Revolution Medicines Inc., a California-based company developing a small-molecule inhibitor of SHP2 in partnership with Sanofi SA and other programs targeting mutant forms of the key signaling protein RAS, has raised a $100 million series C equity financing led by Boxer Capital LLC, an investment firm funded by British businessman Joe Lewis' Tavistock Group, which has backed financings of companies including G1 Therapeutics Inc., Kura Oncology Inc. and, more recently, Encoded Therapeutics Inc.

Cormorant Capital, Deerfield Management, Fidelity Management & Research Co., Vivo Capital and Biotechnology Value Fund, as well as investors in the company's $56 million series B, also joined the syndicate.

The Redwood City, Calif.-based company said proceeds from the round will support continued advancement of its pipeline, which includes programs addressing targets within the RAS pathway such as KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C, and other specific tumor-causing RAS mutants.

Inhibiting mutant forms of RAS has long been seen as a promising strategy for reducing either the size of human tumors or maybe even ultimately eliminating them entirely, Revolution CEO and President Mark Goldsmith told BioWorld. Scientific interest in the pathway has led to a rich field of experimental therapies targeting its function along with the arrival of positive clinical data on Amgen Inc.'s KRAS G12C-targeting AMG-510 and Mirati Therapeutics Inc.'s MRTX-849 validating the theory that mutant forms can potential ameliorate multiple cancer types, including lung, colorectal, endometrial and pancreatic cancers. (See BioWorld, April 23, 2019, and May 17, 2019.)

But while recent clinical successes have focused on binding to the inactive form of RAS, those not actively signaling, the active form of the protein that is responsible for driving cancer signaling takes on a different conformation. It occurs when RAS binds a small cellular molecule called GTP. So far, "nobody has been able to discover a potent high-affinity binder that can potently inhibit the GTP-bound form of RAS" except for Warp Drive Bio, a company Revolution acquired in late 2018, Goldsmith explained.

As it has driven to complete an integration of Warp Drive's tri-complex drug discovery platform with its own in-house technology, a goal its team has now reached, Revolution has been able to "enable discovery of small molecules that potently and selectively inhibit the active form of mutant RAS proteins," Goldsmith said. The company's KRAS G12C program is currently advancing through lead optimization.

Meanwhile, Revolution is continuing to push ahead with work on its Sanofi-partnered lead clinical candidate, RMC-4630, an orally bioavailable small molecule that selectively inhibits SHP2. That protein, which sits at the top of the signaling cascade that the RAS system is a core part of, plays a central role in modulating cell growth signaling activity. (See BioWorld, July 19, 2018.)

A phase I dose-escalation study of RMC-4630 is continuing to enroll and dose patients. The company is also planning to pursue a combination phase Ib/II trial of the candidate, further news of which may emerge shortly, Goldsmith said.

A third of all human cancers are thought to be caused by mutant forms of RAS. But with as many as several dozen different mutated forms thought to be at fault, it seems clear that no one therapy may be the ultimate answer to quelling the destructive proliferation of RAS-addicted tumor cells.

Decades of research as well as Revolution's own research suggest that combining two or more agents capable of impacting the RAS pathway, but at different points, can be effective at either avoiding or delaying or even overcoming resistance, Goldsmith said.

With funding from the equity raise, the company's team is working to build a deep pipeline of inhibitors against various mutant forms of RAS. "Systematic coverage of the RAS signaling cascade, starting with SHP2 at the top and then working our way down through various mutant forms of RAS, gives us a really comprehensive portfolio of potential drug candidates," he said.

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