Amgen Inc. and Revolution Medicines Inc. will collaborate on a clinical trial evaluating the combination of RMC-4630, Revolution's SHP2 inhibitor, and Amgen's AMG-510, a KRAS-G12C inhibitor. Amgen will conduct the phase Ib trial to treat patients with advanced solid tumors harboring the KRAS G12C mutation and Revolution will provide Amgen with RMC-4630.
"We worked closely with Amgen to assure the right biological considerations built in," Revolution's president and CEO, Mark Goldsmith, told BioWorld. "It's more than just a supply agreement."
The phase Ib study is a test to determine if inhibiting the RAS pathway at two nodes simultaneously using RMC-4630 and AMG-510 increases the depth or durability benefits for patients whose tumors have KRAS-G12C.
In June at the American Society of Clinical Oncology meeting in Chicago, Amgen released data from its phase I study evaluating AMG-510 showing there were no dose-limiting toxicities at tested dose levels, and that it showed antitumor activity when administered as a monotherapy in patients with locally advanced or metastatic KRAS-G12C-mutant solid tumors. The phase I, first-in-human, open-label multicenter study enrolled 35 patients, 14 of which had non-small-cell lung cancer and 19 had colorectal cancer.
Combining the two approaches as combination therapy is "compelling," Goldsmith said.
"Amgen is the first group to demonstrate in humans that RAS-selected inhibitors can shrink tumors significantly," Goldsmith said. "Revolution Medicines is the first group to demonstrate in human tumor xenografts that SHP2 inhibition is another means of achieving a similar goal."
RMC-4630 is designed to selectively inhibit SHP2, a cellular protein that helps modulate cell growth by transmitting signals from receptor tyrosine kinases to RAS. AMG-510 is designed to selectively and irreversibly target the KRAS-G12C protein, an oncogenic RAS mutant at the core of RAS signaling.
RMC-4630 and SHP2 are the heart of a global research, development and commercialization agreement Revolution has with Sanofi SA. In return for an exclusive license for global commercialization of any approved products targeting SHP2, the Paris-based pharma agreed to provide Revolution with $50 million up front and up to $500 million in development and regulatory milestone payments and to fund R&D for the joint SHP2 program, which remains, for now, under Revolution's direction. The two companies will equally split the profits and losses in the U.S. Revolution is entitled to tiered royalties on annual net sales ranging from high single-digit to midteen percentages on sales in other markets. It could also receive more than $500 million in development and regulatory milestone payments. (See BioWorld, July 19, 2018.)
"Our development program for RMC-4630 currently includes an ongoing phase I monotherapy trial, an ongoing phase Ib/II study evaluating a combination with cobimetinib, a MEK inhibitor," Goldsmith said.
KRAS used to be the poster child for undruggability. No more. Mirati Therapeutics Inc. is in the clinic with KRAS inhibitors. Boehringer Ingelheim GmbH plans to join them by the end of the year. And multiple other companies are moving programs forward. (See BioWorld, Oct. 30, 2019.)
Revolution recently 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. (See BioWorld, July 10, 2019.)