Cancer research has revealed proteins known to play a role in the disease, but with no known way of stopping what they do. In pharmaceutical parlance, they’re “undruggable.”
Revolution Medicines is trying to drug the undruggable with small molecules that block the signaling pathways these proteins use to help cancer grow and thrive. With one of its experimental therapies now in early-stage testing under a partnership with a large pharmaceutical company and more compounds in the pipeline, the Redwood City, CA, biotech is preparing to go public to finance its research.
In documents filed with securities regulators late Friday, Revolution set a preliminary $100 million target for its IPO. The company has applied for a Nasdaq listing under the stock symbol “RVMD.”
Revolution is developing drugs for what it calls “frontier targets,” proteins that support cancer but have no drug that blocks them. In cases where there is an FDA-approved drug, the therapy doesn’t fully suppress what the protein does to help cancers grow. Revolution is developing drugs to specifically target RAS and mTOR, two signaling pathways that play a role in helping tumors.
RAS proteins act like molecular switches that control the signaling systems regulating cellular growth. In normal cells, these proteins receive and obey the signals that switch them from the active state to the inactive state. But when RAS gets stuck in the active state, these proteins drive cells to become cancerous.
In order for a drug to block a protein, it needs to bind to a site somewhere on the molecule. RAS proteins pose the challenge of lacking druggable binding pockets for a drug, Revolution says in its filing. The company’s technology addresses that problem by using a second protein, which it calls a chaperone, to form a pocket. That druggable pocket is where Revolution’s small molecule drugs are intended to bind to a RAS protein.
Revolution says it is developing small molecule drugs that target multiple types of the active form of the RAS protein, which it calls RAS(ON). It expects to nominate its first RAS(ON) drug candidate this year, according to the filing. The company adds that it believes its approach could treat diverse RAS mutations encompassing colorectal, pancreatic, and non-small cell lung cancer, among others.
Revolution’s most advanced drug, RMC-4630, blocks SHP2, a protein in the RAS signaling pathway. The drug is currently in Phase 1/2 testing with partner Sanofi (NYSE: SNY), and in the IPO filing, Revolution reports preliminary data from that study. As of Nov. 6, 2019, 63 of the 66 patients enrolled in the study had received the drug. In addition to dosing data, Revolution reported early signs that RMC-4630 shows anti-tumor activity against non-small cell lung cancer that has the KRAS mutation, one of the RAS(ON) targets of the company. In one patient, the volume of tumors was reduced by 45 percent.
Sanofi is reimbursing Revolution for most of the research costs of RMC-4630. Through the end of the third quarter of 2019, Sanofi had paid Revolution $83.5 million, which includes the upfront payment to start the alliance plus R&D expenses, according to the filing. The California biotech says it will use the IPO proceeds to fund development of other RAS drugs, bringing them through the preclinical work needed to support an application to start tests of “one or more” of them in humans. The company will also use the new cash to develop RMC-5552, a preclinical compound that addresses the mTOR pathway.
Revolution launched from venture capital firm Third Rock Ventures five years ago. At that time, the startup’s focus was developing new medicines from natural products—compounds found in nature that have therapeutic properties. Revolution’s lead program was an antifungal drug.
As the company continued to work with the natural products technology it licensed from the University of Illinois at Urbana-Champaign, Revolution also made progress in cancer applications, CEO Mark Goldsmith told Xconomy in 2018. Revolution raised additional financing to continue that research and eventually returned the antifungal compound to the Illinois scientist who discovered it. In Revolution’s IPO filing, the biotech says its RAS(ON) drugs and mTORC1 inhibitors are “inspired by natural products.”
Revolution’s research is bolstered by assets from Warp Drive Bio, a biotech that it acquired in 2018. Warp Drive was also developing RAS drugs. At the time of the acquisition, executives declined to offer financial details about the all-stock deal. But Revolution’s IPO filing reveals that it offered shares valued at $69 million.
That Warp Drive deal also turned Sanofi into a Revolution shareholder. As one of Warp Drive’s shareholders, the French pharmaceutical giant was issued shares in Revolution as part of the acquisition. According to the IPO filing, Sanofi’s stake in Revolution is 7.8 percent.
Revolution has raised more than $211 million, most recently a $100.2 million Series C financing last summer. The filing shows that Third Rock Ventures is the company’s largest shareholder, owning a 28.8 percent stake, followed by The Column Group at 18.6 percent.