Revolution Medicines Inc. (NASDAQ:RVMD) shares closed at $28.90, a 70% jump above the $17 price in its upsized IPO of 14 million shares, which raised $238 million, showing further confidence in the Redwood City, Calif.-based company’s bid to blast cancer targets once deemed “undruggable.”

With an emphasis in oncology, Revolution is pursuing the RAS and mTOR signaling pathways. The company’s lead candidate, RMC-4630, is described as a potent and selective inhibitor of SHP2, a central node in the RAS pathway. With Paris-based Sanofi SA, the firm is evaluating RMC-4630 in a multicohort phase I/II program. That setup consists of two active studies: RMC-4630-01, a phase I experiment with RMC-4630 as a single agent, and RMC-4630-02, a phase Ib/II effort testing the compound when used in tandem with the MEK inhibitor Cotellic (cobimetinib, Roche Holding AG), approved in November 2015 for advanced melanoma.

In the IPO prospectus, Revolution reported preliminary data from 63 patients who had enrolled in the phase I study and received RMC-4630 as a monotherapy as of Nov. 6, 2019, and from eight patients who had enrolled in the phase Ib/II combo and received the drug as of Nov. 14, 2019. “The emerging safety profile is consistent with the mechanistic effects of the product candidate on SHP2 and hence the RAS signaling cascade, including edema, reduced red cell production, reduced platelet production, hypertension and fatigue,” the company said. “This safety profile was largely predictable from preclinical studies and clinical studies of other well-known inhibitors of this pathway.” The RMC-4630-01 phase I study is continuing to enroll patients to determine the maximum tolerated dose and recommended phase II dose for the intermittent dosing schedule. Alternative intermittent schedules may be explored, Revolution said. Dose escalation goes on in the study with Cotellic.

Leveraging what Revolution calls its “tri-complex technology platform,” the firm is also developing a portfolio of mutant-selective RAS inhibitors that the company believes are “the first potent, selective, cell-active inhibitors of the active, GTP-bound form of RAS, or RAS(on),” according to SEC paperwork. “These inhibitors also have exhibited antitumor activity in vivo in preclinical models.” The company is prioritizing four mutant RAS(on) targets and expects to nominate the first development prospect this year. “Our pipeline also includes inhibitors of other key nodes within the RAS and mTOR signaling pathways, such as SOS1 and mTORC1,” Revolution said, noting that most of its pipeline remains at the preclinical stage.

“To our knowledge, every targeted therapy approved or in clinical development for the treatment of RAS-dependent cancers acts on targets that lie either upstream or downstream of RAS(on) within the cellular signaling cascade,” the IPO filing said. “Historically, direct inhibition of any RAS protein has been challenging due to a lack of tractable, or ‘druggable,’ binding pockets. However, selective inhibitors of the inactive GDP-bound, or “off” form, of KRAS-G12C are being developed by several companies.”

Competition abounds. Programs taking aim at SHP2 are hosted by such firms as Basel, Switzerland-based Novartis AG and Jacobio Pharmaceuticals Co. Ltd., of Beijing. Several pathway mutations bids, including those directed at KRAS-G12C(off) and KRAS-G12D(off) mutations, are being conducted by Amgen Inc., Mirati Therapeutics Inc., Johnson & Johnson, Astrazeneca plc and Eli Lilly and Co. Mutant RAS is also known to be of interest to Merck & Co. Inc. with Moderna Therapeutics Inc., as well as Boehringer Ingelheim GmbH and Gilead Sciences Inc. In November, Revolution signed a clinical trial collaboration agreement with Amgen, of Thousand Oaks, Calif., to test the pairing of RMC-4630 with Amgen’s KRAS-G12C inhibitor, AMG-510. Amgen is funding the study.

Oncogenic mutations in RAS genes (KRAS, NRAS and HRAS) are found in about 30% of human cancers, with the highest incidence in pancreatic (about 98%), colorectal (52%) and lung (32%) adenocarcinomas. RAS proteins are small guanosine triphosphatases that act as molecular switches on the cytosolic side of the plasma membrane. The zone regularly generates more research. A paper published last month in Cancer Research detailed how South San Francisco-based Calithera Biosciences Inc.’s CB-839, a glutaminase inhibitor also known as telaglenastat, makes KRAS-mutant pancreatic tumors susceptible to gemcitabine. Calithera has a collaboration with New York-based Pfizer Inc. to test the latter’s CDK4/6 inhibitor, Ibrance (palbociclib), and the dual-mechanism PARP inhibitor Talzenna (talazoparib), in combination with telaglenastat. Ibrance was first approved in February 2015 for postmenopausal women with advanced breast cancer. Talzenna won U.S. regulators’ go-ahead in October 2018 for patients with deleterious or suspected deleterious germline BRCA-mutated, HER2‑negative locally advanced or metastatic breast cancer.

At the recent American Society of Clinical Oncology Gastrointestinal Cancers Symposium in San Francisco, Forty Seven Inc., of Menlo Park, Calif., provided updated phase Ib/II results in colorectal cancer (CRC) with its CD47-targeting monoclonal antibody, magrolimab, plus Erbitux (cetuximab, Eli Lilly and Co.). The combination therapy was tested in 74 efficacy-evaluable patients but yielded only two partial responses, both in KRAS wild-type patients. “The trial enrolled patients with relatively low EGFR expression, which may have contributed to lackluster efficacy,” Oppenheimer analyst Mark Breidenbach wrote in a report. “Regardless, with no objective responses in KRAS-mutant patients, we see no clear registrational path forward in CRC,” though the finding has no effect on his firm’s upbeat view of the company’s efforts in hematological oncology.

As part of the IPO, Revolution granted underwriters a 30-day option to buy up to 2.1 million more shares at the offering price. J.P. Morgan, Cowen, SVB Leerink and Guggenheim Securities acted as joint book-running managers in the deal.

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