Revolution Medicines Stock

Revolution Medicines, Inc. operates as a clinical-stage precision oncology company. The company is developing novel targeted therapies for RAS-addicted cancers. The company possesses sophisticated structure-based drug discovery capabilities built upon deep chemical biology and cancer pharmacology know-how and innovative, proprietary technologies that enable the creation of small molecules tailored to unconventional binding sites. Guided by its understanding of genetic drivers and adaptive resistance mechanisms in cancer, the company deploys precision medicine approaches to inform innovative monotherapy and combination regimens.

The company's research and development pipeline comprises RAS(ON) inhibitors that bind directly to RAS variants, which it refers to as RAS(ON) Inhibitors, and RAS companion inhibitors that target key nodes in the RAS pathway or associated pathways, which it refers to as RAS Companion Inhibitors. The company's RAS(ON) Inhibitors are designed to be used as monotherapy, in combination with other RAS(ON) Inhibitors and/or in combination with RAS Companion Inhibitors or other therapeutic agents. The company's RAS Companion Inhibitors are designed primarily for combination treatment strategies centered on its RAS(ON) Inhibitors.

RAS(ON) Inhibitors

The company's RAS(ON) Inhibitors are based on its proprietary tri-complex technology platform, which enables a highly differentiated approach to inhibiting the active, GTP-bound form of RAS, which it refers to as RAS(ON). The company is developing a portfolio of compounds that is the first and only RAS(ON) Inhibitors to use this mechanism of action. The company is evaluating its RAS(ON) Inhibitors alone and in combination with other drugs and investigational drug candidates, including with other RAS(ON) Inhibitors in RAS(ON) Inhibitor doublet regimens.

The company is advancing a deep pipeline of RAS(ON) Inhibitors, including both its innovative RAS(ON) multi-selective inhibitor (RMC-6236) and a series of mutant-selective inhibitors (led by RMC-6291 and RMC-9805). Together, the company considers these three development-stage candidates as the first wave of RAS(ON) inhibitors that it is advancing through clinical development.

RMC-6236

RMC-6236, the company's RAS(ON) multi-selective inhibitor, is designed as an oral, RAS-selective tri-complex inhibitor of multiple RAS(ON) variants containing cancer driver mutations at all three of the major mutation hotspot positions, G12, G13, and Q61. RMC-6236 inhibits all three major RAS isoforms, suppressing the mutant cancer driver and cooperating wild-type RAS proteins.

A monotherapy dose-escalation Phase 1/1b study of RMC-6236, which the company refers to as the RMC-6236-001 study, is ongoing. On October 13, 2023, the company reported updated interim safety, pharmacokinetic (PK) and circulating tumor DNA (ctDNA) data from the RMC-6236-001 study as of a September 11, 2023 data cut-off date.

On October 22, 2023, the company reported updated interim safety and anti-tumor activity data for dose levels of 80 mg daily and above from the RMC-6236-001 study as of an October 12, 2023 data cut-off date. These data demonstrated that RMC-6236 was generally well tolerated across the dose levels analyzed as of the cut-off date. These data also demonstrated preliminary evidence of clinical activity in non-small cell lung cancer (NSCLC) patients and pancreatic ductal adenocarcinoma (PDAC) patients.

On January 9, 2024, the company reported that, with additional follow-up after the October 2023 data reports, the profile of RMC-6236 remained relatively consistent with the description in the October 2023 reports, the objective response rate (ORR) for both NSCLC and PDAC patients had improved and the disease control rate (DCR) remained consistent.

The company expects to disclose updated clinical safety, tolerability and activity data from the RMC-6236-001 study for patients with NSCLC and for patients with PDAC in the second half of 2024. The company expects to disclose initial data from Phase 1 expansion cohorts in the RMC-6236-001 study in tumor types beyond NSCLC and PDAC and genotypes beyond KRAS G12X in the second or third quarter of 2024.

The company is also evaluating RMC-6236 in a series of combination regimens. The company is conducting an open-label Phase 1b/2 platform study evaluating its RAS(ON) Inhibitors in combination with standard(s) of care in advanced NSCLC patients, which it refers to as the RMC-LUNG-101 study. There are two ongoing subprotocols under the RMC-LUNG-101 study, one evaluating the company's RAS(ON) G12C inhibitor, RMC-6291, which it refers to as the RMC-LUNG-101A study, and one evaluating RMC-6236, which it refers to as the RMC-LUNG-101B study. RMC-LUNG-101B is a Phase 1b/2 dose exploration and dose expansion study evaluating RMC-6236 in combination with pembrolizumab, with or without chemotherapy, in patients with RAS-mutated NSCLC. The company expects to disclose initial clinical PK, safety, tolerability and activity data from the RMC-LUNG-101B study in the second half of 2024.

The company is also conducting an open-label Phase 1b clinical trial of RMC-6291 in combination with RMC-6236, which it refers to as the RMC-6291-101 study. This study is ongoing, and the company expects to disclose initial clinical PK, safety, tolerability and activity data in the second half of 2024.

Planning is also underway for one or more combination clinical trials for RMC-6236 with standard of care therapies in first-line treatment settings.

The company is planning a global randomized Phase 3 trial comparing RMC-6236 against docetaxel in patients with RAS-mutated NSCLC who have been treated with immunotherapy and platinum-containing chemotherapy. The study design for this planned trial is subject to change based on regulatory authority feedback. The company expects to initiate this study in the second half of 2024.

The company is also planning a global randomized Phase 3 trial comparing RMC-6236 against a physician's choice of chemotherapy regimens in patients with previously treated RAS-mutated PDAC. The study design for this planned trial is subject to change based on regulatory authority feedback. The company expects to initiate this study in the second half of 2024.

RMC-6291

RMC-6291 is designed as a RAS(ON) oral tri-complex G12C-selective inhibitor. It is designed to exhibit subnanomolar potency for suppressing RAS pathway signaling and growth of RAS G12C-bearing cancer cells and is engineered to be highly selective for RAS G12C over wild-type RAS and other cellular targets. RMC-6291 is designed to be differentiated from first-generation KRAS(OFF) G12C inhibitors, which sequester the KRAS(OFF) G12C form, by its mechanism of directly inhibiting the RAS(ON) G12C form.

A monotherapy dose-escalation Phase 1b study of RMC-6291, which the company refers to as the RMC-6291-001 study, is ongoing.

On October 13, 2023, the company reported interim preliminary safety and anti-tumor data from the RMC-6291-001 study as of an October 5, 2023 data cut-off date. The company observed that RMC-6291 was orally bioavailable and demonstrated dose-dependent pharmacokinetics and that reduction in ctDNA of the KRAS G12C allele across doses was correlated with clinical response.

On January 9, 2024, the company reported that relative to the October 13, 2023 report, the profile of RMC-6291 in the RMC-6291-001 study had remained relatively stable. The company continues dosing patients at a 200 mg twice daily (BID) dose in this study.

The company is evaluating RMC-6291 in the RMC-LUNG-101A study, which is a Phase 1b/2 dose exploration and dose expansion study evaluating RMC-6291 in combination with pembrolizumab, with or without chemotherapy, in patients with RAS-mutated NSCLC. The company expects to disclose initial clinical PK, safety, tolerability and activity data from the RMC-LUNG-101A study in the second half of 2024.

In the RMC-6236 section, the company is conducting an open-label Phase 1/1b clinical trial of RMC-6291 in combination with RMC-6236, which it refers to as the RMC-6291-101 study.

RMC-9805

RMC-9805 is designed as a RAS(ON) oral tri-complex G12D-selective inhibitor. It is designed to exhibit low nanomolar potency for suppressing RAS pathway signaling and growth of RAS G12D-bearing cancer cells and is engineered to covalently inactivate RAS G12D irreversibly.

A monotherapy dose-escalation Phase 1/1b trial of RMC-9805, which the company refers to as the RMC-9805-001 study, is ongoing.

On January 9, 2024, the company reported that, based on its observations of interim data from the RMC-9805-001 study, RMC-9805 demonstrated oral bioavailability in patients, exhibiting pharmacokinetics consistent with expectations from preclinical data. The company also reported that the compound had cleared several dose levels and that it observed favorable tolerability results with no dose-limiting toxicities reported, and that a recommended Phase 2 dose and schedule was not yet reached.

The company expects to disclose initial clinical PK, safety, tolerability and activity data from the RMC-9805-001 study in the second half of 2024.

Additional RAS(ON) Inhibitors

Beyond this first wave of RAS(ON) Inhibitors, the company has other RAS(ON) Inhibitor compounds in its research and development pipeline, including the development candidates RMC-5127 (G12V), RMC-0708 (Q61H) and RMC-8839 (G13C). The company is also pursuing pipeline expansion programs focused on G12R and other targets.

RAS Companion Inhibitors

RMC-4630

The company's RAS Companion Inhibitor RMC-4630 is designed as a potent and selective inhibitor of SHP2.

Amgen is evaluating RMC-4630 in a Phase 1b study in combination with Amgen's KRAS(OFF) G12C agent sotorasib (LUMAKRAS) in Amgen's CodeBreaK 101c study.

The company and Sanofi, its former SHP2 development partner, sponsored several additional studies involving RMC-4630, all of which are being wound down.

The combination of RMC-4630 with an ERK inhibitor in patients with pancreatic cancer is being evaluated as part of an investigator-sponsored study by the Netherlands Cancer Institute.

RMC-5552

The company's RAS Companion Inhibitor RMC-5552 is designed as a selective inhibitor of mTORC1 signaling in tumors. The company is evaluating RMC-5552 as a monotherapy in a Phase 1 study, which it refers to as the RMC-5552-001 study, and it may evaluate RMC-5552 in combination with RAS(ON) Inhibitors for patients with cancers harboring a RAS mutation and co-occurring mutations in the mTOR signaling pathway.

The company reported additional interim data from the ongoing dose-escalation portion of the RMC-5552-001 study in October 2023. The company is supplying RMC-5552 to the Regents of the University of California on behalf of its San Francisco campus (UCSF) for an investigator-initiated Phase 1/1b trial by UCSF of RMC-5552 in patients with recurrent glioblastoma.

RMC-5845

The company's RAS Companion Inhibitor RMC-5845 targets SOS1, a protein that plays a key role in converting RAS(OFF) to RAS(ON) in cells. RMC-5845 is intended for select combination therapies for certain genetically defined tumors. This compound is ready for preparation of an IND application based on its preclinical development.

Strategy

The company's RAS(ON) Inhibitors are unique in that they are the first RAS inhibitors in clinical development to specifically target the activated, or ON, form of oncogenic RAS proteins. This differentiated mechanism of action offers potential improvements over that of the first RAS inhibitors to gain U.S. Food and Drug Administration (FDA) approval (KRAS G12C inhibitors sotorasib and adagrasib), which interact exclusively with the OFF form and confer relatively short clinical benefit. The company's pipeline of RAS(ON) multi-selective and RAS(ON) mutant-selective inhibitors offer an opportunity for RAS(ON) doublet combinations designed to potentially maximize durable clinical benefit.

The company's corporate priorities are to:

Propel RMC-6236 into Phase 3 Pivotal Studies: The company is planning two monotherapy registration studies - one in second line NSCLC and one in second line PDAC, subject to regulatory input and further analysis of data from the RMC-6236-001 study.

Expand the Reach of RMC-6236 Potentially into Additional Lines of Therapy, Tumor Types and Mutations: The company is evaluating a broader potential reach of RMC-6236 monotherapy in patients with tumor types beyond NSCLC and PDAC, and genotypes beyond KRAS G12X. In parallel, the company is evaluating RMC-6236 in a series of combination regimens, including combination with a checkpoint inhibitor and combination with RMC-6291 in the context of a RAS(ON) Inhibitor doublet, and planning is underway for one or more combination clinical trials for RMC-6236 with standard of care therapies.

Qualify Mutant-Selective Inhibitors led by RMC-6291 and RMC-9805 for Late-Stage Development: The company is continuing to evaluate the monotherapy profile of RMC-6291, focusing on dose optimization towards identification of a recommended Phase 2 dose. The company is evaluating the combination of RMC-6291 with RMC-6236, as well as the combination of RMC-6291 with a checkpoint inhibitor. The company is also continuing to evaluate RMC-9805 clinically, focusing initially on the ongoing dose escalation.

innovation Engine

The company has built an innovation engine that enables it to discover and develop novel targeted therapies for elusive high-value frontier cancer targets with particular focus on a cohesive set of disease targets within notorious growth and survival pathways.

Tri-Complex Platform

The company's proprietary tri-complex technology enables it to discover small molecule inhibitors of targets lacking intrinsic drug binding sites by inducing new druggable pockets. This occurs through small molecule-driven formation of a high affinity ternary complex (tri-complex) between the target protein, the small molecule, and a widely expressed cytosolic protein called a chaperone (e.g., cyclophilin A or FKPB12). This platform technology is the foundation of the company's RAS(ON) Inhibitor programs. In this context, the inhibitory effect of tri-complex formation on the RAS(ON) target is mediated by steric occlusion of the site where RAS(ON) binds its downstream effector molecules, such as RAF, which are required for propagating the oncogenic signal. Thus, tri-complex formation with RAS(ON) targets disrupts RAS effector binding and terminates oncogenic signaling. The company's RAS(ON) tri-complex inhibitors, which are inspired by natural products, are Beyond Rule of 5 compounds.

Pipeline

The company's RAS(ON) Inhibitors are based on its proprietary tri-complex technology platform, which enables a highly differentiated approach to inhibiting the active, GTP-bound form of RAS (RAS(ON)). The company is developing a portfolio of compounds that is the first and only RAS(ON) Inhibitors to use this mechanism of action. The company's portfolio of RAS(ON) Inhibitors includes three compounds that it considers as the first wave of RAS(ON) Inhibitors that it is advancing: RMC-6236 (multi), RMC-6291 (G12C) and RMC-9805 (G12D). Beyond this first wave of RAS(ON) Inhibitors, the company has other RAS(ON) Inhibitor compounds in its research and development pipeline, including its development candidates RMC-5127 (G12V), RMC-0708 (Q61H) and RMC-8839 (G13C).

The company is evaluating its RAS(ON) Inhibitors alone and in combination with other drugs and investigational drug candidates, particularly in-pathway agents. RMC-6236, the company's RAS (ON) multi-selective inhibitor, is designed as a potent, oral, RAS-selective tri-complex inhibitor of multiple RAS(ON) variants including cancer drivers at all three of the major mutation hotspot positions, G12, G13, and Q61. RMC-6236 inhibits all three major RAS isoforms, suppressing the mutant cancer driver and cooperating wild-type RAS proteins.

RMC-6236 is being evaluated in an ongoing monotherapy dose-escalation Phase 1/1b clinical study in patients with KRAS G12-mutated tumors, focused on NSCLC, PDAC and CRC, which the company refers to as the RMC-6236-001 study.

On October 13, 2023, the company reported updated interim safety, PK and ctDNA data from the RMC- 6236-001 study. In this study, 131 patients treated across nine dose cohorts ranging from 10 mg daily to 400 mg daily were evaluable for safety and tolerability as of a data cut-off date of September 11, 2023.

RMC-6291 is designed as a RAS(ON) oral G12C-selective inhibitor. It is designed to exhibit subnanomolar potency for suppressing RAS pathway signaling and growth of RAS G12C-bearing cancer cells and is engineered to be highly selective for RAS G12C over wild-type RAS and other cellular targets. RMC-6291 is designed to be differentiated from first-generation KRAS(OFF) G12C inhibitors, which sequester the KRAS(OFF) G12C form, by its potential mechanism of directly inhibiting the RAS(ON) G12C form.

In October 13, 2023, the company reported interim preliminary safety and anti-tumor data from the RMC-6291-001 study. In this study, 63 patients treated across seven dose cohorts ranging from 50 mg daily to 400 mg twice daily were evaluable for initial safety and tolerability as of a data cut-off date of October 5, 2023.

On January 9, 2024, the company reported that, relative to the October 13, 2023 report, the profile of RMC-6291 in the RMC-6291-001 study remained relatively stable. The company continues to dose patients at a 200 mg BID.

RMC-9805 is designed as a RAS(ON) oral G12D-selective inhibitor. It is designed to exhibit low nanomolar potency for suppressing RAS pathway signaling and growth of RAS G12D-bearing cancer cells and is engineered to covalently inactivate RAS G12D for irreversible inhibition. To its knowledge, RMC-9805 is the first drug candidate that covalently modified an aspartic acid residue in preclinical studies.

On January 9, 2024, the company reported that, based on its observations of data from the RMC-9805-001 study, RMC-9805 demonstrated oral bioavailability in patients, exhibiting PK consistent with expectations from preclinical data. The company also reported that the compound has cleared several dose levels and that it observed favorable tolerability results with no dose-limiting toxicities reported and that a recommended Phase 2 dose and schedule was not yet reached.

RMC-5127 is designed as a RAS(ON) oral G12V-selective inhibitor. It is designed to exhibit picomolar potency for suppressing RAS pathway signaling and growth of RAS G12V-bearing cancer cells and is engineered for selective inhibition of RAS G12V over other RAS isoforms via non-covalent binding interactions. RMC-5127 is in the Investigational New Drug application (IND)-enabling stage of preclinical development.

RMC-0708 is designed as a RAS(ON) oral Q61H-selective inhibitor. It is designed to exhibit picomolar potency for suppressing RAS pathway signaling and growth of RAS Q61H-bearing cancer cells and is engineered for selective inhibition of RAS Q61H over other RAS isoforms via non-covalent binding interactions.

RMC-0708 is designed as a RAS(ON) oral Q61H-selective inhibitor. It is designed to exhibit picomolar potency for suppressing RAS pathway signaling and growth of RAS Q61H-bearing cancer cells and is engineered for selective inhibition of RAS Q61H over other RAS isoforms via non-covalent binding interactions.

The company's RAS Companion Inhibitors are designed to suppress cooperating targets and pathways that sustain RAS-addicted cancers.

The company's RAS Companion Inhibitor RMC-4630 is designed as a potent and selective inhibitor of SHP2, a central node in the RAS signaling pathway.

Amgen is evaluating RMC-4630 in a Phase 1b study in combination with Amgen's KRAS(OFF) G12C agent sotorasib (LUMAKRAS) in Amgen's CodeBreaK 101c study.

The company and Sanofi, its former SHP2 development partner, sponsored several additional studies involving RMC-4630, all of which are being wound down.

The combination of RMC-4630 with an ERK inhibitor in patients with pancreatic cancer is being evaluated as part of an investigator-sponsored study by the Netherlands Cancer Institute.

The company's RAS Companion Inhibitor RMC-5552 is designed as a selective inhibitor of hyperactivated mTORC1 signaling in tumors. The company is evaluating RMC-5552 as a monotherapy in a Phase 1 study, which it refers to as the RMC-5552-001 study, and it may evaluate RMC-5552 in combination with RAS inhibitors for patients with cancers harboring a RAS mutation and co-occurring mutations in the mTOR signaling pathway.

mTORC1 is a critical regulator of metabolism, growth and proliferation within cells, including cancer cells. The abnormal activation of mTORC1, and subsequent inactivation of the tumor suppressor 4EBP1, is a mechanism that is frequently harnessed by cancer cells to gain a growth and proliferation advantage over normal cells. RMC-5552 is designed to selectively and deeply inhibit mTORC1, thereby preventing phosphorylation and inactivation of 4EBP1, a downstream protein in the mTOR signaling pathway that normally suppresses expression of certain oncogenes such as C-MYC. RMC-5552 has been shown to have combinatorial activity with KRAS G12C inhibitors in preclinical models of KRAS G12C lung and colon cancer, supporting the role of RMC-5552 in the company's portfolio of RAS Companion Inhibitors.

The company reported additional interim data from the ongoing dose-escalation portion of the RMC-5552-001 study in October 2023 as of a September 4, 2023 data cut-off date.

The company is supplying RMC-5552 to the Regents of the University of California on behalf of its San Francisco campus (UCSF) for an investigator-initiated Phase 1/1b trial by UCSF of RMC-5552 in patients with recurrent glioblastoma.

RMC-5845 targets SOS1, a protein that plays a key role in converting RAS(OFF) to RAS(ON) in cells. RMC-5845 is intended for select combination therapies for certain genetically defined tumors. This compound is ready for preparation of an IND based on the company's preclinical development.

Commercial Plan

The company intends to retain significant development and commercialization rights to its product candidates and if marketing approval is obtained, to commercialize its product candidates on its own, or potentially with a partner, in the United States and other regions. The company has limited sales, marketing and commercial product distribution capabilities. The company intends to build the necessary infrastructure and capabilities over time for the United States, and potentially other regions, in connection with the advancement of its product candidates. Clinical data, the size of the addressable patient population, the size of the commercial infrastructure and manufacturing needs, the status of its pipeline and other factors, may all influence or alter its commercialization plans.

Intellectual Property

Program-Specific Patent Portfolio

The company's patent portfolio is directed to small molecules, platform methodologies and related technology. The company seeks patent protection for product candidates, development programs and related alternatives by filing and prosecuting patent applications in the United States and other countries, as appropriate.

The company owns and, in some cases, co-owns and exclusively licenses, patents and patent applications related to its RAS tri-complex inhibitors and related platform technology. The company's patent portfolio related to this program consists of ownership rights to several patent families that include filings covering compositions of matter or methods of using its development candidates alone or in combination with certain other therapeutic agents, or aspects pertaining to its tri-complex approach to RAS inhibition. The issued patents, and any patents issuing from these patent applications are expected to expire between 2031 (for patents originating from the Warp Drive Bio portfolio) and 2043 (for patents originating from Revolution Medicines' portfolio that did not originate from Warp Drive Bio), without accounting for potentially available patent term adjustments or extensions.

The company owns and co-owns patents and patent applications related to its SHP2 development program. The company's patent portfolio related to this program consists of several owned or co-owned patent families that include filings relating to compositions of matter or methods of using its development candidate, RMC-4630, alone or in combination with certain other therapeutic agents. The issued patents, and any patents issuing from these patent applications, are expected to expire between 2037 and 2043, without accounting for potentially available patent term adjustments or extensions.

The company owns or exclusively licenses from the Regents of the University of California on behalf of its San Francisco campus (UCSF) patents and patent applications related to its mTORC1 development program. The company's patent portfolio related to this program consists of several patent families that include filings covering compositions of matter or methods of using its development candidate, RMC-5552, alone or in combination with certain other therapeutic agents. The issued patents, and any patents issuing from these patent applications, are expected to expire between 2035 and 2043, without accounting for potentially available patent term adjustments or extensions.

The company also owns patent applications related to its SOS1 development program. The company's patent portfolio related to this program consists of ownership of several patent families that include filings relating to compositions of matter or methods of using its development candidate, RMC-5845, alone or in combination with certain other therapeutic agents. The issued patents, and any patents issuing from these patent applications, are expected to expire between 2040 and 2043, without accounting for potentially available patent term adjustments or extensions.

Government Regulation

The U.S. Food and Drug Administration (FDA) and other regulatory authorities at federal, state, and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, marketing and promotion, distribution, post-approval monitoring and reporting, sampling, and import and export of products, such as those the company is developing. Manufacturers also must comply with the FDA's advertising and promotion requirements, such as those related to direct-to-consumer advertising, the prohibition on promoting products for off-label use, industry-sponsored scientific and educational activities and promotional activities involving the internet.

History

Revolution Medicines, Inc. was founded in 2014. The company was incorporated in 2014 as a Delaware corporation.