On March 2, 2021 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage precision oncology company focused on developing targeted therapies to inhibit frontier targets in RAS-addicted cancers, reported its financial results for the fourth quarter and year ended December 31, 2020, and provided a corporate update (Press release, Revolution Medicines, MAR 2, 2021, View Source [SID1234575934]).

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"Revolution Medicines has achieved multiple significant milestones, furthering the company’s position as a leading precision oncology company dedicated to the development of innovative targeted medicines and treatment regimens to address significant unmet needs for patients with RAS-addicted cancers," said Mark A. Goldsmith, M.D., Ph.D., chief executive officer and chairman of Revolution Medicines.

"Our exceptional team delivered two pioneering RAS(ON) inhibitor development candidates into IND-enabling development, RMC-6291 and RMC-6236. RMC-6291 targets the oncogenic KRASG12C(ON) variant through a highly differentiated anti-tumor profile. RMC-6236 uniquely targets numerous RAS(ON) variants responsible for many cancers. We believe these two development candidates hold great promise for potential use in treating patients with a diverse range of RAS-addicted cancers, and we are actively advancing both toward the clinic.

"The company has also made great progress with our RAS Companion Inhibitor portfolio. Our most advanced candidate RMC-4630, a SHP2 inhibitor, is being evaluated in multiple studies to position it as a backbone for targeted combination therapies. We received FDA clearance to begin clinical evaluation of RMC-5552, a potent mTORC1-selective inhibitor, and plan to initiate a monotherapy dose-escalation study imminently. Additionally, we have advanced RMC-5845, our potent, selective, oral inhibitor of SOS1, a major switch in the cycling of RAS(OFF) to RAS(ON), into IND-enabling development.

"To support our expanded and advancing pipeline of development programs, Revolution Medicines recently completed an upsized financing, raising net proceeds of $281 million. We have made tremendous progress as a company and believe that our cohesive portfolio of innovative clinical and preclinical assets will permit rational, mechanism-based combinations and position Revolution Medicines to fulfill our mission."

R&D Highlights

RAS(ON) Inhibitors – Revolution Medicines continues maturing its first-in-class RAS(ON) platform, introducing an expansive collection of tri-complex inhibitors targeting diverse oncogenic RAS variants through highly differentiated chemical and pharmacologic profiles.

Pioneering RAS(ON) assets, RMC-6291 (KRASG12C) and RMC-6236 (RASMULTI), enter IND-enabling development
○ RMC-6291 is a first-in-class, potent, oral and selective tri-complex inhibitor of KRASG12C(ON) and NRASG12C(ON) that has demonstrated deep and sustained anti-tumor activity in preclinical lung cancer models driven by a KRASG12C mutation. The company expects to submit an investigational new drug application (IND) for RMC-6291 in the first half of 2022.

○ RMC-6236 is a first-in-class, potent, oral RAS-selective tri-complex, RASMULTI(ON) inhibitor that has demonstrated pronounced anti-tumor activity in preclinical models of human lung, colorectal and pancreatic cancers caused by multiple RAS variants for which no targeted treatment is currently available. The company expects to submit an IND for RMC-6236 in the first half of 2022.

Continued expansion of other RAS(ON) inhibitor programs – Revolution Medicines continues to progress an expanding portfolio of potent, cell-active RAS(ON) inhibitors with the potential to target RAS variants driving the vast majority of RAS-addicted cancers. In particular, the company’s KRASG12D- and KRASG13C-selective programs continue to advance in lead optimization. The company expects to nominate a third development candidate from its RAS(ON) inhibitor portfolio in the second half of 2021.
RAS Companion Inhibitors – Revolution Medicines continues to advance and expand multiple clinical studies both as monotherapy and in targeted drug combinations designed to achieve maximum clinical benefit.

RMC-4630 (SHP2 Inhibitor) – RMC-4630 is a potent, oral, selective inhibitor of the SHP2 protein, a central node in the RAS signaling pathway. Its development is being advanced in partnership with, and is primarily funded by, Sanofi.
○ RMC-4630 monotherapy has shown initial clinical anti-tumor activity in multiple cancer genotypes. The company has initiated an expansion cohort at the single agent recommended Phase 2 dose and schedule (RP2DS). The company expects to disclose a safety data set from the dose escalation portion of this trial in the first half of 2021.

○ RMC-4630 in combination with cobimetinib (Cotellic) has shown initial clinical activity in patients with colorectal cancer driven by KRAS mutations. The company has initiated expansion cohorts evaluating patients with KRASMUTANT colorectal cancer at the RP2DS for this combination. The company expects preliminary safety and clinical activity data from this expansion study in 2022.

○ Studies evaluating RMC-4630 in combination with multiple inhibitors continue and are expanding.

▪ Dosing and enrollment continue in the Amgen-sponsored Phase 1 study of RMC-4630 in combination with Amgen’s KRASG12C(OFF) inhibitor, AMG 510, or sotorasib. The company expects a RP2DS will be reached in the first half of 2021 with preliminary activity data in the second half of 2021.

▪ Dosing and enrollment continue in the Sanofi-sponsored Phase 1 study of RMC-4630 in combination with the PD-1 inhibitor, pembrozilumab (Keytruda). The company expects a RP2DS will be reached for this combination in the first half of 2021.

▪ Dosing and enrollment continue in the Phase 1 study of RMC-4630 in combination with the EGFR inhibitor, osimertinib (Tagrisso). The company expects initial tolerability and pharmacokinetic (PK) data from this combination in the second half of 2021.

▪ Announced a clinical collaboration agreement with AstraZeneca to study RMC-4630 in combination with an emerging asset targeting KRASG12C from AstraZeneca’s portfolio.

RMC-5552 (mTORC1/4EBP1 Inhibitor) – RMC-5552 is a potent mTORC1- selective inhibitor.
○ Received FDA clearance and initiation of clinical sites for Phase 1 monotherapy dose-escalation study is underway. The company expects to begin dosing patients with monotherapy in the first half of 2021 with initial safety, PK and single agent activity data expected in 2022.

○ The company intends to evaluate RMC-5552 in combination therapies with RAS inhibitors for patients with cancers harboring RAS/mTOR signaling co-mutations.

RMC-5845 (SOS1 Inhibitor) – RMC-5845 is a potent, selective, oral inhibitor of SOS1, a major switch in the cycling of RAS(OFF) to RAS(ON).
○ The company intends to evaluate RMC-5845 for treatment of certain genetically defined RAS-dependent cancers.

○ Recently advanced into IND-enabling development. The company expects to submit an IND in the second half of 2021.

Corporate Highlights

Completed upsized financing to strengthen balance sheet and support advancement of expanding pipeline – The company completed a public offering of common stock in February 2021, raising net proceeds of $281 million. The company plans to use these proceeds to advance the company’s wholly-owned assets into clinical development.
Sanofi collaboration continues to make progress – The company’s funded collaboration with Sanofi for the clinical development of RMC-4630 continues to advance RMC-4630 as a backbone of combination therapy in RAS-addicted cancers.
Fourth Quarter and Full Year 2020 Financial Highlights

Cash Position: Cash, cash equivalents and marketable securities were $440.7 million as of December 31, 2020, compared to $122.8 million as of December 31, 2019. The increase was primarily due to proceeds from the company’s initial public offering in February 2020 and follow-on equity public offering in July 2020. Proceeds from the recently completed offering are not included in the December 31, 2020 cash, cash equivalents and marketable securities balance.

Revenue: Total revenue, consisting of revenue from the company’s collaboration agreement with Sanofi, was $8.8 million for the quarter ended December 31, 2020, compared to $12.1 million for the quarter ended December 31, 2019. Total revenue was $43.0 million for the year ended December 31, 2020, compared to $50.0 million for the year ended December 31, 2019. The decrease was due to lower reimbursed research and development services for RMC-4630 resulting from lower manufacturing costs. During the quarter and year ended December 31, 2019, the company incurred upfront manufacturing costs related to the supply of RMC-4630 for our clinical trials.

R&D Expenses: Research and development expenses were $37.0 million for the quarter ended December 31, 2020, compared to $27.5 million for the quarter ended December 31, 2019. Research and development expenses were $132.3 million for the year ended December 31, 2020, compared to $91.8 million for the year ended December 31, 2019. The increase was primarily due to an increase in research expenses associated with the company’s pre-clinical research portfolio, an increase in personnel-related expenses related to additional headcount, and an increase in stock-based compensation, partially offset by lower costs related to RMC-4630.

G&A Expenses: General and administrative expenses were $5.8 million for the quarter ended December 31, 2020, compared to $4.2 million for the quarter ended December 31, 2019. General and administrative expenses were $21.4 million for the year ended December 31, 2020, compared to $12.4 million for the year ended December 31, 2019. The increase was primarily due to an increase in expenses associated with operating as a public company, an increase in personnel-related expenses related to additional headcount, and an increase in stock-based compensation.

Net Loss: Net loss was $34.2 million for the quarter ended December 31, 2020, compared to net loss of $14.6 million for the quarter ended December 31, 2019. Net loss was $108.2 million for the year ended December 31, 2020, compared to net loss of $47.7 million for the year ended December 31, 2019.

2021 Financial Guidance

Revolution Medicines expects full year 2021 GAAP net loss to be between $170 million and $190 million, which includes estimated non-cash stock-based compensation expense of $20 million to $25 million.