On November 6, 2023 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, reported its financial results for the quarter ended September 30, 2023, and provided an update on corporate progress (Press release, Revolution Medicines, NOV 6, 2023, View Source [SID1234637046]).

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Recent Highlights

RMC-6236: Revolution Medicines presented promising anti-tumor activity data for RMC-6236, a RASMULTI(ON) Inhibitor, in patients with non-small cell lung cancer (NSCLC) or pancreatic ductal adenocarcinoma (PDAC) harboring KRASG12X mutations. The data demonstrated that treatment with RMC-6236 led to meaningful clinical responses at dose levels that were generally well tolerated. The results also provided clinical validation that RMC-6236 as a RASMULTI(ON) Inhibitor can drive objective responses in patients with tumors carrying multiple common KRAS mutations, including G12D, G12V and G12R. These data support the company’s decision to advance RMC-6236 into late-stage clinical development.

RMC-6291: The company presented encouraging anti-tumor activity data for its mutant-selective RASG12C(ON) Inhibitor, RMC-6291, in patients with advanced solid tumors harboring KRASG12C mutations, including NSCLC and colorectal cancer (CRC). The data provided preliminary evidence of anti-tumor activity by treatment with RMC-6291 that was generally well tolerated across dose levels and included preliminary evidence of mechanistic and clinical differentiation from KRASG12C(OFF) inhibitors as indicated by clinical responses in NSCLC patients previously treated with a KRASG12C(OFF) inhibitor and in KRASG12C(OFF) inhibitor naïve CRC patients.

EQRx Acquisition: Last week, Revolution Medicines announced that Institutional Shareholder Services Inc. and Glass Lewis & Co. recommended Revolution Medicines stockholders vote "FOR" the issuance of Revolution Medicines shares in the previously announced all-stock acquisition of EQRx, Inc. at the special meeting of stockholders scheduled for 11:00 a.m. Eastern Time on November 8, 2023. The transaction is expected to close shortly following the stockholder vote, subject to satisfaction of customary closing conditions, including approval by both Revolution Medicines’ and EQRx’s stockholders. Each share of common stock of EQRx issued and outstanding immediately prior to the merger will be converted into the right to receive 0.1112 shares of common stock of Revolution Medicines. If the transaction is completed, Revolution Medicines expects to issue approximately 55 million shares of its common stock in connection with the merger (excluding assumed warrants and earn-out shares). The company estimates that the acquisition will add approximately $1.1 billion in net cash proceeds, after estimated post-closing EQRx wind-down and transition costs, or approximately $20 per share of common stock to be issued with the merger.
"Collectively, the clinical data presented on RMC-6236 and RMC-6291 demonstrate that these two investigational drugs have significant anti-tumor activity across dose levels that have been generally well tolerated in patients with common cancers harboring one of the four most common oncogenic RASG12 mutations. The overwhelmingly positive reaction our team heard from clinical investigators further validates the differentiation of our RAS(ON) Inhibitor platform and clearly supports continued investment in these compounds as monotherapy and/or in combination regimens," said Mark A. Goldsmith, M.D., Ph.D., chief executive officer and chairman of Revolution Medicines. "With the anticipated closing of the EQRx acquisition this month, the infusion of a sizable quantum of capital will allow Revolution Medicines to advance plans designed to fully realize the potential of our RAS(ON) inhibitor investigational drugs as we seek to fulfill our vision of revolutionizing treatment for patients living with RAS-addicted cancers."

Clinical and Development Highlights

Investigational RAS(ON) Inhibitors
RMC-6236 (RASMULTI)
RMC-6236 is an oral, RAS-selective, first-in-class RASMULTI(ON) Inhibitor designed to treat patients with cancers driven by a wide range of common RAS mutations. Initially being developed as monotherapy, planning is underway to also evaluate RMC-6236 in doublet combinations with mutant-selective RAS(ON) Inhibitors as well as other combination treatments.

The ongoing Phase 1/1b monotherapy trial (NCT05379985) is a multicenter, open-label, dose-escalation and dose-expansion study of RMC-6236 in patients with advanced solid tumors harboring select KRASG12 mutations, including G12D, G12V and G12R and was recently expanded to include G13 and Q61 mutations. A maximum tolerated dose has not yet been defined and dose optimization is ongoing.
The company is planning a global, randomized Phase 3 study comparing RMC-6236 against docetaxel in patients with previously treated RAS-mutated NSCLC who have been treated with immunotherapy and platinum-containing chemotherapy. The study design will be finalized after regulatory feedback. The study is expected to start in 2024.
The company is also designing a potential global randomized Phase 3 trial comparing RMC-6236 against a physician’s choice of chemotherapy regimens in patients with previously treated RAS-mutated PDAC. Future study decisions will be made after additional patient follow-up regarding durability of disease control and dose optimization and regulatory feedback. The company believes the study could potentially be initiated in 2024.
A Phase 1/1b clinical trial to evaluate the combination of RMC-6236 and RMC-6291 is currently recruiting patients. Planning is also underway for additional studies of RMC-6236 in combination with standard of care therapies, including immunotherapy and chemotherapy.
RMC-6291 (RASG12C)
RMC-6291, an oral, covalent inhibitor of RASG12C(ON) designed to treat patients with cancers driven by the KRASG12C mutant, is the first of the company’s mutant-selective RAS(ON) Inhibitors to enter clinical development and the first reported clinical-stage inhibitor of KRASG12C that uses a highly differentiated mechanism of action compared to first-generation KRASG12C(OFF) inhibitors. The ongoing Phase 1/1b monotherapy trial (NCT05462717) is a multicenter, open-label, dose-escalation and dose-expansion study of RMC-6291 in patients with advanced KRASG12C mutant solid tumors. A maximum tolerated dose has not yet been defined and dose optimization is ongoing.

In addition to the Phase 1/1b combination study of RMC-6291 and RMC-6236, planning is underway for studies to evaluate RMC-6291 in combination with standard of care therapies, including immunotherapy and chemotherapy.
RMC-9805 (RASG12D)
RMC-9805 is an oral, selective, covalent inhibitor of RASG12D(ON), the most common driver of RAS-addicted human cancers, predominantly among patients with PDAC, NSCLC or CRC. The company believes RMC-9805 is the first oral and covalent inhibitor of RASG12D.

The Phase 1/1b trial (NCT06040541) is an ongoing multicenter, open-label, dose-escalation and dose-expansion study of RMC-9805 in patients with advanced solid tumors harboring the KRASG12D mutation. The primary objectives of the study are to evaluate safety and tolerability, and to inform the recommended Phase 2 dose and schedule for the compound.
RAS Innovation Engine
Beyond the first wave of clinical-stage RAS(ON) Inhibitors, the company continues expanding its pipeline of RAS(ON) Inhibitor candidates.

RAS(ON) Inhibitor development candidates include RMC-5127 (G12V), RMC-0708 (Q61H) and RMC-8839 (G13C).
The company continues drug discovery efforts in RAS(ON) Inhibitor pipeline expansion programs focused on RAS mutation hotspots including G12R, G13D and other important targets.
Third Quarter 2023 Financial Highlights

Cash Position: Cash, cash equivalents and marketable securities were $813.2 million as of September 30, 2023, compared to $644.9 million as of December 31, 2022. The increase was primarily attributable to the company’s public equity offering in March 2023.

Revenue: Total revenue was zero for the quarter ended September 30, 2023, compared to $3.4 million for the quarter ended September 30, 2022.

R&D Expenses: Research and development expenses were $107.7 million for the quarter ended September 30, 2023, compared to $69.5 million for the quarter ended September 30, 2022. The increase was primarily due to an increase in clinical trial and clinical supply manufacturing expenses for RMC-6236 and RMC-6291, research expenses associated with the company’s pre-clinical portfolio, an increase in personnel-related expenses related to additional headcount, and an increase in stock-based compensation.

G&A Expenses: General and administrative expenses were $15.5 million for the quarter ended September 30, 2023, compared to $10.4 million for the quarter ended September 30, 2022. The increase was primarily due to an increase in stock-based compensation and an increase in personnel-related expenses related to additional headcount.

Net Loss: Net loss was $108.4 for the quarter ended September 30, 2023, compared to net loss of $73.3 million for the quarter ended September 30, 2022.

2023 Financial Guidance
Revolution Medicines is updating its projected full year 2023 GAAP net loss to be between $385 and $415 million, which includes estimated non-cash stock-based compensation expense of $45 million and $50 million. Based on the company’s current operating plan, the company projects current cash, cash equivalents and investments can fund planned operations into 2025. The Company’s financial guidance excludes the financial impact of the proposed EQRx transaction.

Webcast
Revolution Medicines will host a webcast this afternoon, November 6, 2023, at 4:30 p.m. Eastern Time (1:30 p.m. Pacific Time). To listen to the live webcast, or access the archived webcast, please visit: View Source Following the live webcast, a replay will be available on the company’s website for at least 14 days.