Revolution Medicines Announces Publication on the Discovery of and Translational Research for RMC-6236, an Investigational RAS(ON) Multi-Selective Tri-Complex Inhibitor Designed to Block Full Spectrum of Oncogenic RAS(ON) Proteins
Revolution Medicines, Inc. announces the publication of a peer-reviewed research paper detailing the discovery and translation of RMC-6236, an investigational RAS(ON) multi-selective inhibitor, with promising preclinical data and case studies. The paper highlights the potential of RMC-6236 in inhibiting RAS-dependent tumor growth across multiple cancer types, achieving deep and durable tumor regressions. Case studies from the Phase 1/1b clinical trial show complete responses in patients with NSCLC and PDAC, supporting the anti-tumor activity of RMC-6236.
The recent findings regarding RMC-6236 suggest a significant advancement in the field of targeted cancer therapy. As an oncologist, the potential of this multi-selective inhibitor to induce complete responses in patients with advanced KRAS-G12V NSCLC and KRAS-G12D PDAC is highly encouraging. The ability to target both mutant and wild-type RAS-GTP is a notable deviation from existing therapies, which primarily focus on specific KRAS mutations in their inactive state.
Moreover, the broad activity across various cancer types, including those with K/N/HRAS mutations, indicates a wide therapeutic window. This could lead to a paradigm shift in treating RAS-driven cancers, which are known for their aggressive nature and limited treatment options. The well-tolerated profile of RMC-6236 at effective dosages is also promising, potentially reducing the severity of side effects compared to more toxic treatments currently in use.
The preclinical data and pharmacokinetic/pharmacodynamic modeling for RMC-6236 provide a strong foundation for the ongoing clinical trials. From a research perspective, the translational approach taken by Revolution Medicines, which includes a rigorous PK/efficacy modeling, is exemplary. The predicted daily doses for tumor control and objective responses being validated by case studies is a robust indicator of the drug's potential efficacy in a clinical setting.
The choice to expand the clinical development program based on these preliminary results is a calculated risk, but one that is backed by solid scientific data. The implications for stakeholders are substantial, as success in the pivotal studies could position RMC-6236 as a leading therapy in the RAS-targeted drug market. However, it is critical to remain cautious until larger clinical trials validate these early findings.
The announcement pertaining to RMC-6236 is likely to have a positive impact on the market perception of Revolution Medicines. The stock market often reacts favorably to promising clinical trial data, especially in the high-stakes arena of oncology drug development. The potential expansion of the clinical program into pivotal studies could signal to investors a higher confidence level in the drug's prospects, possibly influencing the company's stock valuation.
It is important to note that while these developments are promising, the actual market impact will depend on further clinical results, regulatory approvals and the ability of the company to successfully commercialize the drug. Additionally, the competitive landscape, with other companies also targeting RAS mutations, will play a important role in determining the long-term success and market share of RMC-6236.
04/09/2024 - 03:34 PM
Simultaneous publication and presentation of RMC-6236 chemical structure, preclinical data and case studies during the “KRAS: Broadening the Attack Beyond G12C with Small Molecules and Immuno-Oncology" Session at AACR 2024 in San Diego
REDWOOD CITY, Calif., April 09, 2024 (GLOBE NEWSWIRE) -- Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for patients with RAS-addicted cancers, today announced the publication of a peer-reviewed research paper in Cancer Discovery. The scientific paper details the discovery and preclinical to clinical translation for RMC-6236, an investigational RAS(ON) multi-selective inhibitor, and includes exemplary case studies from the current Phase 1/1b clinical trial demonstrating the initial anti-tumor activity of RMC-6236. This original research was led by scientists at Revolution Medicines and conducted in collaboration with researchers from across the U.S. and Europe.
Oncogenic RAS proteins drive up to 30 percent of all human cancers, most notably non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). RAS G12 mutations, such as G12D, G12V and G12C, predominate in human cancers. Currently approved KRAS-targeted cancer therapies target one particular KRAS mutation, KRAS G12C, in the GDP-bound (OFF) state. The paper describes the discovery of RMC-6236, an oral, multi-selective inhibitor of the active GTP-bound (ON) state of both mutant and wild-type RAS. In preclinical studies, RMC-6236 was effective in inhibiting the growth of RAS-dependent tumor cells, while sparing normal tissues. RMC-6236 was found to be well-tolerated and drove deep and durable tumor regressions across multiple cancer types including NSCLC, PDAC, CRC, gastric and gynecologic cancers, with tumor models dependent on KRAS G12 mutations being particularly sensitive. This benefit was found to extend to models with K/N/HRAS hotspot mutations at G13 and Q61 as well.
The paper also highlights translational pharmacokinetics (PK)/efficacy and PK/pharmacodynamics modeling, which predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, case studies from the Phase 1/1b RMC-6236 monotherapy clinical trial are featured, describing two patients with advanced KRAS-G12V NSCLC and KRAS-G12D PDAC, respectively, who were treated with 300 mg of RMC-6236 daily. Each of these two patients achieved a complete response as best response demonstrating the potential anti-tumor activity of RMC-6236.
“The discovery of RMC-6236 allowed for the first-ever therapeutic evaluation of targeted concurrent inhibition of both canonical mutant and wild-type RAS-GTP (RAS(ON)) in RAS-driven cancers. The RMC-6236 clinical data that we have shared not only provide platform validation of our tri-complex inhibitor approach, but also refute the dogma that one could not induce anti-tumor activity by broad inhibition of multiple RAS variants, including wild-type RAS, at doses that would be well tolerated,” said Steve Kelsey, M.D., president, research and development of Revolution Medicines. “The research summarized in our Cancer Discovery paper, combined with the preliminary RMC-6236 clinical data presented in late 2023, provide us and our investigators with the confidence to advance and expand our RMC-6236 clinical development program.”
Revolution Medicines is currently evaluating RMC-6236 as monotherapy in a Phase 1/1b trial in patients with advanced solid tumors harboring G12X, G13X and Q61X mutations (NCT05379985 ). Following promising preliminary data in this Phase 1/1b study, planning is underway to initiate pivotal studies of RMC-6236 as monotherapy in NSCLC and PDAC. RMC-6236 is also being evaluated in combination with pembrolizumab with or without chemotherapy in patients with advanced RAS-mutated solid tumors (NCT06162221 ) and in combination with RMC-6291, the company’s investigational RAS(ON) G12C-selective inhibitor, for patients with advanced KRAS G12C-mutated solid tumors (NCT06128551 ).
Today’s publication coincides with the company’s presentation of RMC-6236 preclinical data and additional clinical case studies during the “KRAS: Broadening the Attack Beyond G12C with Small Molecules and Immuno-Oncology” session today at the American Association for Cancer Research (AACR) Annual Meeting 2024 in San Diego.
The scientific paper can be accessed at the following link: https://doi.org/10.1158/2159-8290.CD-24-0027 .
About Revolution Medicines, Inc.
Revolution Medicines is a clinical-stage oncology company developing novel targeted therapies for RAS-addicted cancers. The company’s R&D pipeline comprises RAS(ON) inhibitors designed to suppress diverse oncogenic variants of RAS proteins, and RAS companion inhibitors for use in combination treatment strategies. The company’s RAS(ON) inhibitors RMC-6236, a RAS(ON) multi-selective inhibitor, RMC-6291, a RAS(ON) G12C-selective inhibitor, and RMC-9805, a RAS(ON) G12D-selective inhibitor, are currently in clinical development. Additional RAS(ON) mutant-selective inhibitors in the company’s development pipeline include RMC-5127 (G12V), RMC-0708 (Q61H) and RMC-8839 (G13C).
Forward Looking Statements This press release contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. Any statements in this press release that are not historical facts may be considered "forward-looking statements," including without limitation statements regarding the potential advantages of Revolution Medicines’ preclinical and preclinical candidates, including the potential efficacy, durability, tolerability and combination potential of RMC-6236; validation of the company’s tri-complex platform; and the company’s RMC-6236 and RMC-6291 development plans. 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 studies and clinical trials, risks that the results of prior preclinical models or studies may not be predictive of future clinical trials, clinical efficacy or other future results, 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, the risk that the wind-down of EQRx, Inc. could take longer than anticipated or result in unexpected costs, and the effects on the company’s business of global events, such as international conflicts or pandemics. For a further description of the risks and uncertainties that could cause actual results to differ from those anticipated in the forward-looking statements, as well as risks relating to the business of Revolution Medicines in general, see Revolution Medicines’ Annual Report on Form 10-K filed with the Securities and Exchange Commission on February 26, 2024, and its future periodic reports to be filed with the Securities and Exchange Commission. Except as required by law, Revolution Medicines undertakes no obligation to update any forward-looking statements to reflect new information, events, or circumstances, or to reflect the occurrence of unanticipated events.
What is the ticker symbol for Revolution Medicines, Inc.?
The ticker symbol for Revolution Medicines, Inc. is RVMD.
What is the name of the investigational RAS multi-selective inhibitor detailed in the research paper?
The investigational RAS multi-selective inhibitor detailed in the research paper is RMC-6236.
What types of cancers do RAS proteins drive?
RAS proteins drive up to 30 percent of all human cancers, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC).
What was the key finding regarding the anti-tumor activity of RMC-6236 in preclinical studies?
RMC-6236 was effective in inhibiting the growth of RAS-dependent tumor cells while sparing normal tissues in preclinical studies.
What were the tumor models sensitive to RMC-6236 in the study?
Tumor models dependent on KRAS G12 mutations were particularly sensitive to RMC-6236.
