state provisions.

Sections 382 and 383 of the Internal Revenue Code (“IRC”) and similar provisions under state law limits the annual use of NOL carry-forwards and tax credit carryforwards, respectively, following an ownership change pursuant to section 382 of the IRC and similar state provisions.

In general, an ownership change occurs for purposes of Section 382 if there are certain cumulative changes in the ownership interest of significant stockholders over a three-year period in excess of 50%.

Based on our analysis under Section 382, we believe that our federal NOL carryforwards, state NOL carryforwards, research and development credits, and orphan drug credits are limited by Section 382 and similar provisions under state law as of December 31, 2023.

The portion of federal NOL carryforwards, state NOL carryforwards, research and development credits, and orphan drug credits that were determined to be limited by Section 382 and similar provisions under state law have been written off as of December 31, 2023.

Future changes in our stock ownership, some of which are outside of our control, could result in ownership changes in the future.

During 2024, we believe we triggered ownership changes under Section 382 of the IRC and similar provisions under state law.

As a result, we believe that our federal NOL carryforwards, state NOL carryforwards, research and development credits, and orphan drug credits are limited by Section 382 and similar provisions under state law as of December 31, 2024.

A portion of federal NOL carryforwards and state NOL carryforwards that we expect we will not be able to utilize were written off.

Similarly, we wrote off all federal and state research and development credits, and federal orphan drug credits we determined we will not be able to utilize due to limitation and expiration periods.

We have approximately $346.4 million of federal NOLs generated prior to such ownership changes inclusive of $309.3 million of federal NOLs which may be carried forward indefinitely.

Since the $309.3 million of federal NOLs may be carried forward indefinitely these have not been written off as of December 31, 2024, but due to the limitations under Section 382, generally we can only use $1.6 million per year against taxable income in the future.

Future changes in our stock ownership, some of which are outside of our control, could result in further ownership changes under section 382 of the IRC.

We may not be able to use some or all of our NOL and tax credit carryforwards, even if we attain profitability.

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Our level of indebtedness and debt service obligations could adversely affect our financial condition and may make it more difficult for us to fund our operations.

In March 2022, we entered into a Loan Agreement with Oxford, as collateral agent and a lender, and Oxford Finance Credit Fund III LP, as a lender (“OFCF III” and together with Oxford, the “Lenders”), pursuant to which the Lenders have agreed to lend us up to an aggregate principal amount of $150.0 million in a series of term loans (the “Term Loans”).

As of December 31, 2023, there was $40.0 million outstanding under the Loan Agreement.

In connection with the Loan Agreement, we granted Oxford a security interest in all of our personal property now owned or hereafter acquired, excluding intellectual property (but including the right to payments and proceeds of intellectual property), and a negative pledge on intellectual property.

This indebtedness may create additional financing risk for us, particularly if our business or prevailing financial market conditions are not conducive to paying off or refinancing our outstanding debt obligations at maturity.

On January 13, 2025 (the “Note Purchase Agreement Closing Date”), we entered into the Note Purchase Agreement pursuant to which we may sell to the Note Purchase Agreement Purchasers, and the Note Purchase Agreement Purchasers may buy from us notes (the “Notes”) in an aggregate principal amount not to exceed $150.0 million, consisting of the following:

● an initial sale of $75.0 million principal amount of Notes;

● at our option, a second sale (the “Second Sale”) of $25.0 million principal amount of Notes, at any time prior to December 31, 2025, upon the FDA approval sufficient for the promotion and sale of avutometinib and defactinib for the treatment of LGSOC and subject to certain other customary conditions precedent;

● at our option, a third sale (the “Third Sale”) of up to $50.0 million principal amount of Notes, at any time prior to December 31, 2026, provided that trailing six-month worldwide net sales of avutometinib and defactinib are at least $55.0 million and subject to certain other customary conditions precedent.

The outstanding principal amount of the Notes bear interest at a rate per annum equal to the sum of (i) the greater of the Term SOFR (as defined in the Note Purchase Agreement) and 4.29%, and (ii) 3.71%, subject to adjustment in certain circumstances set forth in the Note Purchase Agreement and an overall cap of 9.75%, payable quarterly in arrears until the seventh anniversary of the Note Purchase Agreement Closing Date or the date on which all amounts owing to the Note Purchase Agreement Purchasers under the Note Purchase Agreement have been paid in full (the “Note Purchase Agreement Maturity Date”).

For the first eight (8) quarters following the Note Purchase Agreement Closing Date, at our option, up to 50% of the interest due may be paid-in-kind and added to the then-outstanding principal balance of the Notes.

Upon the occurrence and during the continuance of an Event of Default (as defined in the Note Purchase Agreement) under the Note Purchase Agreement, the then-applicable interest rate on all outstanding obligations may be increased by an additional 5.00%.

The Note Purchase Agreement Purchasers will receive 1.00% (the “Revenue Participation Percentage”) of the first $100.0 million of net sales of each Included Product (as defined in the Note Purchase Agreement) by us or our licensees in each calendar year, payable quarterly.

“Included Products” is defined in the Note Purchase Agreement to include (a) avutometinib and defactinib, including any product that contains either one of the foregoing in combination with any other active ingredient(s), and (b) all other compounds, chemical entities or pharmaceutical products being designed, developed, licensed, manufactured or commercialized by us or our subsidiaries from time to time.

The Revenue Participation Percentage will increase pro rata immediately upon the occurrence of the Second Sale and the Third Sale, such that the Revenue Participation Percentage shall increase to a maximum of 2.00% in the event that $150.0 million in aggregate principal amount of Notes has been purchased pursuant to the Note Purchase Agreement following the Third Sale.

The outstanding principal amount of the Notes, interest accrued thereon and any other amounts owing to the Note Purchase Agreement Purchasers under the Note Purchase Agreement will be due in two equal installments on (a) the sixth anniversary of the Note Purchase Agreement Closing Date, and (b) the Note Purchase Agreement Maturity Date.

The Note Purchase Agreement contains no financial covenants.

Our obligations under the Note Purchase Agreement are subject to customary covenants, including limitations on our ability to dispose of assets, undergo a change of control, merge with or acquire other entities, incur debt, incur liens, pay dividends or other distributions to holders of our capital stock, repurchase stock and make investments, in each case subject to certain exceptions.

Our obligations under the Note Purchase Agreement are secured by a security interest on substantially all of our and our subsidiaries’ assets, including our intellectual property related to avutometinib and defactinib, and a negative pledge on intellectual property related to the Company’s collaboration and option agreement with GenFleet, subject to certain exceptions relating to our development of our intellectual property.

This indebtedness could also have other important negative consequences, including we will need to repay our indebtedness by making payments of interest and principal, which will reduce the amount of money available to finance our operations, our research and development efforts and other general corporate activities.

Further, our agreement to pay Oberland the Revenue Participation Percentage with respect to potential future sales of certain of our product candidates may limit future revenue, if any, received from commercial sales of our product candidates, should any of our product candidates receive marketing approval, as well as our ability to generate revenues that are significant or large enough to achieve profitability.

In addition, we may be delayed in satisfying the criteria required under the Note Purchase Agreement to exercise the Second Sale and Third Sale, or may never satisfy such criteria, which may require us to find other sources of funding to finance our operations.

To the extent additional debt is added to our current debt levels, the risks described above could increase.

We may not have cash available in an amount sufficient to enable us to make interest or principal payments on our indebtedness when due.

Failure to satisfy our current and future debt obligations under the Loan Agreement or breaching any covenants under the Loan Agreement, subject to specified cure periods with respect to certain breaches, could result in an event of default and, as a result, could accelerate all of the amounts due.

In the event of an acceleration of amounts due under the Loan Agreement, we may not have enough available cash or be able to raise additional funds through equity or debt financings to repay such indebtedness at the time of such acceleration.

Failure to satisfy our current and future debt obligations under the Note Purchase Agreement or breaching any covenants under the Note Purchase Agreement, subject to specified cure periods with respect to certain breaches, could result in an event of default and, as a result, could accelerate all of the amounts due.

In the event of an acceleration of amounts due under the Note Purchase Agreement, we may not have enough available cash or be able to raise additional funds through equity or debt financings to repay such indebtedness at the time of such acceleration.

In that case, we may be required to delay, limit, reduce or terminate our product candidate development or grant to others the rights to develop and market our product candidates that we would otherwise prefer to develop and market internally.

Oxford could also exercise its rights as collateral agent to take possession and dispose of the collateral securing the term loans for its benefit, which collateral includes substantially all of our property other than our intellectual property.

The Note Purchase Agreement Purchasers could also exercise their rights as collateral agent to take possession and dispose of the collateral securing the Notes for their benefit, which collateral includes substantially all of our property other than our intellectual property.

Our business, financial condition and results of operations could be materially adversely affected as a result of any of these events.

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We rely in part on third parties to conduct our clinical trials and preclinical testing, and if they do not properly and successfully perform their obligations to us, we may not be able to obtain regulatory approvals for and commercialize any of our other product candidates.

We rely on third parties, such as CROs, clinical data management organizations, medical institutions, and clinical investigators, to conduct, provide monitors for, and manage data from all of our clinical trials.

We rely on third parties, such as contract research organizations (“CROs”), clinical data management organizations, medical institutions, and clinical investigators, to conduct, provide monitors for, and manage data from all of our clinical trials.

We compete with many other companies for the resources of these third parties.

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For example, we will remain responsible for ensuring that each of our clinical trials is conducted in accordance with the general investigational plan and protocols for the trial.

Moreover, the FDA and other regulatory agencies require us to comply with standards, commonly referred to as Good Clinical Practices for conducting, recording, and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial participants are protected.

Moreover, the FDA and other regulatory agencies require us to comply with standards, commonly referred to as Good Clinical Practices (“GCP”) for conducting, recording, and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial participants are protected.

Regulatory authorities enforce these GCP requirements through periodic inspections of trial sponsors, principal investigators, and trial sites.

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We do not have any manufacturing facilities or personnel.

We currently obtain all of our supply of our product candidates for clinical development from third-party manufacturers or third-party collaborators, and we expect to continue to rely on third parties for the manufacture of clinical quantities of our product candidates.

We currently obtain all of our supply of our product candidates for clinical development and commercial requirements from third-party manufacturers or third-party collaborators, and we expect to continue to rely on third parties for the manufacture of clinical and commercial quantities of our product candidates.

In addition, we currently rely on third parties for the development of various formulations of our product candidates.

This reliance on third parties increases the risk that we will not have sufficient quantities of our product candidates or such quantities at an acceptable cost or quality, which could delay, prevent, or impair our development or commercialization efforts.

We do not currently have arrangements in place for redundant supply or a second source for bulk drug substance or drug product.

We do not currently have arrangements in place for redundant supply or a second source throughout our supply chain.

Even though we have supply agreements in place with our third-party manufacturers, reliance on third-party manufacturers entails additional risks, including:

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Furthermore, we may not be able to obtain the significant financial capital that may be required in connection with such arrangements.

Even after successfully engaging third parties to execute the manufacturing

process for our product candidates, such parties may not comply with the terms and timelines they have agreed to for various reasons, some of which may be out of their or our control, which could impact our ability to execute our business plans on expected or required timelines in connection with the commercialization of and the continued development of our product candidates.

Even after successfully engaging third parties to execute the manufacturing process for our product candidates, such parties may not comply with the terms and timelines they have agreed to for various reasons, some of which may be out of their or our control, which could impact our ability to execute our business plans on expected or required timelines in connection with the commercialization of and the continued development of our product candidates.

We may also be required to enter into long-term manufacturing agreements that contain exclusivity provisions and/or substantial termination penalties, which could have a material adverse effect on our business prior to and after commercialization.

Our current and anticipated future dependence upon others for the manufacture of our other product candidates or products may adversely affect our future profit margins and our ability to commercialize any products that receive marketing approval on a timely and competitive basis.

If we are not able to establish collaborations, we may have to alter our development and commercialization plans.

If we are not able to establish additional collaborations, we may have to alter our development and commercialization plans.

Our drug development programs and the potential commercialization of our product candidates will require additional cash to fund expenses.

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We face significant competition in seeking appropriate collaborators.

Whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration, and the proposed collaborator’s evaluation of a number of factors.

Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or similar regulatory authorities outside the United States, the potential market for the subject product candidate, the costs and complexities of manufacturing and delivering such product candidate to patients, the potential of competing products, and the existence of uncertainty with respect to our ownership of technology, which can exist if there is a challenge to such ownership without regard to the merits of the challenge and industry and market conditions generally.

Whether we reach definitive agreements for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration, and the proposed collaborator’s evaluation of a number of factors.

Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or foreign regulatory authorities, the potential market for the subject product candidate, the costs and complexities of manufacturing and delivering such product candidate to patients, the potential of competing products, and the existence of uncertainty with respect to our ownership of technology, which can exist if there is a challenge to such ownership without regard to the merits of the challenge and industry and market conditions generally.

The collaborator may also consider alternative product candidates or technologies for similar indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with us for our product candidate.

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If we do not have sufficient funds, we may not be able to further develop our product candidates or bring them to market and generate product revenue.

We may depend on collaborations with third parties for the development and commercialization of our product candidates.

If those collaborations are not successful, we may not be able to capitalize on the market potential of our product candidates.

We may seek third-party collaborators for the development and commercialization of our product candidates.

Our likely collaborators for any collaboration arrangements include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies, and biotechnology companies.

If we do enter into any such arrangements with any third parties, we will likely have limited control over the amount and timing of resources that our collaborators dedicate to the development or commercialization of our product candidates.

We may not realize the benefits of our current or future collaborations or licensing arrangements with third parties for the development and commercialization of our product candidates and may be unsuccessful in consummating future partnerships or capitalizing on the market potential of our product candidates.

Our current or future collaborations or licensing arrangements may not be successful.

Additionally, we have partnered, and intend to further partner, with third parties with respect to the clinical development and commercialization, if approved, of certain of our programs, and we may not be successful in identifying, negotiating and executing partnerships.

Our likely future collaborators for any collaboration arrangements include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies, and biotechnology companies.

Any such arrangements with any third parties may result in us having limited control over the amount and timing of resources that our collaborators dedicate to the development or commercialization of our product candidates.

Our ability to generate revenues from these arrangements will depend on our collaborators’ abilities to successfully perform the functions assigned to them in these arrangements.

Collaborations involving our product candidates would pose the following risks to us:

For example, we have engaged in a strategic collaboration with IQVIA, pursuant to which we intend to leverage IQVIA’s expertise and resources for the commercialization and launch of the investigational combination of avutometinib plus defactinib for the treatment of recurrent KRAS mutant LGSOC.

Accordingly, we will depend on IQVIA and their performance under the strategic collaboration arrangements for the successful commercialization and launch of avutometinib and defactinib for the treatment of recurrent KRAS mutant LGSOC.

If IQVIA does not successfully carry out their responsibilities under the collaboration agreements or does not perform to the standard or level we anticipate, the benefits of the strategic collaboration with IQVIA may not be realized and our commercialization efforts will be harmed.

Collaborations involving our product candidates are subject to numerous risks, which may include that:

● collaborators have significant discretion in determining the efforts and resources that they will apply to these collaborations;

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● collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing;

collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our products or product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours;

● a collaborator with marketing and distribution rights to one or more products may not commit sufficient resources to the marketing and distribution of such product or products;

collaborators could independently develop, or

develop with third parties, products that compete directly or indirectly with our products or product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours;

● agreements with collaborators may not provide exclusive rights to use their intellectual property and technology in all relevant fields of use and in all territories in which we may wish to develop or commercialize our technology and product candidates in the future;

● collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our product candidates;

● a collaborator with marketing, manufacturing or distribution rights to one or more products may not commit sufficient resources to the marketing and distribution of such product or products or otherwise not perform satisfactorily in carrying out these activities;

● collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our proprietary information or expose us to potential litigation;

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Our business could be adversely affected by conditions the adverse geopolitical and macroeconomic developments, including the military conflict between Ukraine and Russia, the ongoing military conflict in the Middle East, and any related sanctions.

While we do not currently have clinical trials in Ukraine, Russia, or Middle East, we have clinical trial sites in Europe.

While we do not currently have clinical trials in Ukraine, Russia, or the Middle East, we have clinical trial sites in Europe.

We also source clinical supply for our product candidates from third party contract manufacturing organizations in Europe.

Additionally, GenFleet intends to file an IND for the lead oncology program in first half of 2024 in China and expects the Phase 1 clinical trial to be conducted in China.

Additionally, GenFleet is conducting a Phase 1/2 clinical trial evaluating GFH375/VS-7375 in China.

For such activities conducted in China, we are exposed to the possibility of product supply disruption and increased costs in the event of changes in the policies of the U.S.

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We are a party to a number of intellectual property license agreements with third parties, including Pfizer and Chugai, and expect to enter into additional license agreements in the future.

Our existing license agreements

impose, and we expect that future license agreements will impose, various diligence, milestone payment, royalty, insurance, and other obligations on us.

Our existing license agreements impose, and we expect that future license agreements will impose, various diligence, milestone payment, royalty, insurance, and other obligations on us.

For example, under our license agreements with Pfizer and Chugai, we are required to use diligent or commercially reasonable efforts to develop and commercialize licensed products under the agreement and to satisfy other specified obligations.

If we fail to comply with our obligations under these licenses, our licensors may have the right to terminate these license agreements, in which event we might not be able to market any product that is covered by these agreements, or to convert the exclusive licenses to non-exclusive licenses, which could materially adversely affect the value of the product candidate being developed under these license agreements.

licenses, which could materially adversely affect the value of the product candidate being developed under these license agreements.

Termination of these license agreements or reduction or elimination of our licensed rights may result in our having to negotiate new or reinstated licenses with less favorable terms, which may not be possible.

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Even if they are unchallenged, our or our licensors’ patents and pending patent applications, if issued, may not provide us with any meaningful protection or prevent competitors from designing around our or our licensors’ patent claims to circumvent our patents by developing similar or alternative technologies or therapeutics in a non-infringing manner.

For example, a third party may develop a competitive therapy that provides benefits similar to

our products but that uses a formulation and/or a method that falls outside the scope of our patent protection.

For example, a third party may develop a competitive therapy that provides benefits similar to our products but that uses a formulation and/or a method that falls outside the scope of our patent protection.

If the patent protection provided by the patents and patent applications we hold, license, or pursue with respect to our products is not sufficiently broad to impede such competition, our ability to successfully commercialize our products could be negatively affected, which would harm our business.

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There also may be prior art of which we are aware, but which we do not believe affects the validity or enforceability of a claim, which may, nonetheless, ultimately be found to affect the validity or enforceability of a claim.

We may in the future, become subject to a third-party pre-issuance submission of prior art or opposition, derivation, revocation, re-examination, post-grant and inter partes review, or interference proceeding and other similar proceedings challenging our patent rights or the patent rights of others in the USPTO or other foreign patent office.

We may in the future, become subject to a third-party pre-issuance submission of prior art or opposition, derivation, revocation, re-

examination, post-grant and inter partes review, or interference proceeding and other similar proceedings challenging our patent rights or the patent rights of others in the USPTO or other foreign patent office.

Such challenges may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated, or held unenforceable, which could limit our ability to stop others from using or commercializing similar or identical products, or limit the duration of the patent protection of our products.

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If we are unable to do so, the institution may offer the intellectual property rights to others, potentially blocking our ability to pursue our program.

If we are unable to successfully obtain rights to required third-

party intellectual property or to maintain the existing intellectual property rights we have, we may have to abandon development of such program and our business and financial condition could suffer.

If we are unable to successfully obtain rights to required third-party intellectual property or to maintain the existing intellectual property rights we have, we may have to abandon development of such program and our business and financial condition could suffer.

The licensing and acquisition of third-party intellectual property rights is a competitive area, and companies, which 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 products.

More established companies may have a competitive advantage over us due to their size, cash resources and greater clinical development and commercialization capabilities.

More established companies may have a competitive advantage over us due to their

size, cash resources and greater clinical development and commercialization capabilities.

Moreover, we may devote resources to potential acquisitions or in-licensing opportunities that are never completed, or we may fail to realize the anticipated benefits of such efforts.

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Such noncompliance can result in partial or complete loss of patent rights in the relevant jurisdiction.

Noncompliance events that could result

in abandonment or lapse of a patent or patent application include, but are not limited to, failure to respond to official actions within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal documents.

Noncompliance events that could result in abandonment or lapse of a patent or patent application include, but are not limited to, failure to respond to official actions within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal documents.

Such an event could have a material adverse effect on our business.

Issued patents covering our products could be found invalid or unenforceable if challenged in court or the USPTO.

If we or one of our licensing partners initiate legal proceedings against a third party to enforce a patent covering our products, the defendant could counterclaim that the patent covering our products, as applicable, is invalid and/or unenforceable.

invalid and/or unenforceable.

In patent litigation in the United States, defendant counterclaims alleging invalidity and/or unenforceability are commonplace, and there are various grounds upon which a third party can assert invalidity or unenforceability of a patent.

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Obtaining and enforcing patents in the drug and biopharmaceutical industry involves both technological and legal complexity, and is therefore costly, time-consuming and inherently uncertain.

In addition, the United States has passed wide-ranging patent reform legislation under the AIA.

In addition, the United States has passed wide-ranging patent reform legislation under the America Invents Act.

Moreover, recent U.S.

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This difficulty with enforcing patents could make it difficult for us to stop the infringement of our patents or marketing of competing products otherwise generally in violation of our proprietary rights.

Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly, put our patent applications at risk of not issuing and could provoke third parties to assert claims against us.

invalidated or interpreted narrowly, put our patent applications at risk of not issuing and could provoke third parties to assert claims against us.

We may not prevail in any lawsuits that we initiate and the damages or other remedies awarded, if any, may not be commercially meaningful.

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Litigation or post-grant proceedings may result in a decision adverse to our interests and, even if we are successful, may result in substantial costs and distract our management and other employees.

We may not be able to prevent, alone or with our licensors,

misappropriation of our trade secrets or confidential information, particularly in countries where the laws may not protect those rights as fully as those within the United States.

We may not be able to prevent, alone or with our licensors, misappropriation of our trade secrets or confidential information, particularly in countries where the laws may not protect those rights as fully as those within the United States.

Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information could be compromised by disclosure during this type of litigation.

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Third parties may assert that we are employing their proprietary technology without authorization.

Patents issued in the United States by law enjoy a presumption of validity that can be rebutted only with evidence that is

“clear and convincing,” a heightened standard of proof.

Patents issued in the United States by law enjoy a presumption of validity that can be rebutted only with evidence that is “clear and convincing,” a heightened standard of proof.

There may be issued third-party patents of which we are currently unaware with claims to compositions, formulations, methods of manufacture or methods for treatment related to the use or manufacture of our products.

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Moreover, we may fail to identify relevant patents or incorrectly conclude that a patent is invalid, not enforceable, exhausted, or not infringed by our activities.

If any third-party patents, held now or obtained in the future by a third party, were found by a court of competent jurisdiction to cover the manufacturing process of our products, constructs or molecules used in or formed during the manufacturing process, or any final product or methods use of the product, the holders of any such patents may be able to block our ability to commercialize the product unless we obtained a license under the applicable patents, or until such patents expire or they are finally determined to be held invalid or unenforceable.

the product, the holders of any such patents may be able to block our ability to commercialize the product unless we obtained a license under the applicable patents, or until such patents expire or they are finally determined to be held invalid or unenforceable.

Similarly, if any third-party patent were held by a court of competent jurisdiction to cover any aspect of our formulations, any combination therapies or patient selection methods, the holders of any such patent may be able to block our ability to develop and commercialize the product unless we obtained a license or until such patent expires or is finally determined to be held invalid or unenforceable.

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Litigation may be necessary to defend against these claims.

If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual

property rights or personnel.

If we fail in 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 defending against such claims, litigation could result in substantial costs and be a distraction to management.

Intellectual property litigation could cause us to spend substantial resources and distract our personnel from their normal responsibilities.

Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses, and could distract our technical and management personnel from their normal responsibilities.

normal responsibilities.

In addition, there could be public announcements of the results of hearings, motions, or other interim proceedings or developments, and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.

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In addition, in the USPTO and in comparable agencies in many foreign jurisdictions, third parties are given an opportunity to oppose pending trademark applications and/or to seek the cancellation of registered trademarks.

Opposition or cancellation proceedings may be filed against our trademarks, and our

trademarks may not survive such proceedings.

Opposition or cancellation proceedings may be filed against our trademarks, and our trademarks may not survive such proceedings.

If we are unable to establish name recognition based on our trademarks and trade names, we may not be able to compete effectively and our business may be adversely affected.

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Our owned or our licensors’ European patents and patent applications could be challenged in the recently created Unified Patent Court (“UPC”) for the European Union.

We may decide to opt out our European patents and patent applications from the UPC.

We may decide to opt out our European patents and

patent applications from the UPC.

However, if certain formalities and requirements are not met, our European patents and patent applications could be challenged for non-compliance and brought under the jurisdiction of the UPC.

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If we are not able to obtain, or if there are delays in obtaining, required regulatory approvals for our product candidates, we will not be able to commercialize such candidates, and our ability to generate revenue will be materially impaired.

Obtaining approval of an NDA can be a lengthy, expensive, and uncertain process.

O btaining approval of an NDA can be a lengthy, expensive, and uncertain process, and the FDA has substantial discretion in the review and approval process and may decide that our data is insufficient for approval and require additional preclinical, clinical, or other studies.

While we have engaged in discussions with the FDA with respect to the scope and nature of our NDA submission for avutometinib in combination with defactinib , the FDA may, for example, require additional data under the RAMP 301 study before approving the NDA for the scope we request, or at all.

There can be no assurance regarding the timing and outcome of the FDA review and approval of our NDA submission.

The activities associated with a product candidate’s development and commercialization, including its design, testing, manufacture, safety, efficacy, recordkeeping, labeling, storage, approval, advertising, promotion, sale, and distribution are subject to comprehensive regulation by the FDA and other regulatory agencies in the United States and by comparable authorities in other countries.

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We have not received approval to market any of our current product candidates from regulatory authorities in any jurisdiction in the United States.

We have only limited experience in filing and supporting the applications necessary to gain marketing approvals and expect to rely on third-party contract research organizations to assist us in this process.

We have only limited experience in filing and supporting the applications necessary to gain marketing approvals and have relied on and expect to rely on third-party contract research organizations to assist us in this process.

Securing FDA approval requires the submission of extensive preclinical and clinical data and supporting information to the FDA for each therapeutic indication to establish the product candidate’s safety and efficacy.

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Changes in marketing approval policies during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application.

The FDA has substantial discretion in the approval process and may refuse to accept any application or may decide that our data is insufficient for approval and require additional preclinical, clinical, or other studies.

In addition, varying interpretations of the data obtained from preclinical and clinical testing could delay, limit or prevent marketing approval of a product candidate.

Any marketing approval we ultimately obtain may be subject to more limited indications than those we propose or subject to restrictions or post approval commitments that render the approved product not commercially viable.

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We have received orphan drug designation for certain of our product candidates, but there can be no assurance that we will be able to prevent third parties from developing and commercializing products that are competitive to these product candidates.

We received orphan drug designation in the United States, the European Union, and Australia for the use of defactinib in ovarian cancer, and in the United States, the European Union, and Australia for the use of defactinib in mesothelioma.

In March 2024, the FDA granted orphan drug designation to avutometinib, alone or in combination with defactinib for the treatment of patients with recurrent LGSOC.

In July 2024, the FDA granted orphan drug designation to avutometinib, in combination with defactinib, for the treatment of pancreatic cancer.

Defactinib has received orphan drug designation in the United States, the European Union, and Australia for the treatment of patients with ovarian cancer.

Orphan drug exclusivity grants seven years of marketing exclusivity under the FDCA, up to ten years of marketing exclusivity in Europe, and five years of marketing exclusivity in Australia.

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In January 2024, the FDA granted fast track designation for combination of avutometinib and LUMAKRAS for the treatment of patients with KRAS G12C-mutant metastatic NSCLC who have received at least one prior systematic therapy and have not been previously treated with a KRAS G12C inhibitor.

In April 2024, the FDA granted fast track designation for avutometinib, in combination with defactinib plus LUMAKRAS for the treatment of patients with KRAS G12C-mutated metastatic NSCLC who received at least one prior systematic therapy.

We may also seek fast track designation for additional product candidates, which we may not receive from the FDA.

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Fast track designation alone does not guarantee qualification for the FDA’s priority review procedures.

We have completed an NDA submission under the FDA’s accelerated approval pathway for one of our product candidates, and we may seek accelerated approval for one more additional product candidates.

The FDA has substantial discretion regarding approvals under the accelerated approval pathway, and we may not be able to obtain accelerated approval for any of our product candidates.

The FDA has accepted for review our NDA under the accelerated approval pathway for avutometinib in combination with defactinib for the treatment of adult patients with recurrent LGSOC, who received at least one prior systemic therapy, and have a KRAS mutation.

We may explore regulatory strategies for our other product candidates that involve use of the FDA’s accelerated approval pathway.

Under the accelerated approval program, the FDA may grant accelerated approval to a drug designed to treat a serious or life-threatening condition that provides meaningful therapeutic benefit over available therapies upon a determination that the drug has an effect on a surrogate endpoint or intermediate clinical endpoint that is reasonably likely to predict clinical benefit.

As a condition of approval, the FDA requires that a sponsor of a drug receiving accelerated approval perform a post-marketing confirmatory clinical trial or trials.

FDA has broad discretion with regard to approval under the accelerated approval program, and FDA’s interpretation of the criteria for accelerated approval, such as what it considers to be available therapies, is subject to change.

No assurance can be given that other therapeutics will not receive full approval prior to our potential receipt of accelerated approval.

If that were to occur, no assurance can be given that we would be successful in proving meaningful benefit over those later approved products.

If we were unable to prove meaningful benefit over any available therapies, we would be effectively blocked from receiving accelerated approval.

Even if we receive approval for any of our product candidates through the accelerated approval program, we will be subject to rigorous post-marketing requirements, including the completion of one or more post-market confirmatory studies, to verify the clinical benefit of our product candidate, and submission to the FDA of all promotional materials prior to their dissemination.

The FDA could seek to withdraw the approval, if received, for multiple reasons, including if we fail to conduct any required post-market confirmatory trial with due diligence, our post-market confirmatory trial does not confirm the predicted clinical benefit, other evidence shows that our product candidate is not safe or effective under the conditions for use, or we disseminate promotional materials that are found by FDA to be false or misleading.

Any delay in obtaining, or inability to obtain, approval through the accelerated approval pathway, or any issues in maintaining any such approvals that we receive, would delay or prevent commercialization of our product candidates, and would materially adversely affect our business, financial condition, results of operations, and cash flows.

Any product candidate for which we obtain marketing approval could be subject to restrictions or withdrawal from the market, and we may be subject to penalties if we fail to comply with regulatory requirements or if we experience unanticipated problems with our products, when and if any of them are approved.

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If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may fail to obtain any marketing approvals, lose any marketing approval that we may have obtained and we may not achieve or sustain profitability.

Our business operations, including our relationships with healthcare providers, third-party payors, and patients, will be subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.

Healthcare providers, including physicians, and third-party payors play a primary role in the recommendation and prescription of any product candidates for which we obtain marketing approval.

Our arrangements with healthcare providers, third-party payors, patients and other parties within the healthcare industry may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell, and distribute any products for which we obtain marketing approval.

Restrictions under applicable federal and state healthcare and regulatory

laws and regulations within the United States include the following, some of which will apply only if and when we have a marketed product:

Our business operations, including our relationships with healthcare providers, third-party payors, and patients, are or will be subject to a broad range of healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings if our activities are challenged as non-compliant.

Pharmaceutical manufacturers and their products are subject to extensive federal and state regulation, including laws intended to prevent fraud and abuse in the healthcare industry.

These laws may constrain the business or financial arrangements and relationships through which we conduct business, including how we conduct research regarding, market, sell, and distribute our products.

In the United States, these laws include, but are not limited to the following, some of which are likely to apply only if or when we obtain marketing approval for a product candidate:

● the federal healthcare anti-kickback statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made under federal and state healthcare programs such as Medicare and Medicaid.

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● the FDCA, which, among other things, strictly regulates drug product and medical device marketing, prohibits manufacturers from marketing such products for off-label use and regulates the distribution of samples;

● federal laws that require pharmaceutical manufacturers to report certain calculated product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under governmental healthcare programs;

● federal laws that require pharmaceutical manufacturers to calculate, report and certify certain complex product prices to the government or provide certain discounts or rebates to government authorities or private entities, often as a condition of reimbursement under governmental healthcare programs, which data may be used in the calculation of reimbursement and/or discounts on approved products;

● federal and state consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers;

● state medical privacy and comprehensive privacy statutes, which regulate the privacy and security of personal information;

● federal and state medical privacy and comprehensive privacy statutes, which regulate the privacy and security of personal information, and may vary significantly, complicating compliance efforts;

● the so-called federal “sunshine law” or Open Payments which requires manufacturers of drugs, devices, biologics, and medical supplies to report to the Centers for Medicare & Medicaid Services information related to payments and other transfers of value to teaching hospitals, physicians, and other healthcare practitioners, as well as ownership and investment interests held by physicians and their immediate family members;

● analogous state laws and regulations, such as state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non- governmental third-party payors, including private insurers, and state laws which regulate interactions between pharmaceutical companies and healthcare providers, require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, require pharmaceutical companies to report information on transfers of value to other healthcare providers, marketing

expenditures or pricing information and/or require licensing of sales representatives.

State laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

Similar healthcare and data privacy laws and regulations exist in the European Union and other foreign jurisdictions, including reporting requirements detailing interactions with and payments to healthcare providers and laws governing the privacy and security of certain protected information.

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and additional governmental resources are being used to enforce these laws and to prosecute companies and individuals who are believed to be violating them.

Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs.

Efforts to ensure that our business

arrangements with third parties will comply with applicable healthcare laws and regulations will involve substantial costs.

Governmental authorities may potentially conclude that our business practices, including arrangements we may have with physicians and other healthcare providers, or patient assistance programs, may not comply with applicable laws.

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If any of the physicians or other providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to criminal, civil, or administrative sanctions, including exclusions from government funded healthcare programs.

Further, defending against any such actions can be costly, time-consuming and may require significant personnel resources.

Therefore, even if we are successful in defending against any such actions that may be brought against us, our business may be impaired.

Our employees, independent contractors, principal investigators, CROs, consultants, and vendors may engage in misconduct or other improper activities, including non-compliance with regulatory standards and requirements, which could cause significant liability for us and harm our reputation.

We are exposed to the risk that our employees, independent contractors, principal investigators, CROs, consultants and vendors may engage in fraud or other misconduct, including intentional failures to:

comply with FDA regulations or similar regulations of comparable foreign regulatory authorities, provide accurate information to the FDA or comparable foreign regulatory authorities, comply with manufacturing standards we have established, comply with federal and state healthcare fraud and abuse laws and regulations and similar laws and regulations established and enforced by comparable foreign regulatory authorities, report financial information or data accurately or disclose unauthorized activities to us.

Such misconduct could also involve the improper use of information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation.

Further, we are exposed to the risk that our employees, independent contractors, principal investigators, CROs, consultants and vendors may engage in fraud or other misconduct, including actions resulting non-compliance with regulatory standards and requirements such as those described above.

It is not always possible to identify and deter misconduct by employees and other third parties, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a failure to be in compliance with such laws, standards, or regulations.

If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business and results of operations, including the imposition of significant fines or other sanctions.

Recently enacted and future legislation may increase the difficulty and cost for us to obtain marketing approval of and commercialize our product candidates and affect the prices we may obtain.

Defending against any such actions can be costly, time-consuming and may require significant personnel resources.

Therefore, even if we are successful in defending against any such actions that may be brought against us, our business may be impaired.

The FDA and other comparable regulatory authorities could require clearance or approval of an in vitro diagnostic or companion diagnostic device as a condition of approval for any product candidates that require or would commercially benefit from such tests, including the combination of avutometinib and defactinib.

If we are unable to successfully validate, develop and obtain regulatory approval for companion diagnostic tests for our product candidates that require or would commercially benefit from such tests, or experience significant delays in doing so, we may not realize the full commercial potential of these product candidates and our drug development strategy and operational results may be harmed.

If safe and effective use of any of our product candidates depends on an in vitro diagnostic, then the FDA generally will require approval or clearance of that test, known as a companion diagnostic, at the same time that the FDA approves our product candidates.

Companion diagnostics, which provide information that is essential for the safe and effective use of a corresponding therapeutic product, are subject to regulation by the FDA and other comparable regulatory authorities as medical devices and require separate regulatory authorization from therapeutic approval prior to commercialization.

The development programs for some of our product candidates contemplate working with developers or obtaining access to marketed companion diagnostic tests, which are assays or tests to identify an appropriate patient population.

For example, in connection with our NDA for the treatment of adult patients with recurrent LGSOC, who received at least one prior systemic therapy and have a KRAS mutation, we may be required to obtain FDA approval or clearance of a companion diagnostic.

If safe and effective use of any of our product candidates we may develop depends on a companion diagnostic, we may not receive marketing approval, or marketing approval may be delayed, if we are unable to or are delayed in developing, identifying, or obtaining regulatory approval or clearance for the companion diagnostic product for use with our product candidate.

In addition, the process of obtaining or creating such companion diagnostics is time consuming and costly and we, and/or future collaborators, may encounter difficulties in developing and obtaining regulatory clearance or approval for the companion diagnostics.

Current and future health care reforms may increase the difficulty and cost for us to obtain marketing approval of and commercialize our product candidates and affect the prices we may obtain.

In the United States and some foreign jurisdictions, there have been, and we expect there will continue to be, a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could, among other things, prevent or delay marketing approval of our product candidates, restrict or regulate post approval activities, and affect our ability to profitably sell any of our product candidates for which we obtain marketing approval.

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Beyond the ACA, there are ongoing and widespread health care reform efforts, a number of which have focused on regulation of prices or payment for drug products.

Drug pricing and payment reform has been a focus of the Biden Administration.

For example, federal legislation enacted in 2021 eliminates a statutory cap on Medicaid drug rebate program rebates effective January 1, 2024.

Drug pricing and payment reform has been an ongoing focus.

For example, federal legislation eliminated a statutory cap on Medicaid drug rebate program rebates effective January 1, 2024.

As another example, the Inflation Reduction Act (“IRA”) of 2022 includes a number of changes intended to address rising prescription drug prices in Medicare Parts B and D, with varying implementation dates.

These changes include caps on Medicare Part D out-of-pocket costs, Medicare Part B and Part D drug price inflation rebates, a new Medicare Part D manufacturer discount drug program (replacing the ACA Medicare Part D coverage gap discount program) and a drug price negotiation program for certain high spend Medicare Part B and D drugs (with the first list of drugs announced in 2023).

Subsequent to the enactment of the IRA, in 2022, the Biden administration released an executive order directing the Department of Health and Human Services (“HHS”) to report on how the CMMI could be leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries.

The report was issued in 2023 and proposed various models that CMMI is currently developing which seek to lower the cost of drugs, promote accessibility, and improve quality of care, models are currently still in development.

The IRA is anticipated to have a significant impact on the pharmaceutical industry.

Subsequent to the enactment of the IRA, in 2024, the Biden Administration announced its commitment to expanding certain IRA reforms.

There have been significant and wide-ranging reforms to federal policy and the federal government under the new Trump Administration.

The focus on drug pricing and payment reform is likely to continue under the new Trump Administration.

Other potential healthcare reform efforts under the Trump Administration could affect access to healthcare coverage or the funding of health care benefits.

There is significant uncertainty regarding the nature or impact of any such reform implemented by the Trump Administration through executive action or by Congress.

Healthcare reform efforts have been and may continue to be subject to scrutiny and legal challenge.

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Pursuant to court order, the removal was delayed and recent legislation imposed a moratorium on implementation of the rule until January 1 2032.

As another example, the IRA drug price negotiation program has been challenged in litigation filed by various pharmaceutical manufacturers and industry groups.

As a further example, the IRA drug price negotiation program has been challenged in litigation filed by various pharmaceutical manufacturers and industry groups.

Recently, there has been considerable public and government scrutiny of pharmaceutical pricing and proposals to address the perceived high cost of pharmaceuticals.

There have also been efforts at the federal level to implement measures to regulate drug pricing or payment for pharmaceutical products, including legislation on drug importation.

Individual states in the United States have also become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical product pricing, including price constraints, restrictions on copayment assistance by pharmaceutical manufacturers, marketing cost disclosure and transparency measures, and, in some cases, measures designed to encourage importation from other countries and bulk purchasing.

We expect continued scrutiny on drug pricing and government price reporting from Congress, agencies, and other bodies.

In addition, other broader legislative changes have been adopted that could have an adverse effect upon, and could prevent, our products’ commercial success.

For example, the Budget Control Act of 2011, as amended, resulted in the imposition of reductions in Medicare (but not Medicaid) payments to providers in 2013 and remains

in effect through 2032 unless additional Congressional action is taken.

For example, the Budget Control Act of 2011, as amended, resulted in the imposition of reductions in Medicare (but not Medicaid) payments to providers in 2013 and remains in effect through 2032 unless additional Congressional action is taken.

Any significant spending reductions affecting Medicare, Medicaid or other publicly funded or subsidized health programs that may be implemented and/or any significant taxes or fees that may be imposed on us could have an adverse impact on our results of operations.

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Congress of the FDA’s approval process may significantly delay or prevent marketing approval, as well as subject us to more stringent product labeling and post marketing testing and other requirements.

Supreme Court’s June 2024 decision in Loper Bright Enterprises v.

Raimondo overturned the longstanding Chevron doctrine, under which courts were required to give deference to regulatory agencies’ reasonable interpretations of ambiguous federal statutes.

The Loper decision could result in additional legal challenges to regulations and guidance issued by federal agencies, including the FDA, on which we rely.

Any such legal challenges, if successful, could have a material impact on our business.

Additionally, the Loper decision may result in increased regulatory uncertainty, inconsistent judicial interpretations, and other impacts to the agency rulemaking process, any of which could adversely impact our business and operations.

We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative action or as a result of legal challenges, either in the United States or abroad.

If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, our business could be materially harmed.

We continue to evaluate federal and state health care reform efforts and the effect that such efforts may have on our business.

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If a prolonged government shutdown occurs, preventing the FDA or other regulatory authorities from conducting their regular inspections, reviews, or other regulatory activities, it could significantly impact the ability of the FDA or other regulatory authorities to timely review and process our regulatory submissions, which could have a material adverse effect on our business.

Separately, in response to the COVID-19 pandemic, the FDA announced its intention to postpone most inspections of foreign and domestic manufacturing facilities and products at various points.

Even though the FDA has since resumed standard inspection operations of domestic facilities where feasible, the FDA has continued to monitor and implement changes to its inspectional activities to ensure the safety of its employees and those of the firms it regulates as it adapts to the evolving COVID-19 pandemic, and any resurgence of the virus, including as a result of the emergence of new variants may lead to further inspectional delays.

Regulatory authorities outside the United States may adopt similar restrictions or other policy measures in response to the COVID-19 pandemic and may experience delays in their regulatory activities.

If a prolonged government shutdown occurs, or if global health concerns continue to prevent the FDA or other regulatory authorities from conducting business as usual or conducting inspections, reviews or other regulatory activities, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material effect on our business.

Due to the recent change in presidential administration, we face uncertainty regarding potential regulatory developments that may adversely affect our business.

We face uncertainty regarding the potential for changes in the regulatory environment following the change in presidential administration in January 2025.

While many of the Trump administration’s proposed policies appear to be focused on deregulation, the new administration and federal government could adopt legislation, regulation, or policy that adversely affects our business or creates a more challenging and costly environment to pursue the development and commercialization of our current or future product candidates.

For example, the federal government, including the FDA, may implement legislative, regulatory, or policy changes regarding the standards for approving drugs that we may be unable to satisfy or regarding the marketing of approved drugs that may limit or prohibit the advertising and promotion of our current or future product candidates, if approved.

Additionally, because one objective of the current Trump administration appears to be to decrease spending in the federal government, the FDA could face staff reductions, which could impact the FDA’s ability to engage in routine regulatory and oversight activities and result in delays or limitations on our ability to proceed with clinical development programs and obtain regulatory approvals.

It is difficult to predict how executive actions that may be

taken under the current Trump administration may affect the FDA’s ability to exercise its regulatory authority.

If such executive actions impose constraints on the FDA’s ability to engage in routine oversight and product review activities in the normal course, our business may be negatively impacted.

Risks Related to Employee Matters and Managing Growth

Our future success depends on our ability to retain our chief executive officer and other key executives and to attract, retain and motivate qualified personnel.

We are highly dependent on the efforts and abilities of the principal members of our senior management and other key personnel, including Daniel Paterson, our President and Chief Executive Officer and Daniel Calkins, our Chief Financial Officer.

Although we have formal employment agreements with Daniel Paterson and Daniel Calkins, these agreements do not prevent them from terminating their employment with us at any time.

Although we have formal employment agreements with Daniel Paterson, Daniel Calkins, Matthew Ros and other members of our senior management and key personnel, these agreements do not prevent them from terminating their employment with us at any time.

We do not maintain “key person” insurance for any of our executives or other employees.

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Our stock price has been volatile.

Since January 27, 2012, when we became a public company, the price for one share of our common stock has reached a high of $194.53 and a low of $3.54 through December 31, 2023, on a post reverse stock split basis.

Since January 27, 2012, when we became a public company, the closing price for one share of our common stock has reached a high of $194.53 and a low of $2.20 through December 31, 2024, on a post reverse stock split basis.

We cannot predict whether the price of our common stock will rise or fall.

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● actual or anticipated changes in estimates as to financial results, development timelines, or recommendations by securities analysts;

● developments regarding the commercialization of our product candidates, including avutometinib and defactinib;

● variations in our financial results or those of companies that are perceived to be similar to us;

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We can issue and have issued shares of preferred stock, which may adversely affect the rights of holders of our common stock.

We have in the past issued, and we may at any time in the future issue, shares of preferred stock, and as of December 31, 2023 we have 1,000,000 shares of our Series A convertible preferred stock, par value $0.0001 per share (the “Series A Convertible Preferred Stock”) and 1,200,000 shares of our Series B convertible preferred stock, par value $0.0001 per share (the “Series B Convertible Preferred Stock” and together with the Series A Convertible Preferred Stock, the “Preferred Stock”) outstanding.

We have in the past issued, and we may at any time in the future issue, shares of preferred stock, and as of December 31, 2024 we have 1,000,000 shares of our Series A convertible preferred stock, par value $0.0001 per share (the “Series A Convertible Preferred Stock”) and 0 shares of our Series B convertible preferred stock, par value $0.0001 per share (the “Series B Convertible Preferred Stock” and together with the Series A Convertible Preferred Stock, the “Preferred Stock”) issued and outstanding.

Our amended and restated certificate of incorporation authorizes us to issue up to 5,000,000 shares of preferred stock with designations, rights and preferences determined from time-to-time by our board of directors.

Accordingly, our board of directors is empowered, without stockholder approval, to issue preferred stock with dividend, liquidation, conversion, voting or other rights superior to those of holders of our common stock.

Accordingly, our board of directors is empowered, without stockholder approval, to issue preferred stock with dividend, liquidation, conversion, voting or

other rights superior to those of holders of our common stock.

For example, our Series B Convertible Preferred Stock ranks senior to our common stock, and the holders of our Series B Convertible Preferred Stock are entitled to a liquidation preference of $1.00 per share of Series B Convertible Preferred Stock in the event of our liquidation, dissolution or winding up, which could limit or eliminate any payments that the holders of our common stock could expect to receive upon our liquidation.

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We also may not make any changes to our amended and restated certificate of incorporation that would limit the rights of the holders of our either series of our preferred stock without the affirmative vote of a majority of such series of preferred stock, which may make it more difficult to take certain corporate actions in the future.

Our stockholders will experience substantial dilution if shares of our Series B Convertible Preferred Stock are converted into common stock or our pre-funded warrants are exercised for common stock.

As of December 31, 2023, there were 1,200,000 shares of our Series B Convertible Preferred Stock outstanding, which are convertible without payment of additional consideration into 4,236,570 shares of our common stock, subject to certain ownership limitations and pre-funded warrants to purchase 1,538,591 shares of our common stock for an exercise price equal to $0.001 per share of common stock.

The conversion of the outstanding shares of our Series B Convertible Preferred Stock into common stock or exercise of our pre-funded warrants would

be substantially dilutive to existing stockholders.

Our stockholders will experience substantial dilution if outstanding warrants or pre-funded warrants are exercised for shares common stock.

As of December 31, 2024, there were pre-funded warrants to purchase up to 5,000,000 shares of our common stock and warrants to purchase up to 18,083,334 shares of our common stock outstanding.

The pre-funded warrants have an exercise price equal to $0.001 per underlying share of common stock and do not expire.

Each warrant has an exercise price equal to $3.50 and is exercisable for one shares of our common stock (or, in certain limited circumstances in lieu of a share of common stock, a pre-funded warrant for one share of our common stock at the warrant exercise price less the exercise price of the pre-funded warrant purchased) .

The warrants expire on January 25, 2026.

The conversion of the outstanding pre-funded warrants and warrants into shares of common stock would be substantially dilutive to existing stockholders.

Any dilution or potential dilution may cause our stockholders to sell their shares, which may contribute to a downward movement in the stock price of our common stock.

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To the extent that we enter into certain licensing arrangements, the ownership interest of our existing stockholders may be diluted if we elect to make certain payments in shares of our common stock.

Debt financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends.

Additional debt financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends.

If we raise additional funds through collaborations, strategic alliances or licensing arrangements with third parties, we may have to relinquish future revenue streams or valuable rights to product candidates or to grant licenses on terms that may not be favorable to us.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1A. Risk Factors