Revolution Medicines outraised its $100 million IPO goal, banking $238 million to advance a suite of cancer programs targeting RAS, a family of proteins that’s been notoriously hard to drug.
Amgen made waves at last year’s American Society of Clinical Oncology meeting by presenting the first clinical data from a KRAS inhibitor—data that the industry had been waiting decades for. And the excitement around the family of targets has carried into 2020—in 2020, Merck promised up to $2.5 billion in a backloaded deal to gain access to small-molecule inhibitors against several drug targets, including the KRAS oncogene, from Taiho and Astex.
In a Securities and Exchange Commission filing, Revolution highlighted its programs targeting RAS(ON), the active, GTP-bound form of RAS, as a top use of IPO proceeds. The company is working on drugs aimed at four mutant RAS(ON) targets, including NRAS-G12C and KRAS-G12C. AMG, the Amgen program that showed KRAS can be drugged, inhibits KRAS-G12C(OFF), the inactive GDP-bound form of KRAS.
The funding will also bankroll a treatment that inhibits SOS1, a protein that spurs the conversion of RAS from the inactive form to the active form, RAS(OFF) to RAS(ON), as well as one that blocks mTOR Complex 1 (mTORC1) to restore the activity of the tumor suppressor 4EBP1.
The company’s lead asset is the Sanofi-partnered RMC-4630, which blocks SHP2, a protein that regulates cell growth by transmitting signals from receptor tyrosine kinases to RAS. The duo teamed up on the program in July 2018, with the Big Pharma handing over $50 million upfront and covering R&D costs for the program. The treatment is in a phase 1 study for a range of tumor types, as well as a phase 1b/2 study testing it in combination with Exelixis and Genentech’s MEK inhibitor Cotellic in patients with relapsed/refractory solid tumors displaying specific genomic mutations.
Revolution isn’t the only company challenging the front-runners in the KRAS race. Boehringer Ingelheim is testing a pan-KRAS inhibitor both on its own and in combination with Novartis’ MEK inhibitor Mekinist (trametinib) in a phase 1 study. Unlike Amgen and Mirati’s candidates, which only drug KRAS-G12C mutations, Revolution's is designed to hit G12 mutations beyond G12C, as well as G13 mutations.