On April 8, 2024 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for patients with RAS-addicted cancers, reported the publication of two peer-reviewed research papers in Nature (Press release, Revolution Medicines, APR 8, 2024, View Source [SID1234641880]). The first paper highlights the discovery and preclinical characterization of RMC-7977, a preclinical tool compound representative of a class of oral RAS(ON) multi-selective inhibitors, including the investigational drug candidate RMC-6236, that target multiple RAS variants. The second paper highlights the systematic evaluation of RMC-7977 in a wide range of preclinical models of PDAC. This original research was led by scientists at Revolution Medicines and conducted in collaboration with researchers from across the U.S. and Europe.

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Oncogenic RAS proteins drive up to 30 percent of all human cancers, most notably non-small cell lung cancer (NSCLC), PDAC and colorectal cancer (CRC). RAS G12 mutations, such as G12D, G12V and G12C, predominate in human cancers. Approved KRAS-targeted cancer therapies target only one particular RAS mutation, KRAS G12C.

The first Nature paper describes RMC-7977, a RAS(ON) multi-selective inhibitor preclinical tool compound, which was designed to inhibit the full spectrum of oncogenic RAS mutations, including RAS codon 12 mutations (RAS G12X) as well as non-mutated wild-type RAS. RMC-7977 engages the intracellular chaperone cyclophilin A (CYPA) to form a binary complex that binds reversibly and with high affinity to RAS proteins that are in the active, GTP-bound or ON state. In preclinical studies, RMC-7977 demonstrated robust, durable anti-tumor activity at well-tolerated doses across a range of RAS-mutated NSCLC, PDAC and CRC models. Importantly, the preclinical study demonstrated that RAS(ON) multi-selective inhibitors, as represented by RMC-7977, have the potential to overcome some of the resistance mechanisms that have been shown to limit the clinical efficacy and durability of current KRAS(OFF) G12C-selective inhibitors, including adaptive signaling mechanisms mediated by activation of wild-type RAS.

The second report describes research into the pharmacology and anti-tumor activity of the tool compound, RMC-7977, which was evaluated across a diverse range of preclinical PDAC models. Broad and pronounced anti-tumor activity was observed across various preclinical models following direct RAS inhibition by RMC-7977 at exposures that were well tolerated in vivo, providing a strong preclinical rationale for evaluating broad-spectrum RAS inhibition in the clinical PDAC setting. Furthermore, careful analysis of recognized clinical resistance mechanisms in a sophisticated model of PDAC treated with RMC-7977 revealed a promising combination treatment regimen that may be capable of countering monotherapy drug resistance.

"This innovative research extends the impact of our tri-complex inhibitor platform to a wide range of common, oncogenic RAS mutants for which no targeted drugs are available, and supported the discovery of RMC-6236, our clinical-stage RAS(ON) multi-selective inhibitor. The findings reverse long-standing scientific dogma by showing that it is possible to obtain meaningful anti-tumor activity by broadly targeting the RAS class of proteins without unacceptable effects in normal tissues," said Mark A. Goldsmith, M.D., Ph.D., chief executive officer and chairman of Revolution Medicines. "The preclinical findings reported in these scientific papers, combined with initial data we have disclosed from an ongoing clinical study of RMC-6236, support further evaluation of RMC-6236 in patients living with RAS-addicted cancers, for whom there remain large unmet medical needs."

The investigational oral drug candidate RMC-6236 is a RAS(ON) multi-selective inhibitor designed to treat patients with cancers driven by a wide range of common RAS mutations. Revolution Medicines is currently evaluating RMC-6236 as monotherapy in a first-in-human trial in patients with advanced solid tumors harboring G12X, G13X, and Q61X mutations (NCT05379985). Based on promising preliminary data in this trial, 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).

The scientific papers published in Nature can be accessed at the following links:

"Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy"
"Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma"