10-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2024

Commission File Number 001-39219

Revolution Medicines, Inc.

(Exact name of Registrant as specified in its Charter)

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (650) 481-6801

Securities registered pursuant to Section 12(b) of the Act:

Title of each class TradingSymbol(s) Name of each exchange on which registered

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☒ No ☐

Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. Yes ☐No ☒

Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐

Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was required to submit such files). Yes ☒ No ☐

Indicate by check mark whether the Registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☒ Accelerated filer ☐

Non-accelerated filer ☐ Smaller reporting company ☐

Emerging growth company ☐

If an emerging growth company, indicate by check mark if the Registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the Registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☒

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the Registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the Registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒

The aggregate market value of the common stock held by non-affiliates of the Registrant as of June 30, 2024 (the last business day of the Registrant’s most recently completed second fiscal quarter) was approximately $6.5 billion, based on the closing price of the Registrant’s common stock, as reported by the Nasdaq Global Select Market on June 30, 2024 of $38.81 per share.

The number of shares of the Registrant’s Common Stock outstanding on the Nasdaq Global Select Market as ofFebruary 21, 2025 was 185,913,326 (excluding 2,173,917 shares underlying pre-funded warrants).

DOCUMENTS INCORPORATED BY REFERENCE

Portions of the Registrant’s definitive Proxy Statement relating to the Registrant’s 2025 Annual Meeting of Stockholders are incorporated herein by reference in Part III of this Annual Report on Form 10-K to the extent stated herein. The proxy statement will be filed with the Securities and Exchange Commission within 120 days of the Registrant’s fiscal year ended December 31, 2024.

Table of Contents

Page

PART I 3

Item 1. Business 3

Item 1A. Risk Factors 36

Item 1B. Unresolved Staff Comments 84

Item 1C. Cybersecurity 84

Item 2. Properties 85

Item 3. Legal Proceedings 85

Item 4. Mine Safety Disclosures 86

Item 6. [Reserved.] 88

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 100

Item 8. Financial Statements and Supplementary Data 101

Item 9A. Controls and Procedures 131

Item 9B. Other Information 131

Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 132

Item 10. Directors, Executive Officers and Corporate Governance 133

Item 11. Executive Compensation 133

Item 14. Principal Accounting Fees and Services 133

Item 15. Exhibits, Financial Statement Schedules 134

SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K contains forward-looking statements concerning our business, operations and financial performance and condition, as well as our plans, objectives and expectations for our business, operations and financial performance and condition. Any statements contained herein that are not statements of historical facts may be deemed to be forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that are in some cases beyond our control and may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements.

In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “predict,” “potential,” “positioned,” “seek,” “should,” “target,” “will,” “would,” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. These forward-looking statements include, but are not limited to, statements about:

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the scope, progress, results and costs of developing our product candidates or any other future product candidates, and conducting preclinical studies and clinical trials;

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the scope, progress, results and costs related to the research and development of our pipeline;

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the timing of and costs involved in obtaining and maintaining regulatory approval for any of current or future product candidates, and any related restrictions, limitations and/or warnings in the label of an approved product candidate;

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our expectations regarding the potential market size and size of the potential patient populations for our product candidates and any future product candidates, if approved for commercial use;

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our ability to maintain and establish new collaborations, licensing or other arrangements and the financial terms of any such agreements;

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our commercialization, marketing and manufacturing capabilities and expectations;

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the rate and degree of market acceptance of our product candidates, as well as the pricing and reimbursement of our product candidates, if approved;

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the implementation of our business model and strategic plans for our business, product candidates and technology, including additional indications for which we may pursue;

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the scope of protection we are able to establish and maintain for intellectual property rights covering our product candidates, including the projected term of patent protection;

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our expectations regarding our ability to obtain, maintain, enforce and defend our intellectual property protection for our product candidates;

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estimates of our expenses, future revenue, capital requirements, our needs for additional financing and our ability to obtain additional capital;

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developments and projections relating to our competitors and our industry, including competing therapies and procedures;

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regulatory and legal developments in the United States and foreign countries;

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the performance of our third-party suppliers and manufacturers;

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our ability to attract and retain key scientific or management personnel; and

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other risks and uncertainties, including those listed under the caption “Risk Factors.”

We have based these forward-looking statements largely on management’s current expectations, estimates, forecasts and projections about our business and the industry in which we operate and management’s beliefs and assumptions and are not guarantees of future performance or development and involve known and unknown risks, uncertainties and other factors that are in some cases beyond our control. These forward-looking statements speak only as of the date of this Annual Report on Form 10-K and are subject to a number of risks, uncertainties and assumptions described in the section titled “Risk Factors” and elsewhere in this Annual Report on Form 10-K. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, we do not plan to publicly update or revise any

forward-looking statements contained herein until after we distribute this Annual Report on Form 10-K, whether as a result of any new information, future events or otherwise.

In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this Annual Report on Form 10-K, and while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain, and you are cautioned not to unduly rely upon these statements.

Investors and others should note that we may announce material business and financial information to our investors using our investor relations website (ir.revmed.com), Securities and Exchange Commission (SEC) filings, webcasts, press releases and conference calls. We use these mediums, including our website, to communicate with our members and public about our company, our products and other issues. It is possible that the information that we make available may be deemed to be material information. We therefore encourage investors and others interested in our company to review the information that we make available on our website.

Summary of Material Risks Associated with Our Business

The principal risks and uncertainties affecting our business include the following:

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We are a clinical-stage precision oncology company with a limited operating history and no products approved for commercial sale. We have incurred significant losses since our inception. We expect to incur losses for at least the next several years and may never achieve or maintain profitability, which, together with our limited operating history, makes it difficult to assess our future viability.

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We have never generated revenue from product sales and may never be profitable.

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We will require substantial additional financing to achieve our goals, which may not be available on acceptable terms, or at all. A failure to obtain this necessary capital when needed could force us to delay, limit, reduce or terminate our product development or commercialization efforts.

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Our business is dependent on the successful development of our current and future product candidates. If we are unable to advance our current or future product candidates through clinical trials, obtain marketing approval and ultimately commercialize any of our product candidates, or we experience significant delays in doing so, our business will be materially harmed.

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Preclinical development is uncertain. Our preclinical programs may experience delays or may never advance to clinical trials, which would adversely affect our ability to obtain regulatory approvals or commercialize our product candidates on a timely basis or at all, which would have an adverse effect on our business.

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Historically, direct inhibition of any RAS protein has been challenging due to a lack of tractable, or “druggable,” binding pockets. Given this approach is unproven, it may not be successful.

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The results of preclinical studies and early-stage clinical trials may not be predictive of future results.

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If we encounter difficulties enrolling patients in our clinical trials, our clinical development activities could be delayed or otherwise be adversely affected.

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We and our collaborators are currently developing and may in the future develop, our product candidates in combination with other therapies, which exposes us to additional risks.

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We face significant competition, and if our competitors develop and market products that are more effective, safer or less expensive than our product candidates, our commercial opportunities will be negatively impacted.

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If we and our collaborators are unable to obtain and maintain sufficient patent and other intellectual property protection for our product candidates and technology, our competitors could develop and commercialize products and technology similar or identical to ours, and we may not be able to compete effectively in our market or successfully commercialize any of our current or future product candidates.

The summary risk factors described above should be read together with the text of the full risk factors below in the section entitled “Risk Factors” and the other information set forth in this Annual Report on Form 10-K, including our consolidated financial statements and the related notes, as well as in other documents that we file with the SEC. The risks summarized above or described below are not the only risks that we face. Additional risks and uncertainties not precisely known to us or that we currently deem to be immaterial may also materially and adversely affect our business, competitive position, financial condition, results of operations, cash flows and growth prospects.

PART I

Item 1. Business.

Overview

We are a clinical-stage precision oncology company developing novel targeted therapies for RAS-addicted cancers. We possess sophisticated structure-based drug discovery capabilities built upon deep chemical biology and cancer pharmacology know-how and innovative, proprietary technologies that enable the creation of small molecules tailored to unconventional binding sites. Guided by our understanding of genetic drivers and adaptive resistance mechanisms in cancer, we deploy precision medicine approaches to inform innovative monotherapy and combination regimens.

Our research and development pipeline comprises RAS(ON) inhibitors that bind directly to RAS variants, which we refer to as RAS(ON) Inhibitors, and RAS companion inhibitors that target key nodes in the RAS pathway or associated pathways. Our RAS(ON) Inhibitors are designed to be used as monotherapy, in combination with other RAS(ON) Inhibitors and/or in combination with RAS companion inhibitors or other therapeutic agents.

RAS(ON) Inhibitors

Our RAS(ON) Inhibitors are based on our proprietary tri-complex technology platform, which enables a highly differentiated approach to inhibiting the active, GTP-bound form of RAS, which we refer to as RAS(ON). We are developing a portfolio of compounds that we believe were the first RAS(ON) Inhibitors to use this mechanism of action. We believe that direct inhibitors of RAS(ON) suppress cell growth and survival and are less susceptible to adaptive resistance mechanisms recognized for RAS(OFF) inhibitors.

We are evaluating our RAS(ON) Inhibitors alone and in combination with other drugs and investigational drug candidates, particularly in-pathway agents. We believe tailored RAS(ON) Inhibitors will be useful to serve the diverse landscape of RAS-addicted cancers optimally. We believe that in some cases, patients may experience maximal clinical benefit from the broad activity of our RAS(ON) multi-selective inhibitor, daraxonrasib (RMC-6236), if approved. In others, we believe treatment with a RAS(ON) mutant-selective inhibitor may be optimal. We further believe that in some cases, it could be beneficial to combine daraxonrasib with a RAS(ON) mutant-selective inhibitor, with daraxonrasib functioning as the backbone of these RAS(ON) Inhibitor doublets. In addition, we believe that in some cases, combination of our RAS(ON) Inhibitors with standard of care therapies, including immunotherapies, may be optimal.

We are advancing a deep pipeline of RAS(ON) Inhibitors, including daraxonrasib (RMC-6236), our RAS(ON) multi-selective inhibitor; elironrasib (RMC-6291), our G12C-selective inhibitor; and zoldonrasib (RMC-9805), our G12D-selective inhibitor. Together, we consider these three clinical-stage candidates as the first wave of RAS(ON) inhibitors that we are advancing through clinical development. We also currently plan to advance RMC-5127 (G12V) into clinical development. In addition, we have other preclinical-stage RAS(ON) inhibitor clinical development opportunities, including the RAS(ON) mutant-selective inhibitors RMC-0708 (Q61H) and RMC-8839 (G13C).

Daraxonrasib (RMC-6236)

Daraxonrasib (RMC-6236), our RAS(ON) multi-selective inhibitor, is designed as an oral, RAS-selective tri-complex inhibitor of multiple RAS(ON) variants containing cancer driver mutations at all three of the major RAS mutation hotspot positions (G12, G13 and Q61). Daraxonrasib inhibits all three major RAS isoforms, suppressing the mutant cancer driver and cooperating wild-type RAS proteins.

A global, randomized Phase 3 registrational trial of daraxonrasib in the second-line (2L) treatment of patients with metastatic pancreatic ductal adenocarcinoma (PDAC), which we call the RASolute 302 study, is ongoing. In the RASolute 302 study, we are randomizing patients in a 1:1 ratio to receive either daraxonrasib at a dose of 300 mg daily or the investigator’s choice of chemotherapy. The RASolute 302 study has a nested trial design allowing for a hierarchical sequence of statistical analysis, with patients with tumors harboring RAS G12X mutations serving as the core population which will be tested first and all enrolled patients serving as the secondary population. We believe this nested design and hierarchical testing increases the probability of trial success based on the core population while creating an opportunity to gain approval for a broader population. Patients in the RASolute 302 study will be evaluated for the dual primary endpoints of progression-free survival (PFS) and overall survival (OS) in the core population, with secondary endpoints including PFS and OS in the secondary population and objective response rate (ORR) and quality of life measures. We currently expect to substantially complete enrollment of the RASolute 302 study in 2025, to enable an expected clinical readout in 2026.

Having finalized the study protocol, we are now activating sites for a global, randomized Phase 3 registrational trial comparing daraxonrasib versus docetaxel in patients with locally advanced or metastatic RAS-mutated non-small cell lung cancer (NSCLC) who have been treated with immunotherapy and platinum-containing chemotherapy, which we call the RASolve 301 study. In the RASolve 301 study, we are randomizing patients in a 1:1 ratio to receive either daraxonrasib or docetaxel. The RASolve 301 study has a nested trial design allowing for a hierarchical sequence of statistical analysis, with patients with tumors harboring RAS G12X (other than G12C) mutations serving as the core population which will be tested first, and all enrolled patients serving as the secondary population. We believe this nested design and hierarchical testing increases the probability of trial success based on the core population while creating an opportunity to gain approval for a broader population. Patients in the RASolve 301 study will be evaluated for the dual primary endpoints of PFS and OS in the core population, with secondary endpoints including PFS and OS in the secondary population and ORR and quality of life measures.

We currently expect to initiate a global, randomized Phase 3 daraxonrasib monotherapy study in patients with first-line (1L) metastatic PDAC in the second half of 2025. We also currently expect to initiate a global, randomized Phase 3 monotherapy study of daraxonrasib as adjuvant treatment for patients with resectable PDAC in the second half of 2025.

On December 2, 2024 we reported updated clinical safety, tolerability, and activity data for daraxonrasib from our first-in-human monotherapy study of daraxonrasib, which we refer to as the RMC-6236-001 study, in patients with previously treated RAS-mutant PDAC as of a data cutoff date of July 23, 2024. We believe these data showed that daraxonrasib was generally well tolerated and demonstrated encouraging antitumor activity that supported our initiation of the RASolute 302 study.

Also on December 2, 2024, we reported clinical safety and tolerability data as of a September 30, 2024 data cutoff date for daraxonrasib from the RMC-6236-001 study in patients with NSCLC with tumors harboring RAS mutations. We also reported clinical activity data as of a September 30, 2024 data cutoff date for daraxonrasib from the RMC-6236-001 study in patients with NSCLC with tumors harboring RAS G12X mutations who had received one or two prior lines of therapy which must have included prior immunotherapy and platinum chemotherapy administered either concurrently or sequentially, but not docetaxel, a study population matching the planned RASolve 301 enrollees. We believe these data showed that daraxonrasib was generally well tolerated and demonstrated encouraging antitumor activity that supported our initiation of the RASolve 301 study.

Based on our observations from the RMC-6236-001 study and our preclinical observations, we believe there is a potential opportunity to evaluate daraxonrasib combinations in earlier lines of therapy in multiple tumor types, and we are currently evaluating several exploratory combination regimens that include daraxonrasib in order to assess the potential for development in these settings. These combinations include daraxonrasib with pembrolizumab, daraxonrasib with elironrasib, daraxonrasib with zoldonrasib and daraxonrasib with standard of care chemotherapy agents.

On December 2, 2024, we disclosed initial clinical safety and tolerability data as of a data cutoff date of October 28, 2024 from our clinical study of the combination of daraxonrasib with pembrolizumab, which we believe showed the combination was generally well tolerated with limited hepatotoxicity.

Also on December 2, 2024, we disclosed initial clinical safety, tolerability and activity data as of a data cutoff date of October 28, 2024 from our clinical study of the combination of daraxonrasib with elironrasib, which we believe showed the combination was generally well tolerated and provide initial proof-of-mechanism for a RAS(ON) inhibitor doublet in patients with colorectal cancer (CRC) who were previously treated with KRAS(OFF) G12C inhibitors. We believe these preliminary data observations support continued development of RAS(ON) inhibitor doublets in a broad range of tumor types and earlier lines of therapy, including 1L patients with NSCLC carrying RAS G12C tumors.

In April 2024, at the American Association for Cancer Research (AACR) Annual Meeting 2024, we reported individual case studies from the RMC-6236-001 study that showed examples of objective responses to daraxonrasib in patients with tumor types beyond PDAC or NSCLC, specifically patients with melanoma and with CRC.

Elironrasib (RMC-6291)

Elironrasib (RMC-6291) is designed as a RAS(ON) oral tri-complex G12C-selective inhibitor. It is designed to exhibit subnanomolar potency for suppressing RAS pathway signaling and growth of RAS G12C-bearing cancer cells and is engineered to be highly selective for RAS G12C over wild-type RAS and other cellular targets. Elironrasib is designed to be differentiated from first-generation KRAS(OFF) G12C inhibitors, which sequester the KRAS(OFF) G12C form, by its mechanism of directly inhibiting the RAS(ON) G12C form.

On October 13, 2023, we reported interim preliminary safety and anti-tumor data from our ongoing first-in-human study of elironrasib, which we refer to as the RMC-6291-001 study, as of an October 5, 2023 data cut-off date, which we believe provide preliminary evidence of clinically meaningful differentiation of elironrasib from KRAS(OFF) G12C inhibitors.

We are evaluating several exploratory combination regimens that include elironrasib in order to assess the potential for development in earlier lines of therapy. These combinations include elironrasib with pembrolizumab and, as discussed in the “Daraxonrasib (RMC-6236)” section above, elironrasib with daraxonrasib. We are also planning a combination study of elironrasib with both daraxonrasib and pembrolizumab.

On December 2, 2024, we disclosed initial clinical safety, tolerability and activity data for the combination of daraxonrasib with elironrasib, as discussed in the “Daraxonrasib (RMC-6236)” section above.

Also on December 2, 2024, we disclosed clinical safety and tolerability data as of a data cutoff date of October 28, 2024 for the combination of elironrasib with pembrolizumab, which we believe showed the combination was generally well tolerated with limited hepatotoxicity.

Zoldonrasib (RMC-9805)

Zoldonrasib (RMC-9805) is designed as a RAS(ON) oral tri-complex G12D-selective inhibitor. It is designed to exhibit low nanomolar potency for suppressing RAS pathway signaling and growth of RAS G12D-bearing cancer cells and is engineered to covalently inactivate RAS G12D irreversibly.

On October 25, 2024, we reported preliminary clinical safety, tolerability and activity data as of a data cutoff date of September 2, 2024 from our first-in-human monotherapy study of zoldonrasib, which we refer to as the RMC-9805-001 study in patients with previously treated solid tumors harboring KRAS G12D mutations.

We believe that these data support our ongoing development of zoldonrasib as a single agent and in combination with other therapies, including with daraxonrasib. An exploratory combination study of zoldonrasib with daraxonrasib is ongoing. We currently expect to disclose additional zoldonrasib clinical safety and antitumor activity data in the second quarter of 2025.

We currently expect to initiate one or more pivotal combination studies in 2026 that incorporate either zoldonrasib or elironrasib and currently expect to share clinical data supporting these plans in the second or third quarter of 2025.

RMC-5127

RMC-5127 is designed as a RAS(ON) oral G12V-selective inhibitor. It is designed to exhibit picomolar potency for suppressing RAS pathway signaling and growth of RAS G12V-bearing cancer cells and is engineered for selective inhibition of RAS G12V over other RAS isoforms via non-covalent binding interactions. We currently expect to advance RMC-5127 to a clinic-ready stage in 2025 and to initiate a first-in-human dose escalation clinical trial of RMC-5127 in 2026.

RMC-0708

RMC-0708 is designed as a RAS(ON) oral Q61H-selective inhibitor. It is designed to exhibit picomolar potency for suppressing RAS pathway signaling and growth of RAS Q61H-bearing cancer cells and is engineered for selective inhibition of RAS Q61H over other RAS isoforms via non-covalent binding interactions. Clinical development of RMC-0708 is subject to our continuing assessment of our portfolio priorities.

RMC-8839

RMC-8839 is designed as a RAS(ON) oral G13C-selective inhibitor. It is designed to exhibit picomolar potency for suppressing RAS pathway signaling and growth of KRAS G13C-bearing cancer cells and is engineered to covalently inactivate KRAS G13C for irreversible inhibition. Clinical development of RMC-8839 is subject to our continuing assessment of our portfolio priorities.

Other Development Opportunities

We have developed RAS companion inhibitors that are designed to suppress cooperating targets and pathways that sustain RAS-addicted cancers. These compounds include RMC-4630, which is designed as a potent and selective inhibitor of SHP2; RMC-5552, which is designed as a selective inhibitor of mTORC1 signaling in tumors; and RMC-5845, which is designed to target SOS1 a protein

that plays a key role in converting RAS(OFF) to RAS(ON) in cells. Additional clinical development of our RAS companion inhibitors is subject to our continuing assessment of our portfolio priorities.

We are also developing preclinical next-generation programs that are designed to sustain our innovation platform beyond our current development-stage assets.

Our Strategy

Overview

Our goal is to revolutionize treatment for patients with RAS-addicted cancers through the discovery, development and delivery of innovative, targeted medicines. RAS proteins drive a significant number of human cancers, and are largely unserved by targeted therapeutics. The KRAS G12C mutation has been clinically validated as a therapeutic target, and the evidence is strong that numerous other oncogenic mutations in the RAS family of proteins are likewise compelling cancer targets. Our collection of RAS(ON) Inhibitors is tailored to target RAS mutations that together comprise the driver mutations in the vast majority of RAS-addicted cancers.

Our RAS(ON) Inhibitors are unique in that they are the first RAS inhibitors in clinical development to specifically target the activated, or ON, form of oncogenic RAS proteins. This differentiated mechanism of action offers potential improvements over that of the first RAS inhibitors to gain U.S. Food and Drug Administration (FDA) approval (KRAS G12C inhibitors sotorasib and adagrasib), which interact exclusively with the OFF form. Based on an emerging understanding of the limitations of first-generation RAS(OFF) drugs in the clinic and findings from our own preclinical research, we believe our RAS(ON) Inhibitors have the potential to deliver deeper antitumor activity and more durable clinical benefit to a broader patient population.

Our pipeline of RAS(ON) multi-selective and RAS(ON) mutant-selective inhibitors offer an opportunity for RAS(ON) doublet combinations designed to potentially maximize durable clinical benefit by effectively targeting the most common KRAS mutant variants in cancer. The consistent finding from the first-generation mutant-selective RAS inhibitors is that the main resistance mechanism that curtails durable efficacy is through reactivation of RAS pathway, highlighting the oncogenic addiction in RAS-mutated cancers. We believe many of these resistance mechanisms may be amenable to inhibition with a RAS(ON) multi-selective inhibitor. The pairing of the RAS(ON) multi-selective inhibitor daraxonrasib with a mutant-selective inhibitor (such as elironrasib or zoldonrasib) may address potential resistances which may ultimately translate to more durable clinical benefit. In addition, our experiments have shown that two inhibitors generally result in more effective inhibition of the primary mutant RAS driver than either inhibitor alone. These doublets form a core part of our strategy to improve the standard of care for patients with RAS-addicted cancers, along with monotherapy and combination with standard of care therapies. This approach is based on our biological understanding of RAS addiction and leverages the unique nature of our pipeline.

Our current corporate priorities are to:

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Execute pivotal trials with daraxonrasib monotherapy in patients with previously treated metastatic PDAC and NSCLC.

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Advance daraxonrasib into earlier-line randomized pivotal trials in patients with PDAC.

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Generate sufficient data to inform development priorities for elironrasib and zoldonrasib and prepare to initiate one or more pivotal trials including these compounds either as monotherapy or in a drug combination.

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Progress our earlier-stage pipeline, including advancing next-generation innovations from the company’s highly productive discovery organization.

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Grow our commercial and operational capabilities and increase precommercial activities in support of a potential commercial launch.

RAS Mutant Epidemiology in the United States.

Variants in RAS proteins account for a significant number of human cancers in the United States, many of which are fatal. Diverse oncogenic RAS variants in three different RAS isoforms (KRAS, NRAS and HRAS) drive distinct human cancers. Based on tumor mutation frequencies from Foundation Medicine data, scaled to estimated patient numbers using cancer incidence from the American Cancer Society (ACS) Cancer Facts and Figures 2023, there are estimated to be more than 200,000 RAS-mutant cancer diagnoses each year in the United States, including approximately 60,000 NSCLC diagnoses (approximately 30% of NSCLC diagnoses), approximately 75,000 CRC diagnoses (approximately 50% of CRC diagnoses) and approximately 56,000 PDAC diagnoses (more than 90% of PDAC diagnoses).

Our Innovation Engine

We have built an innovation engine that enables us to discover and develop novel targeted therapies for elusive high-value frontier cancer targets with a particular focus on a cohesive set of disease targets within notorious growth and survival pathways. This engine is centered around our proprietary tri-complex platform and is bolstered by three complementary pillars:

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Deep chemical biology and cancer pharmacology know-how, including assays and proprietary tool compounds, to define the critical vulnerabilities of “frontier” RAS and related pathway targets, associated signaling circuits in cancer cells and immune system targets;

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Sophisticated structure-based drug discovery capabilities, including proven access to complex chemical space, to create drug candidates tailored to unconventional binding sites on elusive cancer targets; and

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Astute precision medicine approach, embracing patient selection and innovative single agent and combination drug regimens, to translate our preclinical insights into clinical benefit for patients with RAS-addicted cancers.

Our Tri-Complex Platform

Our proprietary tri-complex technology enables us to discover small molecule inhibitors of targets lacking intrinsic drug binding sites by inducing new druggable pockets. This occurs through small molecule-driven formation of a high affinity ternary complex (tri-complex) between the target protein, the small molecule, and a widely expressed cytosolic protein called a chaperone (e.g., cyclophilin A or FKPB12). This platform technology is the foundation of our RAS(ON) Inhibitor programs. In this context, the inhibitory effect of tri-complex formation on the RAS(ON) target is mediated by steric occlusion of the site where RAS(ON) binds its downstream effector molecules, such as RAF, which are required for propagating the oncogenic signal. Thus, tri-complex formation with RAS(ON) targets disrupts RAS effector binding and terminates oncogenic signaling. Our RAS(ON) tri-complex inhibitors, which are inspired by natural products, are “Beyond Rule of 5” compounds.

Pipeline

Our pipeline is summarized below:

RAS(ON) Inhibitor Data

Daraxonrasib (RMC-6236)

Daraxonrasib (RMC-6236), our RAS(ON) multi-selective inhibitor, is designed as a potent, oral, RAS-selective tri-complex inhibitor of multiple RAS(ON) variants including cancer drivers at all three of the major mutation hotspot positions, G12, G13, and Q61.

Daraxonrasib inhibits all three major RAS isoforms, suppressing the mutant cancer driver and cooperating wild-type RAS proteins. Daraxonrasib is being evaluated in the RMC-6236-001 study, an ongoing monotherapy dose-escalation Phase 1/1b clinical study in patients with KRAS G12-mutated tumors, focused on NSCLC, PDAC and CRC.

Daraxonrasib PDAC Monotherapy

On October 23, 2024 we reported updated clinical safety, tolerability, and activity data for daraxonrasib at a dose levels ranging from 160 mg daily to 300 mg daily, from the RMC-6236-001 study in patients with previously treated RAS-mutant PDAC as of a data cutoff date of July 23, 2024 (the PDAC Data Cutoff Date). Daraxonrasib was generally well tolerated in these patients. As of the PDAC Data Cutoff Date, the median PFS for these patients treated with daraxonrasib in the 2L setting with tumors harboring KRAS G12X mutations was 8.5 months (95% confidence interval (CI): 5.3 – 11.7 months), and the median OS was 14.5 months (95% CI: 8.8 months, not estimable (NE)).

On December 2, 2024 we reported updated clinical safety, tolerability, and activity data for daraxonrasib at a dose level of 300 mg daily, from the RMC-6236-001 study in patients with previously treated RAS-mutant PDAC as of the PDAC Data Cutoff Date.

In the RMC-6236-001 study, a total of 76 patients with PDAC treated with a dose of 300 mg of daraxonrasib daily were evaluated for safety and tolerability as of the PDAC Data Cutoff Date (Table 1). The most common treatment-related adverse events (TRAEs) that were observed were rash and gastrointestinal (GI)-related toxicities. One Grade 4 TRAE (platelet count decreased) was observed, and no Grade 5 TRAEs were observed.

Table 1. RMC-6236-001: TRAEs and TRAEs leading to dose modifications in patients with PDAC treated with daraxonrasib at 300 mg daily

Maximum Severity of TRAEs Any Grade Grade ≥3

TRAEs occurring in≥10% of patients, n (%)

Mucosal inflammation 13 (17%) 1 (1%)

Decreased appetite 10 (13%) 0 (0%)

Oedema peripheral 10 (13%) 0 (0%)

Platelet count decreased 8 (11%) 3 (4%)

Other select TRAEs, n (%)

ALT increased 5 (7%) 3 (4%)

Neutrophil count decreased 5 (7%) 2 (3%)

AST increased 4 (5%) 1 (1%)

TRAEs leading to dose modification, n (%) 32 (42%)

Dose interruption 30 (40%)

Dose reduction 19 (25%)

TRAEs leading to dose discontinuation, n (%) 0 (0%)

Specific TRAEs leading to dose reduction in >10% patients, n (%)

Mean dose intensity 89%

Data Cutoff Date of July 23, 2024

1 Includes preferred terms of dermatitis, dermatitis acneiform, eczema, erythema, rash, rash erythematous, rash maculopapular, rash pruritic and rash pustular; multiple types of rash may have occurred in the same patient.

2 No prophylaxis for nausea or vomiting was administered.

3 Includes preferred terms of dermatitis acneiform, rash, and rash maculopapular.

Median duration of treatment was 5.2 months.

ALT, alanine transaminase; AST, aspartate transferase.

We also reported best percentage change in tumor size from baseline for patients with metastatic PDAC with tumors harboring KRAS G12X mutations treated with a dose of 300 mg daily in the 2L setting as of the PDAC Data Cutoff Date (Figure 1). The ORR for patients who received the first dose of daraxonrasib at least 14 weeks prior to the PDAC Data Cutoff Date was 36% (8 of 22 patients) for patients with tumors harboring KRAS G12X mutations and was 27% (10 of 37 patients) for patients with tumors harboring G12X, G13X or Q61X mutations.

Figure 1. RMC-6236-001: Best percentage change in tumor size from baseline in patients with PDAC treated in the 2L setting with daraxonrasib at 300 mg daily

Data Cutoff Date of July 23, 2024

KRAS G12X mutation includes any KRAS mutation where glycine (G) at position 12 is substituted by another amino acid. RAS Other includes mutations in KRAS G13X, KRAS Q61X or mutations in HRAS or NRAS at codons G12X, G13X or Q16X. Among patients with a response (confirmed or unconfirmed), 46% of first response occurred within 2 months of RMC-6236 treatment. 2L in the metastatic setting includes patients who progressed on prior therapy in an earlier setting within 6 months of last dose. ORR analyses included all patients who received first dose of daraxonrasib at least 14 weeks prior to the PDAC Data Cutoff Date (to allow 2 potential scans). Unconfirmed PRs (PR*) with treatment discontinued (will never confirm) were not considered responders but remained in the denominator; ORR (by RECIST v1.1) included confirmed CRs/PRs and unconfirmed CRs/PRs who were still on treatment and may yet be confirmed. One patient included in the denominator of the ORR analyses is not displayed on waterfall due to lack of post-baseline target lesion assessment (patient withdrew consent).

CR, complete response; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; SOD, sum of diameters.

In addition, we reported preliminary PFS data as of the PDAC Data Cutoff Date for patients with metastatic PDAC treated with a dose of 300 mg daily in the 2L setting (Figure 2). As of the PDAC Data Cutoff Date, the median PFS for patients with tumors harboring KRAS G12X mutations was 8.8 months (95% CI: 8.5, NE), and for patients with tumors harboring G12X, G13X or Q61X mutations was 8.5 months (95% CI: 5.9, NE).

Figure 2. RMC-6236-001: Interim PFS in 2L metastatic PDAC patients treated with daraxonrasib at 300 mg daily

Data Cutoff Date of July 23, 2024

RAS Mutant defined as patients with G12X, G13X or Q61X PDAC.

2L in the metastatic setting includes patients who progressed on prior therapy in an earlier setting within 6 months of last dose.

Median follow-up is 6.1 months and 6.6 months for KRAS G12X and RAS Mutant in the 2L setting at 300 mg, respectively.

We also reported preliminary OS data as of the PDAC Data Cutoff Date for patients with metastatic PDAC treated with a dose of 300 mg daily in the 2L setting (Figure 3). The median OS as of the PDAC Data Cutoff Date for patients with tumors harboring KRAS G12X mutations was not estimable (95% CI: NE, NE) and for patients with tumors harboring G12X, G13X or Q61X mutations was also not estimable (95% CI: 8.5 months, NE). As of the PDAC Data Cutoff Date, the OS rate at 6 months was 100% (95% CI: 100%, 100%) for patients with tumors harboring KRAS G12X mutations and was 97% (95% CI: 79%, 100%) for patients with tumors harboring G12X, G13X or Q61X mutations.

Figure 3. RMC-6236-001: Interim OS in 2L PDAC patients treated with daraxonrasib at 300 mg daily

Data Cutoff Date of July 23, 2024

RAS Mutant defined as patients with G12X, G13X or Q61X PDAC.

2L in the metastatic setting includes patients who progressed on prior therapy in an earlier setting within 6 months of last dose.

Median follow-up is 6.1 months and 6.6 months for KRAS G12X and RAS Mutant, respectively.

OS rate at 6 months and 95% CI are from Kaplan-Meier analysis.

Daraxonrasib NSCLC Monotherapy

On December 2, 2024, we also reported updated clinical safety, tolerability, and activity data for daraxonrasib from the RMC-6236-001 study, as of a data cutoff date of September 30, 2024 (the NSCLC Data Cutoff Date) in patients with RAS-mutant NSCLC.

In the RMC-6236-001 study, a total of 124 patients with NSCLC treated across dose cohorts ranging from 120 mg daily to 300 mg daily were evaluated for safety and tolerability as of the NSCLC Data Cutoff Date (Table 2). We believe that these data show that daraxonrasib was generally well tolerated at dose levels between 120 mg daily and 220 mg daily, with an increase in the rate of TRAEs observed at the 300 mg daily dose level. One Grade 4 TRAE (pneumonitis) was observed at the 300 mg daily dose level. No Grade 5 TRAEs were observed. We also reported the TRAEs leading to dose modifications for patients with NSCLC treated across dose cohorts ranging from 120 mg daily to 300 mg daily as of the NSCLC Data Cutoff Date. For patients treated across dose cohorts ranging from 120 mg daily to 220 mg daily, the median treatment duration was 5.5 months, and the median cumulative duration of dose interruption was 8.5 days.

Table 2. RMC-6236-001: TRAEs and TRAEs leading to dose modifications in patients with NSCLC treated with daraxonrasib across dose cohorts ranging from 120 mg daily to 300 mg daily

Any Grade Grade ≥3 Any Grade Grade ≥3 Any Grade Grade ≥3

TRAEs occurring in ≥10% of patients, n (%)

Other select TRAEs, n (%)

TRAEs leading to dose modification, n (%) 64 (52%) 30 (41%) 34 (67%)

TRAEs leading to dose discontinuation, n (%) 7 (6%) 3 (4%) 4 (8%)

TRAEs leading to dose reductions in ≥ 10% patients, n (%)

Mucositis/stomatitis 6 (5%) 1 (1%) 5 (10%)

Mean dose intensity 81% 88% 72%

Data Cutoff Date of September 30, 2024

One Grade 4 pneumonitis (possibly related) observed at 300 mg daily dose level in patient with concomitant pneumocystis pneumonia. No other Grade 4 TRAEs were observed. No Grade 5 TRAEs were observed.

1 Includes preferred terms of rash pustular, rash papular, rash maculopapular, rash macular, rash, erythema, and dermatitis acneiform. Multiple types of rash may have occurred in the same patient.

We also reported best percentage change in tumor size from baseline for patients with NSCLC with tumors harboring RAS G12X mutations who had received one or two prior lines of therapy, which must have included prior immunotherapy and platinum chemotherapy administered either concurrently or sequentially, but did not include docetaxel, who were treated with RMC-6236 across dose cohorts ranging from 120 mg daily to 220 mg daily (NSCLC Efficacy-Evaluable Patients) (Figure 4). The ORR for NSCLC Efficacy-Evaluable Patients who received the first dose of RMC-6236 at least 14 weeks prior to the NSCLC Data Cutoff Date was 38% (15 of 40 patients).

Figure 4. RMC-6236-001: Best percentage change in tumor size from baseline in NSCLC Efficacy-Evaluable Patients

Data Cutoff Date of September 30, 2024

Population includes patients with RAS G12X mutant NSCLC who have received 1 or 2 prior lines of therapy, which must have included prior immunotherapy and platinum chemotherapy administered either concurrently or sequentially, and have not received docetaxel previously. Adjuvant therapy or multimodal therapy with curative intent is considered prior therapy if disease progression occurred or treatment completion was within 6 months of first dose of daraxonrasib.

Among patients with a response (confirmed or unconfirmed), 65% of first response occurred within 2 months of daraxonrasib treatment.

ORR analyses included all patients who received first dose of daraxonrasib at least 14 weeks prior to data cutoff date (to allow 2 potential scans).

ORR (by RECIST v1.1) included confirmed CRs/PRs and unconfirmed CRs/PRs who were still on treatment and may yet be confirmed; unconfirmed PRs (PR*) with treatment discontinued (will never confirm) were not considered responders but remained in the denominator. Three patients included in the denominator of the ORR analyses are not displayed on waterfall due to lack of post-baseline target lesion assessment (2 due to patient request to withdraw from treatment, and 1 due to patient withdrawal of consent); patient with 100% reduction in SOD from baseline was deemed as PD due to new lesion, treatment is ongoing post progression.

CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; SOD, sum of diameter; DCR, disease control rate.

In addition, we reported preliminary PFS data as of the NSCLC Data Cutoff Date for NSCLC-Evaluable Patients (Figure 5). As of the NSCLC Data Cutoff Date, the median PFS for NSCLC Efficacy-Evaluable Patients was 9.8 months (95% CI: 6.0, 12.3).

Figure 5. RMC-6236-001: Interim PFS in NSCLC Efficacy-Evaluable Patients

Data Cutoff Date of September 30, 2024

Population includes patients with RAS G12X mutant NSCLC who have received 1 or 2 prior lines of therapy, which must include prior immunotherapy and platinum chemotherapy administered either concurrently or sequentially, and have not received docetaxel previously. Adjuvant therapy or multimodal therapy with curative intent is considered prior therapy if disease progression occurred or treatment completion was within 6 months of first dose of daraxonrasib.

Median follow-up is 10.8 months.

We also reported interim OS data as of the NSCLC Data Cutoff Date for NSCLC Efficacy-Evaluable Patients (Figure 6). As of the NSCLC Data Cutoff Date, the median OS for NSCLC Efficacy-Evaluable Patients was 17.7 months (95% CI: 13.7, NE).

Figure 6. RMC-6236-001: Interim OS in NSCLC Efficacy-Evaluable Patients

Data Cutoff Date of September 30, 2024

Median follow-up is 10.8 months.

We believe these preliminary data observations from the RMC-6236-001 study as of the NSCLC Data Cutoff Date for NSCLC Efficacy-Evaluable Patients support the initiation of RASolve 301, our global, randomized Phase 3 trial comparing daraxonrasib against docetaxel in patients with RAS-mutated NSCLC who have been treated with one or two prior lines of therapy, which must have included immunotherapy or platinum chemotherapy.

Other Daraxonrasib Monotherapy

At the AACR Annual Meeting 2024, we reported individual case studies from the RMC-6236-001 study that showed examples of objective responses to daraxonrasib in patients with tumor types beyond PDAC or NSCLC, specifically patients with melanoma and with CRC. We believe that these observations may support further development opportunities for daraxonrasib.

Daraxonrasib with Pembrolizumab Combination

On December 2, 2024, we reported that, based on the initial observations of 20 previously treated patients in our RMC-LUNG-101 Phase 1b clinical study, as of a data cutoff date of October 28, 2024, the combination of daraxonrasib at a dose level of 200 mg daily with pembrolizumab at the standard dose level of 200 mg once every three weeks was generally well tolerated. TRAEs of Grade 1 aspartate aminotransferase (AST) elevation were reported in two patients (10%) and a TRAE of Grade 2 AST elevation was reported in one patient (5%). A TRAE of Grade 1 alanine transaminase (ALT) elevation was reported in one patient (5%), and a TRAE of

Grade 3 ALT elevation was reported in one patient (5%). We believe these observations support continued evaluation of the combination of daraxonrasib with pembrolizumab in NSCLC patients in the 1L setting.

Daraxonrasib with Elironrasib Combination

On December 2, 2024, we reported clinical safety and tolerability data for the combination of daraxonrasib at dose levels ranging from 100 mg daily to 300 mg daily with elironrasib (RMC-6291), our RAS(ON) oral tri-complex G12C inhibitor, at dose levels of 100 mg and 200 mg twice daily, from our RMC-6291-101 Phase 1b clinical study, which we refer to as the RMC-6291-101 study, as of a data cutoff date of October 28, 2024 (the Daraxonrasib/Elironrasib Data Cutoff Date) in patients with advanced RAS G12C mutant solid tumors.

In the RMC-6291-101 study, a total of 74 patients were evaluated for safety and tolerability as of the Daraxonrasib/Elironrasib Data Cutoff Date (Table 3). The combination of daraxonrasib with elironrasib was generally well tolerated across all dose levels tested. One Grade 4 TRAE (hypokalemia), which led to dose interruption, was associated with Grade 3 diarrhea. No Grade 5 TRAEs were observed.

Table 3. RMC-6291-101: TRAEs and TRAEs leading to dose modifications in patients treated with the combination of daraxonrasib and elironrasib

All Dose Levels (N=74)

Maximum Severity of TRAEs Grade 1 Grade 2 Grade 3 Grade 4 Any Grade

TRAEs occurring in≥10% of patients, n (%)

Other select TRAEs, n (%)

Electrocardiogram QT prolonged 0 (0%) 0 (0%) 2 (3%) 0 (0%) 2 (3%)

Data Cutoff Date of October 28, 2024

Median duration of treatment was 2.3 months.

The mean dose intensities for elironrasib and daraxonrasib were 95% and 92%, respectively.

1 Rash bundled term includes dermatitis acneiform, rash maculopapular, rash, rash pustular, and erythema.

ALT, alanine transaminase; AST, aspartate transferase.

We also reported best percentage change in tumor size from baseline for patients from the RMC-6291-101 study with CRC who were previously treated with a KRAS(OFF) G12C inhibitor as of the Daraxonrasib/Elironrasib Data Cutoff Date (Figure 7). The ORR for patients who received the first dose of study drugs at least 8 weeks prior to the Daraxonrasib/Elironrasib Data Cutoff Date was 25% (3 of 12 patients), including one patient with an unconfirmed complete response, and the disease control rate (DCR) was 92% (11 of 12 patients). As reference values, we also reported that the ORR for patients with CRC treated with daraxonrasib monotherapy at a dose of 300 mg daily in the RMC-6236-001 study as of a data cutoff date of September 30, 2024 was 9% (2 of 22 patients), and the ORR for patients with CRC previously treated with a KRAS(OFF) G12C inhibitor who were subsequently treated with elironrasib monotherapy at a dose of 200 mg twice daily in the RMC-6291-001 study as of a data cutoff date of October 28, 2024 was 0% (0 of 6 patients).

Figure 7. RMC-6291-101: Best percentage change in tumor size from baseline in patients with CRC who were previously treated with a KRAS(OFF) G12C inhibitor

Data Cutoff Date of October 28, 2024

ORR and DCR (CR+PR+SD) analyses include all patients who received first dose of study drug(s) at least 8 weeks prior to the data cutoff date (to allow 1 potential scan). Unconfirmed PRs (PR*) with treatment discontinued (will never confirm) were not considered responders but included in the denominator; ORR (by RECIST v1.1) included confirmed CRs/PRs and unconfirmed CRs/PRs who were still on treatment and may yet be confirmed. Two patients with 8 weeks follow up do not appear in waterfall due to one patient with no tumor assessment entered in database and one patient with missing target lesion measurements (overall response entered as SD). One patient with CR* has confirmed PR.

SOD, sum of diameters; SD, stable disease; CR, complete response; CR*, unconfirmed complete response; PR, partial response; PR*, unconfirmed PR; RECIST, Response Evaluation Criteria in Solid Tumors.

We believe these preliminary clinical safety and antitumor activity data provide initial proof-of-mechanism for a RAS(ON) Inhibitor doublet in patients previously treated with a KRAS(OFF) G12C inhibitor CRC patients and that they support continued development of our RAS(ON) Inhibitor doublets in a broad range of tumor types and earlier lines of therapy.

Elironrasib (RMC-6291)

Elironrasib (RMC-6291) is designed as a RAS(ON) oral G12C-selective inhibitor. It is designed to exhibit subnanomolar potency for suppressing RAS pathway signaling and growth of RAS G12C-bearing cancer cells and is engineered to be highly selective for RAS G12C over wild-type RAS and other cellular targets. Elironrasib is designed to be differentiated from first-generation KRAS(OFF) G12C inhibitors, which sequester the KRAS(OFF) G12C form, by its potential mechanism of directly inhibiting the RAS(ON) G12C form. We believe direct inhibition of the ON form offers important biological advantages, including more rapid termination of RAS signaling and more robust inhibition in the face of known resistance mechanisms.

Elironrasib Monotherapy

A monotherapy dose-escalation Phase 1b study of elironrasib, which we refer to as the RMC 6291-001 study, is ongoing.

On October 13, 2023, we reported interim preliminary safety and anti-tumor data from the RMC-6291-001 study as of an October 5, 2023 data cut-off date. The data demonstrated that elironrasib was generally well tolerated across dose levels. These data also

demonstrated preliminary evidence of clinical activity in patients with KRAS G12C NSCLC previously treated with, or naïve to, a KRAS(OFF) G12C inhibitor and preliminary evidence of clinical activity in patients with KRAS G12C CRC who had not been previously treated with a KRAS(OFF) G12C inhibitor. We observed that elironrasib was orally bioavailable and demonstrated dose-dependent pharmacokinetics and that reduction in ctDNA of the KRAS G12C allele across doses was correlated with clinical activity. We believe these data provided preliminary evidence of clinically meaningful differentiation of elironrasib from KRAS(OFF) G12C inhibitors.

Daraxonrasib with Elironrasib Combination

See “Daraxonrasib (RMC-6236) – Daraxonrasib with Elironrasib Combination” above.

Elironrasib with Pembrolizumab Combination

On December 2, 2024, based on the initial observations of 15 patients in our RMC-LUNG-101 Phase 1b clinical study, as of a data cutoff date of October 28, 2024, we reported that the combination of elironrasib at a dose level of 200 mg twice daily with pembrolizumab at the standard dose level of 200 mg once every three weeks was generally well tolerated. A TRAE of Grade 1 AST elevation was reported in one patient (7%) and a TRAE of Grade 1 ALT elevation was reported in one patient (7%). There were no TRAEs of Grade 2 or higher AST or ALT elevations reported. We believe these observations, together with its observations reported above from the combination of daraxonrasib with elironrasib and the combination of daraxonrasib with pembrolizumab, support exploration of the triplet combination of elironrasib, daraxonrasib, and pembrolizumab, which we believe has the potential to provide a chemotherapy-sparing option for patients with NSCLC in the 1L setting.

Zoldonrasib (RMC-9805)

Zoldonrasib (RMC-9805) is designed as a RAS(ON) oral G12D-selective inhibitor. It is designed to exhibit low nanomolar potency for suppressing RAS pathway signaling and growth of RAS G12D-bearing cancer cells and is engineered to covalently inactivate RAS G12D for irreversible inhibition. To our knowledge, zoldonrasib is the first drug candidate that covalently modified an aspartic acid residue in preclinical studies.

The RMC-9805-001 study, a monotherapy dose-escalation Phase 1/1b trial of RMC-9805, is ongoing. We have identified 1,200 mg once daily as the recommended zoldonrasib Phase 2 dose for PDAC.

Zoldonrasib Monotherapy

On October 25, 2024, we reported preliminary clinical safety, tolerability and activity data for zoldonrasib from the RMC-9805-001 study as of a data cutoff date of September 2, 2024 (the Zoldonrasib Data Cutoff Date) in patients with previously treated solid tumors harboring KRAS G12D mutations.

In the RMC-9805-001 study, a total of 179 patients treated across dose cohorts ranging from 150 mg to 1,200 mg once daily and from 300 mg to 600 mg twice daily were evaluated for safety and tolerability as of the Zoldonrasib Data Cutoff Date (Table 4). As of the Zoldonrasib Data Cutoff Date, the most common TRAEs that were observed were GI-related toxicities. TRAEs of any grade led to dose reduction in approximately 3% of patients. No TRAEs led to treatment discontinuation, and there were no treatment-related Grade 4 or 5 adverse events (AEs) or serious adverse events (SAEs) reported.

Table 4. RMC-9805-001: TRAEs for all patients treated with zoldonrasib (150 mg to 1,200 mg once daily or 300 mg to 600 mg twice daily)

Maximum Severity of TRAEs Grade 1 Grade 2 Grade 3 Any Grade

TRAEs occurring in≥10% of patients, n (%)

Other select TRAEs, n (%)

TRAEs leading to dose reduction, n (%) 5 (3%) 0 (0%) 0 (0%) 5 (3%)

TRAEs leading to treatment discontinuation, n (%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)

Median time on treatment was 2.8 months (range: 0.1 – 8.9 months).

‡ Includes preferred terms of dermatitis, dermatitis acneiform, dermatitis psoriasiform, eczema, erthyema, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic and rash pustular.

ALT, alanine transaminase; AST, aspartate transferase.

We also reported the TRAEs for 99 patients who received 1,200 mg of zoldonrasib per day (1,200 mg once daily (n=60) or 600 mg twice daily (n=39)) as of the Zoldonrasib Data Cutoff Date (Table 5). The most common TRAEs observed were GI-related toxicities and rash. TRAEs of any grade led to dose reduction in approximately 4% of these patients. No TRAEs led to treatment discontinuation in these patients, and there were no treatment-related Grade 4 or 5 AEs or SAEs reported.

Table 5. RMC-9805-001: TRAEs for patients treated with 1,200 mg per day (1,200 mg once daily (n=60) or 600 mg twice daily (n=39))

Maximum Severity of TRAEs Grade 1 Grade 2 Grade 3 Any Grade

TRAEs occurring in≥10% of patients, n (%)

Other select TRAEs, n (%)

ALT elevation 5 (5%) 0 (0%) 1 (1%) 6 (6%)

AST elevation 3 (3%) 1 (1%) 0 (0%) 4 (4%)

TRAEs leading to dose reduction, n (%) 4 (4%) 0 (0%) 0 (0%) 4 (4%)

TRAEs leading to treatment discontinuation, n (%) 0 0 (0%) 0 (0%) 0 (0%)

ALT, alanine transaminase; AST, aspartate transferase.

We also reported best percentage change in tumor size from baseline as of the Zoldonrasib Data Cutoff Date for patients with PDAC in the second-line or later (2L+) setting who received 1,200 mg per day (1,200 mg once daily (n=20) or 600 mg twice daily (n=20)) (Figure 8). For these patients who received a first dose of zoldonrasib at least 14 weeks prior to the Zoldonrasib Data Cutoff Date, the ORR (including both confirmed and pending responses) was 30%, and the DCR was 80%.)

Figure 8. RMC-9805-001: Best percentage change in tumor size from baseline and response rates for 2L+ PDAC patients treated with 1,200 mg daily

Data Cutoff Date of September 2, 2024

All treated patients with PDAC who received a first daily dose at least 14 weeks prior to the Zoldonrasib Data Cutoff Date (applies to Waterfall plot and ORR table); 3 additional patients (n=2 at 1,200 mg daily; n=1 at < 1,200 mg daily) are not displayed on the Waterfall plot due to withdrawal of consent or clinical progression.

Among patients with a response (confirmed or unconfirmed), 55% of first response occurred after 2 months of zoldonrasib treatment (all dose levels).

CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; PRu*, unconfirmed partial response; SD, stable disease; RECIST, Response Evaluation Criteria in Solid Tumors.

We believe that these preliminary safety and clinical activity data as of the Zoldonrasib Data Cutoff Date support ongoing development of zoldonrasib as a single agent and in combination with other therapies, including daraxonrasib.

Commercial Plan

We intend to retain significant development and commercialization rights to our product candidates and, if marketing approval is obtained, to commercialize our product candidates on our own, or potentially with one or more collaborators, in the United States and other regions. We currently have limited sales, marketing and commercial product distribution capabilities. We have begun to build the necessary capabilities in the United States in support of a potential commercial launch, and over time expect to expand the infrastructure and capabilities for the United States, and potentially other regions, in connection with the advancement of our pipeline of product candidates. Clinical data, the indications and lines of therapy we pursue, the specific compounds from our pipeline we advance, our combination therapy and testing strategies, the size of the addressable patient populations, the commercial infrastructure and manufacturing needs and other factors, may all influence or alter our commercialization plans.

Manufacturing

We rely on and will continue to rely on contract manufacturing organizations (CMOs) for both drug substance and drug product. Currently, all of our manufacturing is outsourced to well-established third-party manufacturers. We have entered into contracts with CMOs for production of drug substance and drug product for our clinical trials and IND-enabling development studies, and plan to enter into additional contracts with these or other manufacturers for additional supply.

Our outsourced approach to manufacturing relies on CMOs to first develop manufacturing processes that are compliant with current Good Manufacturing Practice (cGMP), then produce material for preclinical and clinical studies. Our agreements with CMOs may obligate them to develop and qualify upstream and downstream processes, develop drug product process, validate (and, in some cases, develop) suitable analytical methods for test and release as well as stability testing, produce drug substance for preclinical testing, produce cGMP-compliant drug substance, or produce cGMP-compliant drug product. We conduct audits of CMOs prior to initiation

of activities under these agreements and monitor operations to ensure compliance with the mutually agreed process descriptions and to cGMP regulations.

Competition

The biotechnology and pharmaceutical industries, and the oncology sector in particular, are characterized by rapid evolution of technologies, fierce competition and strong defense of intellectual property rights. While we believe that our discovery programs, technology, knowledge, experience and scientific resources provide us with competitive advantages, we face competition from major pharmaceutical and biotechnology companies, academic institutions, government agencies and public and private research institutions, among others.

Any product candidates that we successfully develop and commercialize will compete with currently approved therapies and new therapies that may become available in the future. Key product features that would affect our ability to effectively compete with other therapeutics include the efficacy, safety and convenience of our products and the ease of use and effectiveness of any complementary diagnostics and/or companion diagnostics.

There are a number of companies developing or marketing treatments for cancer, including many major pharmaceutical and biotechnology companies. These treatments consist of small molecule drug products, biologics, cell-based therapies and traditional chemotherapy. Smaller and other early-stage companies may also prove to be significant competitors. In addition, academic research departments and public and private research institutions may be conducting research on compounds that could prove to be competitive.

There are several programs in clinical development targeting KRAS G12C, including programs directed at KRAS(OFF) G12C being conducted by Amgen Inc., Betta Pharmaceuticals Co., Ltd., Bristol Myers Squibb Company, Chengdu Huajian Future Technology Co. Ltd., D3 BIO, Inc., Eli Lilly, GenEros Biopharma Ltd., Genhouse Bio Co. Ltd., Guangzhou BeBetter Medicine Technology Co., Ltd., HUYA Bioscience, Innovent Biologics, Inc. (licensed to Genfleet Therapeutics), InventisBio, Jacobio Pharmaceuticals Co. Ltd., Jiangsu Hansoh Pharmaceutical Group Co., Ltd., Merck, Sharpe & Dohme LLC, Roche, Shanghai Junshi Biosciences Co., Ltd., Shanghai YingLi Pharmaceutical, Shouyao Holdings (Beijing) Co. Ltd. and Suzhou Zelgen Biopharmaceuticals. BridgeBio Pharma, Inc. and Frontier Medicines each have a dual KRAS(ON/OFF) G12C program in the clinic. There are also several clinical programs directed at KRAS G12D, including those being conducted by Astellas Pharma Inc., AstraZeneca, Eli Lilly, Genentech, Incyte Corporation, Jiangsu Hengrui Pharmaceuticals Company Ltd, Quanta Therapeutics, Tyligand Bioscience and Zelgen Biopharmaceuticals. In addition, there are a few clinical programs directed at KRAS G12V, including those being conducted by Affini-T Therapeutics and Yingkai Saiwei (Beijing) Biotechnology. Other clinical programs directed at mutant RAS, including pan-RAS inhibitors and Plk1 inhibitors, are being conducted, including those by Alaunos Therapeutics, Inc., BeiGene, Boehringer Ingelheim, Cardiff Oncology, Chugai Pharmaceutical Co., Ltd., Eli Lilly, Elicio Therapeutics, Gritstone bio, Inc., Moderna, Inc., Pfizer, Inc., Quanta Therapeutics, RasCal Therapeutics, Shanghai YingLi Pharmaceutical, Silenseed Ltd., Silexion Therapeutics and Targovax ASA.

The above list includes corporate competitors that we are currently aware of and that are currently conducting clinical trials or marketing in geographies where we currently anticipate conducting clinical trials for our product candidates. However, companies operating in other geographies and smaller and other early-stage companies may also prove to be significant competitors. In addition, academic research departments and public and private research institutions may be conducting research on compounds that could prove to be competitive.

The availability of coverage and reimbursement from government and other third-party payors will also significantly affect the pricing and competitiveness of our products. If and when our products receive FDA approval, they could be subject to maximum fair price (MFP) negotiation and application by the Centers for Medicare & Medicaid Services (CMS) under terms of the Inflation Reduction Act of 2022 (the IRA), nine years after launch in the United States. Our competitors may also obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter a given market.

Many of the companies against which we may compete have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors also 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.

Intellectual Property

Our success depends in part on our ability and the ability of our collaborators to obtain and maintain proprietary protection for our technology, programs and know-how related to our business, defend and enforce our intellectual property rights, in particular, our patent rights, preserve the confidentiality of our trade secrets, and operate without infringing valid and enforceable intellectual property rights of others. We endeavor to establish, maintain and enforce intellectual property rights that protect our business interests.

The term of individual patents depends upon the legal term of patents in the countries in which they are obtained. In most countries in which we file, including the United States, the patent term is generally 20 years from the earliest date of filing a non-provisional patent application, assuming the patent has not been terminally disclaimed over a commonly owned patent or a patent naming a common inventor, or over a patent not commonly owned but that was disqualified as prior art as the result of activities undertaken within the scope of a joint research agreement. In the United States, the term of a patent may also be eligible for patent term adjustment for delays within the U.S. Patent and Trademark Office (the USPTO). In addition, for patents that cover an FDA-approved drug, the Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-Waxman Act), may permit a patent term extension of up to five years beyond the expiration of the patent. While the length of such patent term extension is related to the length of time the drug is under regulatory review, patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent per approved drug may be extended and only those claims covering the approved drug product, a method for using it or a method for manufacturing it may be extended. Similar provisions are available in Europe and certain other foreign jurisdictions to extend the term of a patent that covers an approved drug. In the future, if and when our products receive FDA approval, we expect to apply for patent term extensions on patents covering those products. We plan to seek any available patent term extension to any issued patents we may be granted in any jurisdiction where such extensions are available; however, there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and, if granted, the length of such extensions.

We also rely on trade secrets, know-how and confidential information relating to our programs to develop and maintain our proprietary position, and seek to protect and maintain the confidentiality of such items to protect aspects of our business that are not amenable to, or that we do not currently consider appropriate for, patent protection. Our trade secrets include, for example, certain program specific syntheses, manufacturing schema, formulations, biomarkers, patient selection strategies and certain aspects of our proprietary tri-complex technology platform. It is our policy to require our employees, consultants, contractors, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements prior to the commencement of employment or consulting relationships with us, and for employees, contractors and consultants to enter into invention assignment agreements with us. These agreements generally provide that all confidential information developed or made known to the individual during the course of the individual’s relationship with us is to be kept confidential and not to be disclosed to third parties except in specific circumstances. Where applicable, the agreements provide that all inventions to which the individual contributed as an inventor shall be assigned to us, and, as such, will become our property. There can be no assurance, however, that these agreements will be self-executing or otherwise provide meaningful protection or adequate remedies for our trade secrets or other proprietary information, including in the event of unauthorized use or disclosure of such information. We also seek to preserve the integrity and confidentiality of our trade secrets and confidential information by maintaining physical security of our premises and physical and electronic security of our information technology systems. While we have confidence in the measures we take to protect and preserve our trade secrets, such measures can be breached, and we may not have adequate remedies for any such breach. In addition, our trade secrets may otherwise become known or be independently discovered by competitors. For more information regarding the risks related to intellectual property, please see “Risk factors—Risks related to intellectual property.”

Our Program-Specific Patent Portfolio

Our patent portfolio is directed to small molecules, platform methodologies and related technology. We seek patent protection for product candidates, development programs and related alternatives by filing and prosecuting patent applications in the United States and other countries, as appropriate.

We own and, in some cases, co-own or exclusively license, patents and patent applications related to our RAS tri-complex inhibitors and related platform technology. Our patent portfolio related to this program consists of ownership rights to several patent families that include filings covering compositions of matter or methods of using our development candidates alone or in combination with certain other therapeutic agents, or aspects pertaining to our tri-complex approach to RAS inhibition. The issued patents, and any patents issuing from these patent applications are expected to expire between 2031 (for patents originating from the Warp Drive Bio portfolio) and 2044 (for patents from our portfolio that did not originate from Warp Drive Bio), without accounting for potentially available patent term adjustments or extensions.

We also own, co-own or exclusively license patents and patent applications related to our RAS companion inhibitors. These patents include filings relating to compositions of matter or methods of using our development candidate. The issued patents, and any patents

issuing from these patent applications, are expected to expire between 2035 and 2043, without accounting for potentially available patent term adjustments or extensions.

Government Regulation

The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, marketing and promotion, distribution, post-approval monitoring and reporting, sampling, and import and export of products, such as those we are developing. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

U.S. Drug Regulation

In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act (the FDCA) and its implementing regulations. FDA approval is required before any new drug can be marketed in the United States. Drugs are also subject to other federal, state and local statutes and regulations. Failure to comply with applicable FDA or other requirements may subject a company to a variety of administrative or judicial sanctions, such as FDA clinical holds, refusal to approve pending applications, withdrawal of an approval, warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, civil penalties and criminal prosecution.

The process required by the FDA before product candidates may be marketed in the United States generally involves the following:

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completion of certain extensive preclinical laboratory tests and animal studies, including safety and toxicity studies performed in accordance with applicable regulations, including the FDA’s Good Laboratory Practice (GLP) regulations;

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manufacture of clinical drug supply in accordance with the FDA’s cGMP regulations for use in clinical studies;

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submission to the FDA of an Investigational New Drug application (IND), which must become effective before human clinical studies may begin and must be updated annually or when certain changes or updates are made;

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approval by an independent institutional review board (IRB) or ethics committee representing each clinical site before a clinical study may be initiated;

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performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practice (GCP), regulations to establish the safety and efficacy of the product candidate for each proposed indication;

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preparation of and submission to the FDA of a New Drug Application (NDA) after completion of all pivotal trials;

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a determination by the FDA within 60 days of its receipt of an NDA to file the application for review;

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satisfactory completion of an FDA advisory committee review, if applicable;

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satisfactory completion of an FDA pre-approval inspection of the manufacturing facility(ies) where the product is manufactured to assess compliance with cGMP regulations, and of potential inspection selected clinical investigation sites to assess compliance with GCP;

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payment of user fees for FDA review of the NDA; and

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FDA review and approval of an NDA to permit commercial marketing of the product for its particular labeled uses in the United States.

Preclinical and Clinical Studies

Preclinical tests include laboratory (in vitro) evaluation of product chemistry, formulation and toxicity, as well as animal (in vivo) studies to assess the characteristics and potential safety and efficacy of the product candidate. The conduct of certain preclinical tests that provide safety and toxicological information must comply with certain federal regulations and requirements, including GLP. The results of preclinical testing are submitted to the FDA as part of an IND along with other information, including information about the product’s chemistry, manufacturing and controls (CMC) and any available human data or literature to support use of the product in humans. An IND is a request for allowance from the FDA to administer an investigational product to humans. Long-term preclinical tests, such as animal tests of reproductive toxicity and carcinogenicity, may continue after the IND is submitted.

The central focus of an IND submission is on the general investigational plan and the protocol(s) for human studies. An IND must become effective before human clinical trials may begin. An IND will automatically become effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to the proposed clinical studies. In such a case, the IND

may be placed on clinical hold, and the IND sponsor and the FDA must resolve any outstanding concerns or questions before clinical studies can begin.

For each successive clinical trial conducted with the investigational drug, a separate, new protocol submission to an existing IND must be made, along with any subsequent changes to the investigational plan. Sponsors are also subject to ongoing reporting requirements, including submission of IND safety reports for any serious adverse experiences associated with use of the investigational drug or findings from preclinical studies suggesting a significant risk for human subjects, as well as IND annual reports on the progress of the investigations conducted under the IND.

Clinical studies involve the administration of the investigational drug to human subjects under the supervision of qualified investigators in accordance with GCP, which include among other things, the requirement that all research subjects provide their informed consent for participation in each clinical study. Clinical studies are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the efficacy criteria to be evaluated. A protocol for each clinical study and any subsequent protocol amendments must be submitted to the FDA as part of the IND. Additionally, approval must also be obtained from each clinical study site’s IRB before a study may be initiated at the site, and the IRB must monitor the study until completed. Sponsors of clinical trials generally must register and report ongoing clinical studies and clinical study results to public registries, including the website maintained by the U.S. National Institutes of Health, ClinicalTrials.gov.

Human clinical trials are typically divided into three or four phases. Although the phases are usually conducted sequentially, they may overlap or be combined.

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Phase 1. The drug is initially introduced into healthy human subjects or into patients with the target disease or condition. These studies are designed to evaluate the safety, dosage tolerance, metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and if possible, to gain early evidence on effectiveness. In the case of some products for severe or life-threatening diseases, such as cancer, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.

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Phase 2. The drug is administered to a limited patient population to evaluate tolerance and optimal dose, identify possible adverse side effects and safety risks, and preliminarily evaluate efficacy. Multiple Phase 2 trials may be conducted to obtain additional data prior to beginning Phase 3 trials.

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Phase 3. The drug is administered to an expanded patient population, generally at geographically dispersed clinical study sites to generate enough data to statistically evaluate dosage, clinical effectiveness and safety, to establish the overall benefit-risk relationship of the investigational product and to provide an adequate basis for product labeling.

In some cases, the FDA may condition approval of an NDA for a product candidate on the sponsor’s agreement to conduct additional clinical studies after approval. In other cases, a sponsor may voluntarily conduct additional clinical studies after approval to gain more information about the drug in the approved indication. Such post-approval studies are sometimes referred to as Phase 4 clinical studies.

The FDA, the IRB, other regulatory authorities or the clinical study sponsor may suspend or terminate a clinical study at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk. The sponsor may also suspend or terminate a clinical study based on evolving business objectives and/or competitive climate.

Concurrent with clinical trials, companies may complete additional in vivo studies and develop additional information about the characteristics of the product candidate. Companies must also finalize a process for manufacturing the product in commercially applicable quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product and, among other things, must use validated methods for testing the product against specifications to confirm its identity, strength, quality and purity. Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product does not undergo unacceptable deterioration over its shelf life.

U.S. Review and Approval Process

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of preclinical studies and other non-clinical studies and clinical trials, together with detailed information relating to the product’s CMC and proposed labeling, among other things, are submitted to the FDA in the form of an NDA requesting approval to market the product for one or more indications. The submission of an NDA requires payment of a substantial application user fee to the FDA, unless a waiver or exemption applies.

An NDA must include all relevant data available from pertinent preclinical and clinical studies, including negative or ambiguous results as well as positive findings, among other things. Data can come from company-sponsored clinical studies intended to test the

safety and effectiveness of a use of a product, or from a number of alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the investigational product to the satisfaction of the FDA.

The FDA reviews all submitted NDAs before it accepts them for filing. The FDA has 60 days from its receipt of an NDA to determine whether the application will be accepted for filing based on the agency’s threshold determination that it is sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an application for filing. In this event, the application must be resubmitted with the additional information and is subject to payment of additional user fees. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review. Under applicable performance goals established by the Prescription Drug User Fee Act (the PDUFA), the FDA endeavors to review applications subject to standard review within ten to twelve months, and to review applications subject to priority review within six to eight months, depending on whether the drug is a new molecular entity.

The FDA may refer applications for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee for review, evaluation and recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, the FDA may inspect one or more clinical sites to assure that relevant study data were obtained in compliance with GCP requirements.

After the FDA evaluates the NDA and conducts any inspections of manufacturing facilities and/or clinical trial sites, it may issue an approval letter or a complete response letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications. A complete response letter indicates that the review cycle of the application is complete, and the application will not be approved in its present form. A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information, including additional clinical trials or other significant and time-consuming requirements related to clinical trials, nonclinical testing or manufacturing in order for the FDA to reconsider the application. Even with submission of this additional information, the FDA may ultimately decide that an application does not satisfy the regulatory criteria for approval.

If regulatory approval of a product is granted, such approval will be granted for particular indications and may entail limitations on the indicated uses for which such product may be marketed. For example, as a condition of NDA approval, the FDA may require a risk evaluation and mitigation strategy (REMS) program to help ensure that the benefits of the drug outweigh its risks. If the FDA determines a REMS program is necessary during review of the application, the drug sponsor must agree to the REMS plan at the time of approval. A REMS program may be required to include various elements, such as a medication guide or patient package insert, a communication plan to educate healthcare providers of the drug’s risks, or other elements to assure safe use, such as limitations on who may prescribe or dispense the drug, dispensing only under certain circumstances, special monitoring and the use of patient registries. In addition, all REMS programs must include a timetable to periodically assess the strategy following implementation. The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls and specifications.

Further, product approval may require substantial post-approval testing and surveillance to monitor the drug’s safety and efficacy, and the FDA has the authority to prevent or limit further marketing of a product based on the results of these post-marketing programs. Moreover, changes to the conditions established in an approved application, including changes in indications, labeling or manufacturing processes or facilities may require submission and FDA approval of a new NDA or a supplemental NDA (sNDA) before the changes can be implemented. An sNDA for a new indication typically requires clinical data similar to that supporting the original approval, and the FDA uses similar procedures in reviewing supplements as it does in reviewing original applications.

Expedited Development and Review Programs

The FDA offers a number of expedited development and review programs for qualifying product candidates, and we may seek one or more of these programs for our current or future products.

Investigational drug products may be eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. Fast track designation applies to the combination of the product and the specific indication for which it is being studied. The sponsor of a fast track product candidate has opportunities for frequent interactions with the FDA review team during product development and, once an NDA is submitted, the application may be eligible for priority review. A fast track product candidate may also be eligible for rolling review,

where the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

A product candidate intended to treat a serious or life-threatening disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review. A product candidate can receive breakthrough therapy designation if preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and FDA’s commitment to expedite the development and review of the product, including involvement of senior managers.

After an NDA is submitted for a product candidate, including a product candidate with a fast track designation and/or breakthrough therapy designation, the NDA may be eligible for priority review. An NDA is eligible for priority review if the product candidate has the potential to provide a significant improvement in the treatment, diagnosis or prevention of a serious disease or condition compared to marketed products. Depending on whether a drug contains a new molecular entity, priority review designation means the FDA’s goal is to take an action on the marketing application within six months of the 60-day filing date, compared with 12 months under standard review.

Additionally, product candidates studied for their safety and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. As a condition of accelerated approval, the FDA will generally require the sponsor to perform adequate and well-controlled confirmatory clinical studies to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit, and may require that such confirmatory trials are underway prior to granting any accelerated approval. The FDA may withdraw approval of a drug or an indication approved under accelerated approval if, for example, sponsor fails to conduct the confirmatory trial in a timely manner, or if the confirmatory trial fails to verify the predicted clinical benefit of the product. In addition, the FDA requires pre-approval of promotional materials as a condition for accelerated approval, which could adversely impact the timing of the commercial launch of the product.

Fast track designation, breakthrough therapy designation, priority review and accelerated approval do not change the scientific or medical standards for approval or the quality of evidence necessary to support approval, but they may expedite the development or review process. Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or the time period for FDA review or approval may not be shortened.

Orphan Drug Designation

We intend to pursue orphan drug designation for one or more of our product candidates with respect to certain oncology indications, as appropriate, with the potential to obtain orphan drug exclusivity for our products, if approved.

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for this type of disease or condition will be recovered from sales in the United States for that drug. Orphan drug designation must be requested before submitting an NDA. After the FDA grants orphan drug designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. The orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review or approval process.

If a product that has orphan drug designation subsequently receives the first FDA approval for the disease for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications, including a full NDA, to market the same drug for the same disease or condition for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity. Orphan drug exclusivity does not prevent the FDA from approving a different drug for the same disease or condition, or the same drug for a different disease or condition. Orphan drug exclusivity also could block the approval of a product for seven years if a competitor obtains approval of the “same drug” as defined by the FDA, or if a product candidate is determined to be contained within the approved product for the same disease or condition. Among the other benefits of orphan drug designation are opportunities for grant funding towards clinical trial costs, tax credits for certain research and a waiver of the application user fee.

A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the disease or condition for which it received orphan designation. In addition, exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

Pediatric Information and Pediatric Exclusivity

Under the Pediatric Research Equity Act (PREA), certain NDAs and certain sNDAs must contain data to assess the safety and efficacy of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may grant deferrals for submission of pediatric data or full or partial waivers. A deferral may be granted for several reasons, including a finding that the drug is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric clinical trials begin. Generally, the FDA requires that a sponsor that is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan (iPSP), within 60 days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of a Phase 2/3 or Phase 3 study. The iPSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information. The FDA and the sponsor must reach an agreement on the iPSP. A sponsor can submit amendments to an agreed-upon iPSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials and/or other clinical development programs.

A drug product can also obtain pediatric market exclusivity in the United States. Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms. This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.

Post-Approval Requirements

Once an NDA is approved, a product will be subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to drug listing and registration, recordkeeping, periodic reporting, product sampling and distribution, adverse event reporting and advertising, marketing and promotion. Drugs may be marketed only for the approved indications and in accordance with the provisions of the approved labeling. While physicians may prescribe a product for uses in patient populations that are not described in the product’s approved labeling, or “off-label” uses, manufacturers may only promote a product for the approved indications and in accordance with the provisions of the approved labeling of such product. However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA approved labeling. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of “off-label” uses, and a company that is found to have improperly promoted “off-label” uses may be subject to significant liability.

After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing user fee requirements, under which the FDA assesses an annual program fee for each product identified in an approved NDA. In addition, quality-control, drug manufacture, packaging and labeling procedures must continue to conform to cGMP after approval. Drug manufacturers and certain of their subcontractors are required to register their establishments with the FDA and certain state agencies. Registration with the FDA subjects entities to periodic unannounced and announced inspections by the FDA and these state agencies, during which the applicable agency inspects manufacturing facilities to assess compliance with cGMP requirements and other laws. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting requirements upon manufacturers and their subcontractors. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance. The FDA may withdraw approval of a product if compliance with regulatory requirements is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical studies to assess new safety risks; or imposition of distribution restrictions or other restrictions under a REMS program.

Other potential consequences include, among other things:

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restrictions on the marketing or manufacturing of a product, complete withdrawal of the product from the market or product recalls;

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fines, warning or untitled letters or holds on clinical studies;

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refusal by the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of existing product approvals;

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product seizure or detention, or refusal by the FDA to permit the import or export of products;

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mandated modifications of promotional materials and labeling and the issuance of corrective information;

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the issuance of safety alerts, Dear Healthcare Provider letters, press releases or other communications containing warnings or other safety information about the product; or

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injunctions or the imposition of civil or criminal penalties.

Manufacturers also must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for “off-label” use, industry-sponsored scientific and educational activities and promotional activities involving the internet.

The FDA may also require post-approval studies and clinical trials if the FDA finds that scientific data, including information regarding related drugs, deem them appropriate. The purpose of such studies can include, among other things, assessments designed to evaluate a known serious risk or signals of serious risk related to the drug or to identify an unexpected serious risk when available data indicate the potential for a serious risk. The FDA may also require a labeling change if it becomes aware of new safety information that it believes should be included in the labeling of a drug.

International Regulation

In addition to regulations in the United States, we could become subject to a variety of foreign regulations regarding development, approval, commercial sales and distribution of our products if we seek to market our product candidates in other jurisdictions. Regardless of whether we obtain FDA approval for a product, we must obtain the necessary approvals by the comparable regulatory authorities of foreign countries before we can commence clinical trials or marketing of the product in those countries. The approval process varies from country to country and can involve additional product testing and additional review periods, and the time may be longer or shorter than that required to obtain FDA approval. The requirements governing, among other things, the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from country to country. Regulatory approval in one country does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country may negatively impact the regulatory process in others. If we fail to comply with applicable foreign regulatory requirements, we may be subject to fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Non-Clinical Studies and Clinical Trials

Similar to the United States, the various phases of non-clinical and clinical research in the European Union, or EU, are subject to significant regulatory controls.

Non-clinical studies are performed to demonstrate the health or environmental safety of new chemical or biological substances. Non-clinical (pharmaco-toxicological) studies must be conducted in compliance with the principles of GLP as set forth in EU Directive 2004/10/EC (unless otherwise justified for certain particular medicinal products, e.g., radio-pharmaceutical precursors for radio-labeling purposes). In particular, non-clinical studies, both in vitro and in vivo, must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP principles, which define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical studies. These GLP standards reflect the Organisation for Economic Co-operation and Development requirements.

Clinical trials of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), GCP guidelines, as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki. If the sponsor of the clinical trial is not established within the EU, it must appoint an EU entity to act as its legal representative. The sponsor must take out a clinical trial insurance policy, and, in most EU member states, the sponsor is liable to provide “no fault” compensation to any study subject injured in the clinical trial.

The regulatory landscape related to clinical trials in the EU has been subject to recent changes. The EU Clinical Trials Regulation (CTR), which was adopted in April 2014 and repeals the EU Clinical Trials Directive, became applicable on January 31, 2022, with a three-year transition period. Unlike directives, the CTR is directly applicable in all EU member states without the need for member states to further implement it into national law. The CTR notably harmonizes the assessment and supervision processes for clinical trials throughout the EU via a Clinical Trials Information System, which contains a centralized EU portal and database.

The CTR provides for a centralized process and only requires the submission of a single application for multi-center trials. The CTR allows sponsors to make a single submission to both the competent authority and an ethics committee in each member state, leading to a single decision per member state. The CTA must include, among other things, a copy of the trial protocol and an investigational medicinal product dossier containing information about the manufacture and quality of the medicinal product under investigation. The assessment procedure of the CTA has been harmonized as well, including a joint assessment by all member states concerned, and a separate assessment by each member state with respect to specific requirements related to its own territory, including ethics rules. Each member state’s decision is communicated to the sponsor via the centralized EU portal. Once the CTA is approved, clinical study development may proceed.

The CTR transition period ended on January 31, 2025, and all clinical trials (and related applications) are now fully subject to the provisions of the CTR.

Medicines used in clinical trials must be manufactured in accordance with cGMP. Other national and EU-wide regulatory requirements may also apply.

Marketing Authorization

In order to market our product candidates in the EU and many other foreign jurisdictions, we must obtain separate regulatory approvals. More concretely, in the EU, medicinal product candidates can only be commercialized after obtaining a marketing authorization (MA). To obtain regulatory approval of a product candidate under EU regulatory systems, we must submit a MA application (MAA). The process for doing this depends, among other things, on the nature of the medicinal product. There are two types of MAs.

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“Centralized MAs” are issued by the European Commission through the centralized procedure based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the European Medicines Agency (EMA), and are valid throughout the EU. The centralized procedure is compulsory for certain types of medicinal products such as (i) medicinal products derived from biotechnological processes, (ii) designated orphan medicinal products, (iii) advanced therapy medicinal products (ATMPs) (such as gene therapy, somatic cell therapy and tissue engineered products) and (iv) medicinal products containing a new active substance indicated for the treatment of certain diseases, such as cancer, HIV/AIDS, diabetes, neurodegenerative diseases or autoimmune diseases and other immune dysfunctions, and viral diseases. The centralized procedure is optional for products containing a new active substance not yet authorized in the EU, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU. Once the evaluation is finalized, the EMA sends the CHMP’s opinion to the European Commission which has up to 67 days to adopt a legally binding decision and issue a MA.

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“National MAs” are issued by the competent authorities of the EU member states, only cover their respective territory, and are available for product candidates not falling within the mandatory scope of the centralized procedure described above. Where a product has already been authorized for marketing in an EU member state, this national MA can be recognized in another member state through the mutual recognition procedure. If the product has not received a national MA in any member state at the time of application, it can be approved simultaneously in various member states through the decentralized procedure. Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the member states in which the MA is sought, one of which is selected by the applicant as the reference member state. The timeframe to obtain national MAs varies depending on the concerned procedure. Under the mutual recognition procedure, the reference member state (where the medicinal product is already authorized) must prepare the assessment report within 90 days. The concerned member states have up to 90 days to recognize the decision of the reference member state, and approve the summary of product characteristics, labeling and packaging. Then, each member state has a 30-day period to grant the national MA. Under the decentralized procedure, the evaluation period is 120 days for the reference member state, followed by a 90-day period for the concerned member states to approve the summary of product characteristics, labeling and packaging. Then, each member state has a 30-day period to grant the national MA. In order to grant the MA, the EMA or the competent authorities of the EU member states make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy. MAs have an initial duration of five years. After these five years, the authorization may be renewed on the basis of a reevaluation of the risk-benefit balance.

Data and Marketing Exclusivity

In the EU, new products authorized for marketing (i.e., reference products) generally receive eight years of data exclusivity and an additional two years of market exclusivity upon receipt of MA. If granted, the data exclusivity period prevents generic and biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar MA in the EU during a period of eight years from the date on which the reference product was first authorized in

the EU. The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from the initial MA of the reference product in the EU. The overall 10-year market exclusivity period can be extended to a maximum of 11 years if, during the first 8 years of those 10 years, the MA holder obtains an authorization for one or more new therapeutic indications, which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies. However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical or biological entity, and products may not qualify for data exclusivity.

Orphan Medicinal Products

The criteria for designating an “orphan medicinal product” in the EU are similar in principle to those in the United States. A medicinal product can be designated as an orphan if its sponsor can establish that: (1) the product is intended for the diagnosis, prevention or treatment of a life threatening or chronically debilitating condition; (2) either (a) such condition affects not more than 5 in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from the orphan status, would not generate sufficient return in the EU to justify the necessary investment for its development; and (3) there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized for marketing in the EU or, if such method exists, the product will be of significant benefit to those affected by that condition. In the EU, orphan designation entitles a party to a number of incentives, such as protocol assistance and scientific advice specifically for designated orphan medicines, and potential fee reductions depending on the status of the sponsor.

Orphan designation must be requested before submitting an MAA. An EU orphan designation entitles a party to incentives such as reduction of fees or fee waivers, protocol assistance, and access to the centralized procedure. Upon grant of a MA, orphan medicinal products are entitled to ten years of market exclusivity for the approved indication, which means that the competent authorities cannot accept another MAA, or grant a MA, or accept an application to extend a MA for a similar medicinal product for the same indication for a period of ten years. The period of market exclusivity is extended by two years for orphan medicinal products that have also complied with an agreed pediatric investigation plan (PIP). No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications. Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The orphan exclusivity period may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for which it received orphan destination, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity or where the prevalence of the condition has increased above the threshold. Additionally, MA may be granted to a similar product for the same indication at any time if: (i) the second applicant can establish that its product, although similar, is safer, more effective or otherwise clinically superior; (ii) the applicant consents to a second orphan medicinal product application; or (iii) the applicant cannot supply enough orphan medicinal product.

The aforementioned EU rules are generally applicable in the European Economic Area (EEA), which consists of the 27 EU member states plus Norway, Liechtenstein and Iceland.

Brexit and the Regulatory Framework in the United Kingdom

Since the end of the Brexit transition period on January 1, 2021, and the implementation of the Windsor Framework on January 1, 2025, the United Kingdom (UK) has not been directly subject to EU laws with respect to medicinal products. The EU laws that have been transposed into UK law through secondary legislation remain applicable in Great Britain (GB) (comprising England, Scotland and Wales), but new legislation such as the (EU) CTR is not applicable in GB.

Since January 1, 2021, the Medicines and Healthcare products Regulatory Agency (MHRA) has been the UK’s standalone medicines and medical devices regulator. As a result of the Northern Ireland Protocol, different rules applied in Northern Ireland than in GB; broadly, Northern Ireland continued to follow the EU regulatory regime. However, on January 1, 2025, a new arrangement called the “Windsor Framework” came into effect and reintegrated Northern Ireland under the regulatory authority of the MHRA with respect to medicinal products. The Windsor Framework removes EU licensing processes, and EU labelling and serialization requirements in relation to Northern Ireland, and introduces a UK-wide licensing process for medicinal products.

The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, including a 150-day assessment and a rolling review procedure. In order to obtain a UK MA to commercialize products in the UK, an applicant must be established in the UK and must follow one of the UK national authorization procedures or one of the remaining post-Brexit international cooperation procedures to obtain an MA to commercialize products in the UK. Since January 1, 2024, an international recognition procedure has been in place whereby the MHRA has been able to conduct targeted assessments of an MAA by recognizing approvals from trusted partner agencies such as the European Medicines Agency.

The UK regulatory framework in relation to clinical trials is derived from pre-existing EU legislation (as implemented into UK law, through secondary legislation). Whether the regulation of clinical trials in the UK will mirror the (EU) CTR in the long term is not yet certain; however, on December 12, 2024, the UK government introduced a legislative proposal - the Medicines for Human Use (Clinical Trials) Amendment Regulations 2024 - that, if implemented, will replace the current regulatory framework for clinical trials in the UK. The legislative proposal aims to provide a more flexible regime to make it easier to conduct clinical trials in the UK, increase the transparency of clinical trials conducted in the UK and make clinical trials more patient centered. The UK government has provided the legislative proposal to the UK Parliament for its review and approval. Once the legislative proposal is approved (with or without amendment), which is expected to occur in early 2026, it will be adopted into UK law. Under the terms of the Northern Ireland Protocol, provisions of the (EU) CTR which relate to the manufacture and import of investigational medicinal products and auxiliary medicinal products currently apply in Northern Ireland.

Other Healthcare Laws

Pharmaceutical companies are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business. Such laws include, without limitation, U.S. federal and state anti-kickback, fraud and abuse, false claims, consumer fraud, pricing reporting, and transparency laws and regulations, as well as similar laws in jurisdictions outside the United States.

For example, the U.S. federal Anti-Kickback Statute prohibits, among other things, individuals or entities from knowingly and willfully offering, paying, soliciting or receiving remuneration, directly or indirectly, overtly or covertly, in cash or in kind to induce or in return for purchasing, leasing, ordering or arranging for or recommending the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs. A person or entity does not need to have actual knowledge of this statute or specific intent to violate it in order to have committed a violation.

The federal civil and criminal false claims laws, including the civil False Claims Act, prohibit, among other things, any individual or entity from knowingly presenting, or causing to be presented, a false claim for payment to the federal government or knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government. In addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the civil False Claims Act.

The federal Health Insurance Portability and Accountability Act of 1996 (HIPAA), created additional federal civil and criminal statutes that prohibit, among other things, knowingly and willfully executing a scheme to defraud any healthcare benefit program. Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the healthcare fraud statute implemented under HIPAA or specific intent to violate it in order to have committed a violation.

The federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to CMS information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain non-physician practitioners (defined to include physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, anesthesiology assistants and certified nurse midwives) and teaching hospitals, and further requires applicable manufacturers and applicable group purchasing organizations to report annually to CMS ownership and investment interests held by physicians and their immediate family members.

Similar state and local laws and regulations may also restrict business practices in the pharmaceutical industry, such as state anti-kickback and false claims laws, which may apply to business practices, including but not limited to, research, distribution, sales and marketing arrangements and claims involving healthcare items or services reimbursed by non-government third-party payors, including private insurers, or by patients themselves; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, or otherwise restrict payments that may be made to healthcare providers and other potential referral sources; state laws and regulations that require drug manufacturers to file reports relating to pricing and marketing information or which require tracking gifts and other remuneration and items of value provided to physicians, other healthcare providers and entities; and state and local laws that require the registration of pharmaceutical sales representatives.

Violation of any of such laws or any other government regulations that apply may result in penalties, including, without limitation, civil and criminal penalties, damages, fines, additional reporting obligations, the curtailment or restructuring of operations, exclusion from participation in government healthcare programs and individual imprisonment.

Data Privacy and Security

We may be subject to numerous federal, state and foreign laws, regulations that govern the collection, use, disclosure and protection of health-related and other personal information. In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws and consumer protection laws and regulations govern the collection, use, disclosure and protection of health-related and other personal information. In addition, certain foreign laws govern the privacy and security of personal data, including health-related data. Privacy and security laws, regulations and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts and can result in investigations, proceedings or actions that lead to significant civil and/or criminal penalties and restrictions on data processing.

Coverage and Reimbursement

Sales of any pharmaceutical product depend, in part, on the extent to which such product will be covered by third-party payors, such as federal, state and foreign government healthcare programs, commercial insurance and managed healthcare organizations, and the level of reimbursement for such product by third-party payors. Significant uncertainty exists as to the coverage and reimbursement status of any newly approved product. Decisions regarding the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis. One third-party payor’s decision to cover a particular product does not ensure that other payors will also provide coverage for the product. As a result, the coverage determination process can require manufacturers to provide scientific and clinical support for the use of a product to each payor separately and can be a time-consuming process, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

In addition, third-party payors are increasingly reducing reimbursements for pharmaceutical products and services. The U.S. government and state legislatures have continued implementing cost-containment programs, including price controls, restrictions on coverage and reimbursement and requirements for substitution of generic products. Third-party payors are increasingly challenging the prices charged, examining the medical necessity and reviewing the cost effectiveness of pharmaceutical products, in addition to questioning their safety and efficacy. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit sales of any product. Decreases in third-party reimbursement for any product or a decision by a third-party payor not to cover a product at all could reduce physician usage and patient demand for the product.

In international markets, reimbursement and healthcare payment systems vary significantly by country, and many countries have instituted price ceilings on specific products and therapies. For example, the EU provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. A member state may approve a specific price for the medicinal product, or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market. Pharmaceutical products may face competition from lower-priced products in foreign countries that have placed price controls on pharmaceutical products and may also compete with imported foreign products. Furthermore, there is no assurance that a product will be considered medically reasonable and necessary for a specific indication, will be considered cost-effective by third-party payors, that an adequate level of reimbursement will be established even if coverage is available or that the third-party payors’ reimbursement policies will not adversely affect the ability of manufacturers to sell products profitably.

Healthcare Reform

In the United States and certain foreign jurisdictions, there have been, and we expect there will continue to be, a number of legislative and regulatory changes to the healthcare system. In March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (the ACA), was signed into law, which substantially changed the way healthcare is financed by both government and private insurers in the United States. The ACA contains a number of provisions, including those governing enrollment in federal healthcare programs, reimbursement adjustments and fraud and abuse changes. Additionally, the ACA increased the minimum level of Medicaid rebates payable by manufacturers of brand name drugs from 15.1% to 23.1%; required collection of rebates for drugs paid by Medicaid managed care organizations; imposed a non-deductible annual fee on pharmaceutical manufacturers or importers that sell certain “branded prescription drugs” to specified federal government programs; expanded eligibility criteria for Medicaid programs; created a Patient-Centered Outcomes Research Institute to oversee, identify priorities in and conduct comparative clinical effectiveness research, along with funding for such research; and established a Center for Medicare and Medicaid Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.

Since its enactment, there have been judicial, executive and congressional challenges to certain aspects of the ACA. In June 2021, the U.S. Supreme Court dismissed a judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Other legislative changes have been proposed and adopted since the ACA was enacted, including aggregate reductions of Medicare payments to providers, which will remain in effect through 2032, with the exception of a temporary suspension that occurred from May 1, 2020 through March 31, 2022, absent additional congressional action. Moreover, there has recently been heightened government scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted legislation designed, among other things, to bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs and reform government program reimbursement methodologies for pharmaceutical products. On August 16, 2022, the IRA was signed into law. Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023) and replaces the Part D coverage gap discount program with a new manufacturer discounting program (which began in 2025). The IRA permits the Secretary of the Department of Health and Human Services to implement many of these provisions through guidance, as opposed to regulation, for the initial years. CMS has published the negotiated prices for the initial ten drugs, which will first be effective in 2026, and the list of the subsequent 15 drugs that will be subject to negotiation, although the Medicare drug price negotiation program is currently subject to legal challenges. For that and other reasons, it is currently unclear how the IRA will be effectuated.

Individual states in the United States have also become increasingly active in implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure, drug price reporting and other transparency measures and, in some cases, mechanisms to encourage importation from other countries and bulk purchasing. Some states have enacted legislation creating so-called prescription drug affordability boards, which ultimately may attempt to impose price limits on certain drugs in these states. Furthermore, there has been increased interest by third-party payors and government authorities in reference pricing systems and publication of discounts and list prices.

We expect that additional state, federal and foreign healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal, state and foreign governments will pay for healthcare product candidates and services, which could result in reduced demand for our product candidates once approved or additional pricing pressures.

Employees and Human Capital Resources

As of December 31, 2024, we had 534 full-time employees. Within our workforce, as of December 31, 2024, 423 employees were engaged in research and development. None of our employees are represented by labor unions or covered by collective bargaining agreements. We consider our relationship with our employees to be good.

Our human capital resources objectives include meeting hiring goals, deepening our oncology and public company expertise, integrating new employees, and retaining, incentivizing and developing our existing employees. We provide competitive compensation and benefit programs, including competitive salaries, incentive programs, equity awards, an employee stock purchase plan, healthcare and insurance benefits. The principal purposes of our equity incentive programs are to attract, retain and motivate selected employees, consultants and directors through the granting of stock-based compensation awards and to align the interests of these individuals with those of our stockholders. We regularly review our compensation practices to support our employees, including evaluating innovative health and wellness programs to continue to respond to employee needs.

We are committed to creating an environment where diverse perspectives are encouraged and supported. This commitment is memorialized as one of our corporate core values (Inclusiveness and Fairness) and is brought to life for every employee during our cultural integration sessions for new hires and through an informal network of cultural champions that we foster. As of December 31, 2024, females represented 58% of our full-time employees, and 426 of our employees self-identified their race, of which 55% self-identified as an “underrepresented minority,” as that term is defined by Nasdaq rules.

We are equally committed to the development of our employees and one of our corporate core values (Exceptional Together) captures this commitment. We offer our employees career-specific training and resources and support development opportunities through company-sponsored programs, including learning, mentoring, and coaching opportunities. We host regular company-wide sessions where our employees discuss ideas related to corporate initiatives and scientific breakthroughs and recognize each other’s contributions. In addition, we conduct an anonymous all-employee engagement survey at least annually, and take the results of this survey into account in management of our employees and business.

Corporate Information

We were founded in October 2014 as a Delaware corporation. Our principal executive offices are located at 700 Saginaw Drive, Redwood City, California 94063, and our telephone number is (650) 481-6801.

On November 9, 2023, we completed the announced acquisition of EQRx, Inc., a Delaware corporation (EQRx), pursuant to an Agreement and Plan of Merger, dated as of July 31, 2023. See “Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations – Acquisition of EQRx, Inc”.

Our website address is www.revmed.com. We make available on or through our website certain reports and amendments to those reports that we file with or furnish to the SEC in accordance with the Securities Exchange Act of 1934, as amended (the Exchange Act). These include our annual reports on Form 10-K, our quarterly reports on Form 10-Q, and our current reports on Form 8-K, and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act. We make this information available on or through our website free of charge as soon as reasonably practicable after we electronically file the information with, or furnish it to, the SEC. References to our website address do not constitute incorporation by reference of the information contained on the website, and the information contained on the website is not part of this document or any other document that we file with or furnish to the SEC. The SEC maintains a site on the worldwide web that contains reports, proxy and information statements and other information regarding our filings at www.sec.gov.

Item 1A. Risk Factors.

Investing in our common stock involves a high degree of risk. You should carefully consider the risks described below, as well as the other information in this Annual Report on Form 10-K, including our financial statements and the related notes and the section titled “Management’s Discussion and Analysis of Financial Condition and Results of Operations” before deciding whether to invest in our common stock. The occurrence of any of the events or developments described below or other risks we face could materially and adversely affect our business, competitive position, financial condition, results of operations, cash flows and growth prospects. In such an event, the market price of our common stock could decline, and you may lose all or part of your investment. Additional risks and uncertainties not presently known to us or that we currently deem immaterial also may impair our business operations and the market price of our common stock.

Risks related to our limited operating history, financial position and need for additional capital

Biopharmaceutical product development is a highly speculative undertaking and involves a substantial degree of risk. We are a clinical-stage precision oncology company, and we have only a limited operating history upon which you can evaluate our business and prospects. We currently have no products approved for commercial sale, have not generated any revenue from sales of products and have incurred losses in each year since our inception in October 2014. In addition, we have not yet demonstrated an ability to successfully overcome many of the risks and uncertainties frequently encountered by companies in new and rapidly evolving fields, particularly in the biopharmaceutical industry.

Since our inception, we have incurred significant net losses. Our net losses were $600.1 million, $436.4 million and $248.7 million, for the years ended December 31, 2024, 2023 and 2022, respectively. As of December 31, 2024, we had an accumulated deficit of $1.7 billion. We have funded our operations to date primarily with proceeds from the sale of common stock and preferred stock, as well as upfront payments and research and development cost reimbursement received under our collaboration agreement with Genzyme Corporation, an affiliate of Sanofi (the Sanofi Agreement). The Sanofi Agreement was terminated in June 2023, and Sanofi has no further reimbursement obligations following this termination. To date, we have devoted substantially all of our resources to organizing and staffing our company, business planning, raising capital, acquiring and discovering development programs, securing intellectual property rights and conducting discovery, research and development activities for our programs. We have not yet demonstrated our ability to successfully complete any clinical trials, including pivotal clinical trials, obtain marketing approvals, manufacture a commercial-scale product, or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for successful product commercialization. Our product candidates will require substantial additional development time and resources before we will be able to apply for or receive regulatory approvals and, if approved, begin generating revenue from product sales. We expect to continue to incur significant expenses and operating losses for the foreseeable future.

We have never generated revenue from product sales and may never be profitable.

Our ability to generate revenue from product sales and achieve profitability depends on our ability, alone or with our collaboration partners, to successfully complete the development of, and obtain the regulatory approvals necessary to commercialize, our development programs. We do not anticipate generating revenue from product sales for the next several years, if ever. Our ability to generate future revenue from product sales depends heavily on our, and any potential future collaborators’, success in:

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completing clinical and preclinical development of product candidates and programs and identifying and developing new product candidates;

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seeking and obtaining marketing approvals for our product candidates;

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launching and commercializing product candidates for which we obtain marketing approval by establishing a sales force, marketing, medical affairs and distribution infrastructure or, alternatively, collaborating with a commercialization partner;

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achieving adequate coverage and reimbursement by third-party payors for our product candidates;

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establishing and maintaining supply and manufacturing relationships with third parties that can provide adequate, in both amount and quality, products and services to support clinical development and the market demand for our product candidates, if approved;

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obtaining market acceptance of our product candidates as viable treatment options, if approved;

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addressing any competing technological and market developments;

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negotiating favorable terms in any collaboration, licensing or other arrangements into which we may enter and performing our obligations under such collaborations;

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maintaining, protecting, enforcing and expanding our portfolio of intellectual property rights, including patents, trademarks, trade secrets and know-how;

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defending against third-party interference, infringement or other intellectual property-related claims, if any; and

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attracting, hiring and retaining qualified personnel.

Even if one or more of our product candidates is approved for commercial sale, we anticipate incurring significant costs associated with commercializing any approved product candidate, including prior to a potential launch of any approved product candidate. Our expenses could increase beyond expectations if we are required by the U.S. Food and Drug Administration (the FDA), the European Medicines Agency (the EMA) or other regulatory agencies to perform clinical trials or studies in addition to those that we currently anticipate. Even if we are able to generate revenue from the sale of any approved products, we may not become profitable and may need to obtain additional funding to continue operations.

Our operations have consumed substantial amounts of cash since our inception. Since our inception, we have invested a significant portion of our efforts and financial resources in research and development activities for our initial preclinical and clinical product candidates.

Preclinical studies, clinical trials and additional research and development activities will require substantial funds to complete. As of December 31, 2024, we had cash, cash equivalents and marketable securities of $2.3 billion. Through December 31, 2024, we have raised $2.1 billion in underwritten public offerings, net of underwriting discounts and commissions and offering expenses and have completed sales generating $246.4 million in gross proceeds pursuant to at-the-market equity offering programs. Our acquisition of EQRx, Inc. (the EQRx Acquisition) added $1.1 billion to our working capital in 2023. We expect to continue to spend substantial amounts to continue the preclinical and clinical development of our current and future programs and to prepare for their potential commercialization. If we are able to gain marketing approval for our product candidates, we will require significant additional amounts of cash in order to launch and commercialize our product candidates, if approved, to the extent that their launch and commercialization are not the responsibility of another collaborator that we may contract with in the future. In addition, other unanticipated costs may arise. Because the design and outcome of our current, planned and potential future clinical trials is highly uncertain, we cannot reasonably estimate the actual amounts necessary to successfully complete the development and commercialization of our product candidates.

The timing and amount of our future funding requirements depends on many factors, including:

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the scope, progress, results and costs of researching and developing our product candidates and programs, and of conducting preclinical studies and clinical trials;

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the cost of manufacturing our current and future product candidates for clinical trials in preparation for marketing approval and in preparation for commercialization;

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RVMD US Equity

RVMD · 10-K · period ended 2024-12-31

Item 1. Business.

Item 1A. Risk Factors.

RVMD US Equity☆

RVMD · 10-K · period ended 2024-12-31

Item 1. Business.

Item 1A. Risk Factors.

RVMD US Equity