On January 11, 2022 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing novel targeted therapies for RAS-addicted cancers, reported progress across its pipeline of targeted therapeutics spanning its RAS(ON) Inhibitor and RAS Companion Inhibitor portfolios (Press release, Revolution Medicines, JAN 11, 2022, View Source [SID1234598582]). These updates were announced in a corporate presentation delivered by Mark A. Goldsmith, M.D., Ph.D., the company’s chief executive officer and chairman, at the 40th Annual J.P. Morgan Healthcare Conference.
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RAS(ON) Inhibitors
As a centerpiece of this presentation, Dr. Goldsmith provided updates on the company’s expanding portfolio of innovative RAS(ON) Inhibitors. The company is on track to file investigational new drug (IND) applications in the first half of 2022 for its two most advanced RAS(ON) Inhibitors, RMC-6236 (RASMULTI) and RMC-6291 (KRASG12C), both of which have shown attractive preclinical profiles including strong anti-tumor activity.
Dr. Goldsmith also introduced two new mutant-selective RAS(ON) Inhibitors that Revolution Medicines has advanced into IND-enabling development. RMC-9805 is an oral, mutant-selective, covalent inhibitor of KRASG12D, which is the primary tumor driver in more than 50,000 new patients with colorectal, pancreatic or lung cancer annually in the United States. Evaluation in preclinical in vivo cancer models has demonstrated best-in-class potential for RMC-9805, and the company aims to file an IND application in the first half of 2023.
RMC-8839 is an oral, mutant-selective, covalent inhibitor of KRASG13C. Revolution Medicines believes that RMC-8839 is the first compound to directly target KRASG13C, an important therapeutic target primarily for lung and select colorectal cancer patients who are not currently served by any targeted RAS drug. This first-in-class development candidate has demonstrated strong anti-tumor responses in in vivo cancer models and the company aims to file an IND application in the second half of 2023.
In addition to its four development-stage RAS(ON) Inhibitors, the company disclosed that it has ongoing discovery programs pursuing additional mutant-selective compounds for various cancer mutations at RAS hotspots G12, G13 and Q61, with the goal of nominating a fifth development candidate in the second half of 2022.
RAS Companion Inhibitors
Dr. Goldsmith also provided updates on the company’s class-leading, clinical-stage RAS Companion Inhibitors: RMC-4630, the company’s investigational SHP2 inhibitor, and RMC-5552, the company’s potent, selective inhibitor of mTORC1.
The first patient has been dosed in RMC-4630-03, a global, multicenter, open-label Phase 2 study evaluating the efficacy, safety, tolerability, and pharmacokinetics of RMC-4630 in combination with Lumakras (sotorasib), Amgen’s KRASG12C inhibitor, in subjects with advanced non-small cell lung cancer. Revolution Medicines is sponsoring the RMC-4630-03 study under its global partnership with Sanofi and conducting the trial in collaboration with Amgen, which is supplying sotorasib to study sites globally. The study’s first patient was enrolled and dosed at Sarah Cannon Research Institute in Nashville, Tennessee, by study investigator Melissa Johnson, M.D., Director of the Lung Cancer Research Program.
The company also reported initial findings from the ongoing dose escalation portion of its Phase 1/1b clinical trial of RMC-5552, including preliminary evidence of clinical activity against advanced tumors with mutations associated with hyperactive mTORC1 signaling. To date, all four efficacy evaluable patients treated with 6 mg per week have experienced disease control, including one patient exhibiting a confirmed partial response with a 63% reduction from baseline and the other three with stable disease. A strategic priority is to evaluate RMC-5552 in combination with RAS(ON) Inhibitors in patients carrying both RAS and mTOR pathway mutations, representing approximately 30,000 new patients per year in the United States.
"We begin 2022 with strong momentum in our efforts to serve critical unmet medical needs for patients with diverse RAS-addicted cancers," said Dr. Goldsmith. "We now have four development-stage RAS(ON) Inhibitors with compelling preclinical profiles, the first two of which are expected to enter the clinic this year and the other two advancing toward IND filings in 2023. In addition, both of our clinical-stage RAS Companion Inhibitors have now shown encouraging initial single agent clinical activity and are continuing in monotherapy and/or combination treatment studies. Our cohesive portfolio of development-stage assets is designed to inhibit the cancer drivers of all major RAS-addicted forms of human lung, colorectal and pancreatic cancer, and we remain optimistic that the era of targeted treatment for patients with these cancers is within reach."