UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM
CURRENT REPORT
Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
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. ☐
Item 2.02 Results of Operations and Financial Condition.
On January 10, 2023, Revolution Medicines, Inc. (the “Company”) confirmed to investors that it continues to expect that its net loss for the year ended December 31, 2022 to be between $245 million and $265 million, which includes estimated non-cash stock-based compensation expense of approximately $30 million to $35 million.
The information furnished under this Item 2.02 of this Current Report on Form 8-K shall not be deemed “filed” under the Securities Act of 1934, as amended (the “Exchange Act”), nor shall it be incorporated by reference into any future filings under the Securities Act of 1933, as amended (the “Securities Act”), or under the Exchange Act unless the Company expressly sets forth in such future filing that such information is to be considered “filed” or incorporated by reference therein.
Item 7.01 Regulation FD Disclosure.
On January 10, 2023, the Company provided a corporate presentation relating to its research and development programs by posting an additional corporate presentation to the investor section of the Company’s website at: ir.revmed.com/events-and-presentations. The Company’s additional corporate presentation is attached hereto as Exhibit 99.1.
The furnishing of the attached presentation is not an admission as to the materiality of any information therein. The information contained in the slides is summary information that is intended to be considered in the context of more complete information included in the Company’s filings with the U.S. Securities and Exchange Commission (the “SEC”) and other public announcements that the Company has made and may make from time to time by press release or otherwise. The Company undertakes no duty or obligation to update or revise the information contained in this Current Report on Form 8-K, although it may do so from time to time as its management believes is appropriate. Any such updating may be made through the filing of other reports or documents with the SEC, through press releases or through other public disclosures. For important information about forward looking statements, see the slide titled “Legal Disclaimer” in Exhibit 99.1 attached hereto.
The information furnished under this Item 7.01 and in the presentation attached as Exhibit 99.1 to this Current Report on Form 8-K shall not be deemed “filed” for purposes of Section 18 of the Exchange Act or otherwise subject to the liabilities of that section or Sections 11 or 12(a)(2) of the Securities Act. The information contained in this Item 7.01 and in the presentation attached as Exhibit 99.1 to this Current Report on Form 8-K shall not be incorporated by reference into any filing with the SEC made by the Company, whether made before or after the date hereof, regardless of any general incorporation language in such filing.
Forward-Looking Statements
This Current Report on Form 8-K contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. Any statements in this report that are not historical facts may be considered “forward-looking statements,” including, without limitation, statements regarding the Company’s expected net loss and stock-based compensation expense. Forward-looking statements are typically, but not always, identified by the use of words such as “may,” “will,” “would,” “believe,” “intend,” “plan,” “anticipate,” “estimate,” “expect” and other similar terminology indicating future results. Such forward-looking statements are subject to substantial risks and uncertainties that could cause the Company’s development programs, future results, performance or achievements to differ materially from those anticipated in the forward-looking statements. Such risks and uncertainties include, without limitation, risks and uncertainties inherent in the drug development process, including the Company’s programs’ early stage of development, the process of designing and conducting preclinical and clinical trials, the regulatory approval processes, the timing of regulatory filings, the challenges associated with manufacturing drug products, the Company’s ability to successfully establish, protect and defend its intellectual property, other matters that could affect the sufficiency of the Company’s capital resources to fund operations, reliance on third parties for manufacturing and development efforts, changes in the competitive landscape and the effects on the Company’s business of the COVID-19 pandemic, global events and other macroeconomic conditions. For a further description of the risks and uncertainties that could cause actual results to differ from those anticipated in these forward-looking statements, as well as risks relating to the business of the Company in general, see the Company’s Quarterly Report on Form 10-Q filed with the SEC on November 7, 2022, and its future periodic reports to be filed with the SEC. Except as required by law, the Company undertakes no obligation to update any forward-looking statements to reflect new information, events or circumstances, or to reflect the occurrence of unanticipated events.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits.
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99.1 |
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SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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REVOLUTION MEDICINES, INC. |
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Date: |
January 10, 2023 |
By: |
/s/ Mark A. Goldsmith |
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Mark A. Goldsmith, M.D., Ph.D. |
On Target to Outsmart Cancer TM January 10, 2023
Legal Disclaimer This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act. All statements other than statements of historical facts contained in this presentation, including statements regarding our future results of operations and financial position, business strategy, prospective products, availability of funding, ability to manage existing collaborations and establish new strategic collaborations, licensing or other arrangements, the scope, progress, results and costs of developing our product candidates or any other future product candidates, the potential market size and size of the potential patient populations for our product candidates, the timing and likelihood of success of obtaining product approvals, plans and objectives of management for future operations, the scope of protection we are able to establish and maintain for intellectual property rights covering our product candidates, future results of anticipated products, and the impact of the COVID-19 pandemic on our business are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that 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. Because forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified and some of which are beyond our control, 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. The information included in these materials is provided as of January 10, 2023 and is qualified as such. Except as required by applicable law, we undertake no obligation to update any forward-looking statements or other information contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. For a further description of the risks and uncertainties that could cause actual results to differ from those anticipated in these forward-looking statements, as well as risks relating to the business of Revolution Medicines in general, see Revolution Medicines’ Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 7, 2022, and its future periodic reports to be filed with the Securities and Exchange Commission. This presentation concerns product candidates that are under clinical investigation and which have not yet been approved for marketing by the U.S. Food and Drug Administration (FDA). These product candidates are currently limited by Federal law to investigational use, and no representation is made as to their safety or effectiveness for the purposes for which they are is being investigated. The fiscal year 2022 financial information contained in this presentation is preliminary and subject to completion of our financial closing and other operational procedures, final adjustments and review by our independent auditors.
RAS Companion Inhibitors Class-leading drug candidates to counter treatment resistance RAS(ON) Inhibitors Groundbreaking class of drug candidates for robust cancer suppression HIGH UNMET NEED IN RAS-ADDICTED CANCERS 30% of human cancers(1), largely unserved by targeted therapeutics STRONG CLINICAL VALIDATION OF RASMUTANT AS CANCER DRIVER Proof-of-principle from first-gen KRASG12C inhibitors(2) DEEP, SCIENCE-DRIVEN CLINICAL AND PRECLINICAL PIPELINE On Target to Outsmart Cancer (1) Prior et al., Cancer Research 2020 (2) Lumakras approved by the FDA in May 2021, Krazati approved by the FDA in December 2022
Excessive RAS(ON) Signaling Drives 30% of Human Cancers, Targeted by Our Pipeline Strategy RAS-Addicted Cancers New patients per year (U.S.)(1) Normal RAS Cancer Mutations Cell Membrane Tightly regulated RAS(ON) proteins control cell growth Excessive RAS(ON) signaling drives uncontrolled cell growth 230,000 All 67,000 Lung cancer 79,000 Colorectal cancer 49,000 Pancreatic cancer = RAS(OFF) = RAS(ON) G12C, G12D, G12V, G12R G13C, G13D Q61H, Q61K, Q61L Exemplary mutations in KRAS, HRAS and/or NRAS (1) Estimated using tumor mutation frequencies from Foundation Medicine Insights August 2020 and scaled to estimated patient numbers using cancer incidence from ACS Cancer Facts and Figures 2020 (see appendix for additional detail); lung cancer = non-small cell lung cancer
Deep, Science-Driven Clinical and Preclinical Pipeline of Targeted Therapies for RAS-Addicted Cancers RAS Companion Inhibitors RAS(ON) Inhibitors RAS(ON) Cancer Drivers RAS Cooperating Targets Multiple pipeline expansion programs + Clinical-stage Drug Candidates 2 IND-ready Drug Candidate 1 Clinical-stage Drug Candidates 2 Development-stage Drug Candidates 3
a Groundbreaking RAS(ON) Inhibitors Bind Near RAS Cancer Mutation Hotspots and Suppress Cancer Signaling Potent, selective, oral and drug-like inhibitors Deep and sustained suppression of RAS(ON) cancer signaling RAS-Q61 RAS-G13 RAS-G12 Oncogenic RAS(ON) RAS(ON) Inhibitor Inhibited RAS(ON) RAS(ON) Inhibitor Cyclophilin A Inside cell Oncogenic RAS(ON) Bind Suppress
Current Portfolio of RAS(ON) Inhibitors Targets Every RAS Cancer Mutation Hotspot (1) Calculated using tumor mutation frequencies from Foundation Medicine Insights August 2020 and scaled to estimated patient numbers using cancer incidence from ACS Cancer Facts and Figures 2020 (see appendix for additional detail) RMC-8839 G13C RMC-0708 Q61H RMC-6291 G12C RMC-9805 G12D RMC-6236 MULTI/G12X Relative Frequency in Human RAS Cancers(1) G12 Q61 G13
RMC-6236: First-in-Class RASMULTI(ON) Inhibitor with Broad Potential Against RAS-Addicted Cancers KRASG12X includes KRASG12D, KRASG12V, KRASG12R and KRASG12C 137,000 New KRASG12X patients per year (U.S.)(1) Pancreatic 32% Other 6% Colorectal 32% Lung 30% Characterization above is based on RVMD preclinical research Highly Potent and Selective RAS(ON) Inhibitor Suppresses diverse mutant RAS cancer drivers and cooperating wild-type RAS proteins Robust Anti-tumor Activity in Cancer Models Deep and sustained inhibition drives durable anti-tumor activity in tumors with common RAS variants Attractive PK/ADME Profile Favorable in vivo oral bioavailability, clearance and concentration in tumors for effective target coverage in RAS-addicted cancer cells (1) Calculated using tumor mutation frequencies from Foundation Medicine Insights August 2020 and scaled to estimated patient numbers using cancer incidence from ACS Cancer Facts and Figures 2020 (see appendix for additional detail); lung cancer = non-small cell lung cancer
RMC-6236: Highly Active with Durable Benefit Across in Vivo Models of Major Human Cancers with KRASG12X Drivers RVMD preclinical research as of 06/01/22 RMC-6236 dosed at 25 mg/kg po qd; n=1-10/group Progression defined as tumor doubling from baseline NSCLC = non-small cell lung cancer; PDAC = pancreatic ductal adenocarcinoma; CRC = colorectal cancer Responses assigned according to mRECIST (see appendix) ORR = objective response rate; DCR = disease control rate; PFS = progression-free survival NSCLC 53% ORR (8/15) 100% DCR (15/15) PDAC 61% ORR (11/18) 89% DCR (16/18) 44% ORR (8/18) 56% DCR (10/18) CRC RMC-6236 – Median not reached Control – Median 9 days PFS Control (n=215, 51 models) RMC-6236 (n=191, 51 models)
RMC-6236 Phase 1/1b Trial: Clinical Translation of Preclinical Single Agent Profile and Initial Platform Validation (1) Long-term in mouse models defined as up to 90 days of treatment (2) Ongoing study - ClinicalTrials.gov Identifier: NCT05379985 https://clinicaltrials.gov/ct2/show/NCT05379985?term=RMC-6236&draw=2&rank=1 KRASG12X includes KRASG12A, KRASG12D, KRASG12R, KRASG12S, KRASG12V MTD = maximum tolerated dose; RP2DS = recommended Phase 2 dose and schedule; ctDNA = circulating tumor DNA Dosing and Safety Anti-Tumor Activity Preclinical Profile Aims of Phase 1/1b Clinical Trial(2) Oral dosing (daily and intermittent): drug levels that drive sustained RAS pathway suppression Safety: well-tolerated in active range, dose-limiting toxicities “on target” and reversible Long-term treatment(1) at active doses Tumor selection: active in diverse RASMUTANT NSCLC, pancreatic and CRC models; KRASG12X most sensitive Activity: deep regressions across KRASG12X tumors, especially NSCLC and pancreatic models Oral dosing: once daily to reach active exposures + option for intermittent schedule; surrogate markers of activity (ctDNA) Safety: short- and long-term safety and tolerability at active exposures RP2DS Patient selection: signal-seeking across diverse KRASG12X tumors Efficacy: initial clinical responses by RECIST; formal proof-of-concept via expansion cohorts bearing select genotypes/histologies with inadequate SOC
RMC-6291: Mutant-Selective RAS(ON) Inhibitor with Best-in-Class Potential for KRASG12C Cancers 29,000 New KRASG12C patients per year (U.S.)(1) Pancreatic 3% Other 3% Colorectal 18% Lung 76% Highly Potent and Selective RAS(ON) Inhibitor Highly active against KRASG12C Covalent for irreversible inhibition Low off-target risk and acceptable safety profile Robust Anti-tumor Activity in Cancer Models Rapid, deep and sustained inhibition drives durable anti-tumor effects across multiple KRASG12C tumor types, with complete responses in some models Attractive PK/ADME Profile Favorable in vivo oral bioavailability and clearance for effective target coverage in KRASG12C-addicted cancer cells (1) Calculated using tumor mutation frequencies from Foundation Medicine Insights August 2020 and scaled to estimated patient numbers using cancer incidence from ACS Cancer Facts and Figures 2020 (see appendix for additional detail); lung cancer = non-small cell lung cancer Characterization above is based on RVMD preclinical research
RMC-6291: Superior Response Rates and Durability in Mouse Clinical Trial with 25 KRASG12C NSCLC Models RMC-6291 (n=108, 25 models) Adagrasib (n=118, 25 models) Control (n=114, 25 models) RMC-6291 – Median not reached Adagrasib – Median not reached Control – Median 9 days PFS RVMD preclinical research as of 11/20/22 Adagrasib dosed at 100 mg/kg po qd; RMC-6291 dosed at 200 mg/kg po qd; n=3 to 10/group Progression defined as tumor doubling from baseline p<0.001 by Log-rank test (RMC-6291 vs adagrasib treatment in the KM analysis ) NSCLC = Non-small cell lung cancer Responses assigned according to mRECIST (see appendix) Responses
RMC-6291 Phase 1/1b Trial: Clinical Translation of Preclinical Single Agent Profile and Initial Platform Validation (1) Long-term in mouse models defined as up to 90 days of treatment (2) Ongoing study - ClinicalTrials.gov Identifier: NCT05462717 https://www.clinicaltrials.gov/ct2/show/NCT05462717?term=RMC-6291&draw=2&rank=1 MTD = maximum tolerated dose; RP2DS = recommended Phase 2 dose and schedule; ctDNA = circulating tumor DNA Dosing and Safety Anti-Tumor Activity Preclinical Profile Aims of Phase 1/1b Clinical Trial(2) Oral dosing (daily): drug levels that drive maximal target crosslinking and sustained RAS pathway suppression Safety: well-tolerated in active range, highly selective for KRASG12C Long-term treatment(1) at active doses Tumor selection: active in KRASG12C NSCLC and CRC tumor models, including some resistant to KRASG12C(OFF) inhibitors Activity: deep and durable regressions across KRASG12C tumors, especially NSCLC Oral dosing: once daily to reach active exposures + option for BID schedule; surrogate markers of activity (ctDNA) Safety: short- and long-term safety and tolerability at active exposures RP2DS Patient selection: KRASG12C solid tumors; KRASG12C(OFF) inhibitor-treated patients included in dose escalation Efficacy: initial clinical responses by RECIST; formal proof-of-concept via expansion cohorts focused on NSCLC patients without prior KRASG12C(OFF) inhibitor treatment
RMC-9805: First-in-Class Mutant-Selective RAS(ON) Inhibitor for KRASG12D Cancers 55,000 New KRASG12D patients per year (U.S.)(1) Pancreatic 38% Other 8% Colorectal 40% Lung 14% Highly Potent and Selective RAS(ON) Inhibitor Highly active against KRASG12D Covalent for irreversible inhibition Low off-target risk and acceptable safety profile Robust Anti-tumor Activity in Cancer Models Rapid, deep and sustained inhibition drives durable regressions in KRASG12D lung, pancreatic and colorectal cancers Attractive PK/ADME Profile Favorable in vivo oral bioavailability and clearance for effective target coverage in KRASG12D-addicted cancer cells (1) Calculated using tumor mutation frequencies from Foundation Medicine Insights August 2020 and scaled to estimated patient numbers using cancer incidence from ACS Cancer Facts and Figures 2020 (see appendix for additional detail); lung cancer = non-small cell lung cancer Characterization above is based on RVMD preclinical research
Drug Exposure and Pathway Suppression after Oral Dosing(1) RMC-9805: Selective, Covalent Binding and Inhibition of KRASG12D(ON) with Apoptosis Induction in Vivo Control RMC-9805 RAS signaling (pERK) Apoptosis (cleaved caspase 3) RVMD preclinical research RMC-9805 dosed at 100 mg/kg po in HPAC subcutaneous xenograft model (PDAC, KRASG12D/WT) (1) PK/PD data collected at indicated timepoints after a single dose (2) Histopathology data collected 24h after a single dose Selective Covalent Binding to KRASG12D(ON) X-linked KRAS KRAS H/NRAS KRAS: WT G12D G13D G12C G13C RAS Signaling Inhibition and Apoptosis Induction(2) Tumor PD Blood PK Tumor PK
RMC-9805 Drives Deep and Durable Tumor Regressions in Models of Pancreatic Cancer and Brain Metastasis Control RMC-9805 HPAC (KRASG12D) - Brain Xenograft(2) HPAC (KRASG12D) - Pancreas Xenograft(1) RVMD preclinical research RMC-9805 dosed at 100 mg/kg po qd (1) HPAC pancreas orthotopic xenograft model (PDAC, KRASG12D/WT). Mice images were taken on day 21 post implantation. (2) HPAC intracranial xenograft model (PDAC, KRASG12D/WT). Mice images were taken on day 35 post implantation. high low
RMC-9805: Highly Active in Vivo Across Diverse KRASG12D Cancer Models RVMD preclinical research as of 11/02/22 RMC-9805 dosed at 100 mg/kg po qd; n=2-8/group NSCLC = non-small cell lung cancer; PDAC = pancreatic ductal adenocarcinoma; CRC = colorectal cancer Responses assigned according to mRECIST (see appendix) ORR = objective response rate; DCR = disease control rate CRC 14% ORR (1/7) 57% DCR (4/7) PDAC 78% ORR (7/9) 78% DCR (7/9) NSCLC 67% ORR (6/9) 78% DCR (7/9)
RAS(ON) Inhibitors Induce Anti-Tumor Immunity via Multiple Mechanisms in Immunocompetent Models Additive Benefit Supports Clinical Combination Strategies with Immune Therapies % Tumors progression-free Control Anti-PD1 RMC-6236 Combination Control Anti-PD1 RMC-6291 Combination Control Anti-PD1 RMC-9805 Combination Days post-tumor implant Mechanisms of Action Antigen presentation Myeloid suppressive cells T-cell infiltration G12C G12D G12C RVMD preclinical research RMC-9805 experiment conducted in CT26 syngeneic tumor model (KRASG12D); RMC-6236 and RMC-6291 experiments conducted in CT26 model engineered to express KRASG12C RMC-6236 (25 mg/kg po qd) or RMC-6291 (200 mg/kg po qd) dosed for 14 days; RMC-9805 (100 mg/kg po qd) dosed for 42 days; anti-PD-1 (10 mg/kg ip biw, for 21 days) Vertical dashed lines represent treatment stop; Kaplan-Meier progression defined as tumor doubling from baseline
RMC-0708: First-in-Class Mutant-Selective RAS(ON) Inhibitor for KRASQ61H Cancers Highly Potent and Selective RAS(ON) Inhibitor Highly active against KRASQ61H Non-covalent, highly selective over wild-type RAS Low off-target risk and acceptable safety profile Robust Anti-tumor Activity in Cancer Models Rapid, deep and sustained inhibition drives durable regressions in KRASQ61H lung, pancreatic and colorectal cancers Attractive PK/ADME Profile Favorable in vivo oral bioavailability and clearance for effective target coverage in KRASQ61H-addicted cancer cells (1) Calculated using tumor mutation frequencies from Foundation Medicine Insights August 2020 and scaled to estimated patient numbers using cancer incidence from ACS Cancer Facts and Figures 2020 (see appendix for additional detail); lung cancer = non-small cell lung cancer Characterization above is based on RVMD preclinical research Lung 26% Other 4% Pancreatic 23% Colorectal 22% 10,000 New KRASQ61H patients per year (U.S.)1) Multiple Myeloma 26%
NSCLC(2) RMC-0708: Sustained Pathway Inhibition in Vivo and Tumor Regressions in KRASQ61H Cancer Models RVMD preclinical research RMC-0708 dosed at 30 mg/kg po qd (1) PK/PD data collected at indicated timepoints after a single dose (2) HCC2108 subcutaneous xenograft model (NSCLC, KRASQ61H/Q61H) (3) T3M-4 subcutaneous xenograft model (PDAC, KRASQ61H/WT) R = number of regressions >10% from initial; CR = number of regressions ≥80% from initial Each animal represented as a separate bar in waterfall plots Control RMC-0708 Tumor PD Blood PK Tumor PK PDAC(3) Drug Exposure and Pathway Suppression after Oral Dosing(1,2) End of study
On Target to Outsmart Pancreatic Cancer: RAS(ON) Inhibitors Covering All KRASMUTANT Drivers(1) RMC-6236 & RMC-9805 RMC-6236 RMC-6236 RMC-6236 G12D G12V G12R G12C Other(1) 49,000 New KRASMUTANT pancreatic cancer patients per year (U.S.)(1) Dismal survival rates No approved targeted therapies Devastating disease >90% driven by KRAS mutations (1) Calculated using tumor mutation frequencies from Foundation Medicine Insights August 2020 and scaled to estimated patient numbers using cancer incidence from ACS Cancer Facts and Figures 2020 (see appendix for additional detail); RMC-6236 tested against all mutations occurring at >2% frequency in pancreatic cancer Q61H RMC-6236 & RMC-6291 RMC-6236 & RMC-0708
RAS(ON) Cancer Drivers SHP2 WT RAS RAS Companion Inhibitors Suppress Cooperating Targets and Pathways that Sustain RAS-Addicted Cancers RMC-4630 RMC-5552 mTORC1 RMC-6236
Evaluation of RMC-4630 in Combination with Sotorasib in KRASG12C Cancer Patients (1) Ongoing study - ClinicalTrials.gov Identifier: NCT03634982 https://clinicaltrials.gov/ct2/show/NCT03634982?term=RMC-4630&draw=2&rank=1 (2) Ongoing study - ClinicalTrials.gov Identifier: NCT04185883 https://clinicaltrials.gov/ct2/show/NCT04185883?term=codebreak+101&draw=2&rank=1 (3) Falchook et. al. Sotorasib in Combination with RMC-4630, a SHP2 Inhibitor, in KRAS p.G12C-Mutated NSCLC and Other Solid Tumors. 2022 World Conference on Lung Cancer. August 6-9, 2022. Vienna, Austria. Abstract #OA03.03. (4) Ongoing study - ClinicalTrials.gov Identifier: NCT05054725 https://clinicaltrials.gov/ct2/show/NCT05054725?term=RMC-4630&draw=2&rank=2 Phase 1/1b Clinical Trial(1) Selected single agent RP2DS: Oral dosing of 200 mg D1D2 weekly: well-tolerated, safety profile consistent with on-pathway inhibition Anti-tumor activity in certain KRASMUTANT and NF1LOF cancers evidenced by SD, PR and/or CR Dosing: Focused primarily on 200 mg D1D2 weekly combined with sotorasib at 960 mg daily Safety: short- and long-term safety and tolerability Patient Selection: NSCLC patients without prior KRASG12C inhibitor treatment stratified into two cohorts: KRASG12C with or without co-mutations such as KEAP1 or STK11 Efficacy: demonstrate clinical benefit additive to sotorasib Amgen’s CodeBreaK 101c Clinical Trial(2) In KRASG12C patients, “the combination of sotorasib with RMC-4630 was safe and tolerable”(3) with sotorasib at 960 mg po qd and RMC-4630 at 140-200 mg po D1D2 weekly 75% ORR/100% DCR among KRASG12C inhibitor-naïve NSCLC patients treated at top two doses of RMC-4630 (n=4) Dosing and Safety Anti-Tumor Activity Aims of RMC-4630-03 Phase 2 Trial(4)
AKT Toxicity and resistance RMC-5552: First-in-Class Bi-steric mTORC1-Selective Inhibitor for Cancers with Hyperactive mTOR Signaling Characterization above is based on RVMD preclinical research mTORC2 substrate mTOR active site inhibitors Rapalogs RMC-5552 mTORC1 substrates Highly Potent and Selective mTORC1 Inhibitor Bi-steric mechanism enables selectivity for mTORC1 Capable of reactivating the tumor suppressor 4EBP1 Robust Anti-tumor Activity in Cancer Models Selective inhibition of mTORC1 drives durable regressions in mTOR pathway-mutant models Attractive PK/ADME Profile Weekly dosing provides favorable PK exposure and prolonged target modulation in vivo S6K Anti-tumor 4EBP1 Anti-tumor
RMC-5552: Compelling Profile as RAS Companion Inhibitor Preliminary radiologic and molecular evidence of activity at tolerated doses: Disease control across diverse tumors, including durable stable disease Objective response and regressions Favorable changes in surrogate markers 3 of 6 patients with stable disease and oncogenic mTOR pathway variants had molecular responses(1) (1) n = 6 molecular response-evaluable patients with oncogenic mTOR pathway variants detected by ctDNA treated at 6 mg or higher majority dose. ”Oncogenic” defined as pathogenic or likely pathogenic by blinded adjudication process using publicly available variant data. Molecular response defined by 50% decrease or greater in mean VAF at C3D1 by Guardant360® Molecular Response algorithm. VAF = variant allele fraction Phase 1/1b Single Agent Study Best Tumor Change in Efficacy Evaluable Patients Treated at 6 mg or 8 mg IV Weekly (2) n = 28 efficacy evaluable subjects. DCR = disease control rate. *Patient received one dose of 12 mg, followed by weekly doses of 6 mg, had complete loss of oncogenic PTEN variant by ctDNA, and has been on RMC-5552 for >12 months. #Patient received one dose of 10 mg, followed by weekly doses of 6 mg. Both patients were on RMC-5552 for >24 weeks. Data as of 12/19/2022. PD = progressive disease, SD = stable disease, PR = partial response, mo = months 71% DCR(2)
RMC-5552 Phase 1/1b Trial: Clinical Optimization of Single Agent Profile for Combination with RAS(ON) Inhibitor Portfolio (1) Ongoing study - ClinicalTrials.gov Identifier: NCT04774952 https://clinicaltrials.gov/ct2/show/NCT04774952?term=rmc-5552&draw=2&rank=1 MTD = maximum tolerated dose; RP2DS = recommended Phase 2 dose and schedule; ctDNA = circulating tumor DNA Dosing and Safety Anti-Tumor Activity Preclinical Profile Aims of Phase I/Ib Clinical Trial(1) Dosing: Once weekly dosing achieves levels that drive sustained inhibition of mTORC1 signaling and activation of 4EBP1 Safety: Well-tolerated, highly mTORC1 selective Single Agent: Strong activity in tumor models with hyperactivated mTORC1 RAS Companion: Combinatorial activity with RAS(ON) inhibitors Dosing: Establish optimal IV regimen based on safety, anti-tumor activity and surrogate markers of activity (ctDNA) Single Agent: Evidence of activity at tolerated doses in tumors with hyperactive mTORC1 signaling RAS Companion: Identify appropriate dose and schedule for combinations with RAS(ON) inhibitors Safety: Demonstrate short- and long-term safety and tolerability at active exposures
Overcoming Resistance: RMC-6291 + RMC-6236 Combination Induces Regressions in KRASG12C NSCLC Model RASMULTI(ON) Inhibitor Deployed as a RAS Companion Inhibitor RVMD preclinical research NCI-H2122 subcutaneous xenograft model (NSCLC, KRASG12C/G12C) RMC-6291 dosed at 100 mg/kg po qd; RMC-6236 dosed at 10 mg/kg po qd RMC-6291, RMC-6236 and Combination - n = 15/group, Control – n=8 NSCLC = non-small cell lung cancer Control RMC-6291 Combination RMC-6236 Mean Tumor Volume (mm3) Dosing start Days post-implant
Deep Pipeline of Targeted Therapies for Majority of RAS-Addicted Cancers PRECLINICAL IND-ENABLING CLINICAL PHASE 1 CLINICAL PHASE 2 CLINICAL PHASE 3 RAS(ON) INHIBITORS RMC-6236 RASMULTI RMC-6291 KRASG12C RMC-9805 KRASG12D RMC-0708 KRASQ61H RMC-8839 KRASG13C Pipeline Expansion G12R, G12V, G13D, Q61X, other RAS COMPANION INHIBITORS RMC-4630(1) SHP2 RMC-5552 mTORC1/4EBP1 RMC-5845(2) SOS1 (1) Sanofi collaboration on RMC-4630/SAR442720 terminated effective June 2023 (2) IND-ready, active development deferred
Anticipated Milestones MILESTONE (EXPECTED TIMING) RAS(ON) INHIBITORS RMC-6236 (RASMULTI) Provide evidence of first-in-class single agent activity (mid-2023) RMC-6291 (KRASG12C) Provide preliminary evidence of superior profile (2H2023) RMC-9805 (KRASG12D) Announce dosing of first patient (mid-2023) RAS COMPANION INHIBITORS RMC-4630 (SHP2) Provide topline data from RMC-4630-03 (2H2023) RMC-5552 (mTORC1/4EBP1) Provide additional evidence of single agent activity (2023)
Financial Information Financial Position Cash, cash equivalents and marketable securities as of September 30, 2022 $655.0 million(1) With current cash, cash equivalents and marketable securities the company projects it can fund planned operations through 2024. (2) Includes non-cash stock-based compensation expense of approximately $30 million to $35 million 2022 Financial Guidance 2022 GAAP net loss of $245 million to $265 million(2)
Focused on serving high unmet needs across numerous cancers driven by diverse RAS mutations Targeted RAS(ON) Inhibitors with compelling preclinical profiles entered clinic in 2022 Targeted RAS Companion Inhibitors designed to counter drug resistance have shown initial clinical activity and evaluation continues Development-stage portfolio covers RAS drivers of all major RAS-addicted cancers
Appendix RAS cancer epidemiology statistics are estimated using tumor mutation frequencies from Foundation Medicine Insights August 2020 and scaled to estimated patient numbers using cancer incidence from ACS Cancer Facts and Figures 2020: RAS mutations include: KRAS G12(A,C,D,R,S,V), KRAS G13(C,D), KRAS Q61(H, K, L), KRAS A146T, KRAS wild-type amplification, NRAS G12C, NRAS Q61(H,K,L,R,P), HRAS mutations of known/likely function (including HRAS Q61(H,L)), BRAF class 3 mutations, NF1 loss of function mutations, PTPN11 mutations of known/likely function. NF1 LOF mutations = 50% of all NF1 mutations of known/likely function. BRAF class 3 mutations = D287H, D594(A,E,G,H,N,V,Y), F595L, G466(A,E,R,V,E,D,R), N581(I,S), S467L,T599I, V459L. Includes 12 major types: non-small cell lung cancer, colorectal, pancreatic adenocarcinoma, renal, gastroesophageal, head and neck squamous cell, ovarian and biliary cancers, acute myeloid leukemia, and advanced melanoma, bladder and uterine/endometrial cancers causing mortality. KRASQ61H epidemiology statistics include multiple myeloma in addition to 12 major types named above Est. worldwide annual incidence of RAS-mutated cancers is 3.4 million per Prior et al., Cancer Research 2020 RAS mutations drive 30% of human cancers per Prior et al., Cancer Research 2020 Mouse tumor responses on slides 9, 12 and 17 assigned according to mRECIST (modified from Gao et al. Nat Med. 2015): mPD = progressive disease; mSD = stable disease; mPR = partial response; mCR = complete response PK = pharmacokinetic; ADME = absorption, distribution, metabolism, and excretion