Revolution Medicines Inc. (Revmed) strengthened its balance sheet with a $56 million series B while bolstering its C-suite with a trio of executives. The financing will enable the company to advance its lead SHP2 program through IND and into what Mark Goldsmith, president and CEO, called an "exciting" clinical trial program.

"We're progressing our development candidate productively through the late stages of IND-enabling development with the goal of completing our IND for submission," leading to a first-in-human study once the company receives FDA clearance, Goldsmith told BioWorld. "Once the initial dose-escalation phase has demonstrated initial safety and adequate drug exposure, we'll be able to open cohorts focused on subsets of patients carrying tumors with defined genetic mutations that our preclinical work showed would confer particular sensitivity to the SHP2 inhibitor. We're planning to pursue both monotherapy as well as certain rational, mechanistically compelling combinations with other targeted therapies in order to delay or overcome drug resistance."

Founded in 2014, Revmed hauled in a $45 million series A the following year. Back then, the Third Rock Ventures-spawned company was focused on discovering and developing therapies derived from natural products to treat serious infections and non-infectious diseases, including life-threatening fungal infections, based on work conducted by Martin Burke, professor of chemistry at the University of Illinois at Urbana-Champaign and Revmed's co-founder and scientific advisory board chair. (See BioWorld Today, Feb. 4, 2015.)

In December 2016, the company, of Redwood City, Calif., added $25 million in a series A extension, bringing in The Column Group as an investor. At the same time, Revmed deftly pivoted from serious infectious diseases to emerging targets in cancer and the immune system, naming chemical biologist and cancer investigator Kevan Shokat as an academic co-founder and member of the company's scientific advisory board along with co-founders Burke and Michael Fischbach, who joined the team in June 2016. The company also appointed industry veteran Julian Adams, structural biologist John Kuriyan and clinical and translational oncologist Trever Bivona to its scientific advisory board.

Last year, Revmed scientists, in collaboration with researchers at the University of California, San Francisco School of Medicine, published a paper in BioRxIV describing studies of the RAS-MAP kinase cell growth signaling pathway known to be hyperactive in many human cancers, along with the regulation of that pathway by the enzyme SHP2 (PTPN11). The research revealed an unexpected dependence of some cancer-causing forms of proteins in the RAS-MAP kinase pathway on the normal biochemical actions of SHP2. Revmed said that small-molecule inhibitors of SHP2 that it designed could disrupt those functions, curtailing tumor growth.

Activation of certain proteins in the RAS-MAP kinase pathway drives cancer by amplifying normal growth signals rather than functioning as fully independent or autonomous drivers of cancer, according to the researchers. Among those proteins are certain cancer-causing forms of KRAS, NF1 and BRAF, common in prevalent cancers such as non-small-cell lung cancer. Those oncoproteins behave semi-autonomously by requiring cues from SHP2 before initiating cancer-causing effects, yet they have been largely untouched by conventional drug discovery, leaving a gap in cancer treatment. The Revmed discovery, thus, offered a potential roadmap for the company to develop an inhibitor of SHP2 to treat patients with cancers containing clinically important mutations previously considered undruggable.

Last week, at the American Association for Cancer Research annual meeting in Chicago, Revmed reported additional data on its SHP2 program, including the discovery of a subset of clinically relevant SHP2 mutants that are sensitive to SHP2 allosteric inhibitors; evidence of preclinical efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, NF1 loss and RAS-GTP-dependent oncogenic BRAF; and the discovery of an oral allosteric inhibitor of SHP2 dubbed RMC-4550.

"We've demonstrated great momentum not only by advancing our development candidate against SHP2 but also by uncovering a new, potentially high-impact paradigm regarding how SHP2 regulates the canonical RAS growth signaling pathway and how to target selected cancer mutations with our SHP2 inhibitor," Goldsmith said.

'We're certainly looking at the public markets'

In fact, "we've strengthened our innovation engine in a number of ways" since the series A, added Goldsmith, who remained a venture partner at Third Rock until this year. "On the drug discovery side, we continue to deploy modular chemical synthesis for some important aspects of our medicinal chemistry efforts, have expanded our structure-, biophysics- and computationally based drug discovery toolkit, and have incorporated fragment-based methods. On the translational side, we've significantly deepened our cancer biology and development science organizations by adding experienced individuals to lead cancer pharmacology, immuno-oncology, biomarker discovery, regulatory affairs and clinical development."

Revmed, which has expanded from a dozen employees in 2015 to more than 60 across research, development and corporate functions, named more three key hires alongside the series A. Ryan Martins, chief financial officer, joined the company from Ultragenyx Pharmaceutical Inc., where he served as vice president of finance, corporate strategy and investor relations. Xiaolin Wang, senior vice president of clinical development, previously served on the senior leadership team at Acerta Pharma LLC, where she was instrumental in moving Calquence (acalabrutinib) to approval last year to treat adults with mantle cell lymphoma. Hirdesh Uppal, vice president of development sciences, joined Revmed from Medivation Inc., where he led translational medicine and diagnostics until the company's $14 billion acquisition by Pfizer Inc. in 2016. Uppal also held drug development roles at Roche Holding AG and its Genentech unit.

With its senior leadership in place, Revmed will focus on adding "selected individuals in several functions," Goldsmith said.

In conjunction with the financing – led by Nextech Invest with participation from Casdin Capital, Schroder Adveq, The Column Group, Third Rock and undisclosed institutional investors – Revmed added Nextech partner Thilo Schroeder and Barbara Weber, CEO of Third Rock-spawned Tango Therapeutics Inc. and a part-time Third Rock venture partner, to its board.

Revmed launched its financing initiative "a few months ago," Goldsmith said, by introducing the company to experienced life science investor groups.

"We had a very good reception based on the progress of our innovative SHP2 program and pipeline, our organization and our strategy," he said, adding that the round was upsized to satisfy investor demand.

"This strong financing by a leading group of investors provides the fuel to continue driving our lead program into the clinic and advancing our pipeline," Goldsmith added. "In this business, success always generates demand for more capital, so we will continue considering the most effective options for financing as we execute our long-term plan. We're certainly looking at the public markets and will engage in that direction at the right time," with Martins leading the company's capital formation strategy, he said.

In addition to its SHP2 program – one of just four in discovery along with two assets, SHP-099 and TNO-155, that Novartis AG has moved into phase I studies, according to Cortellis Competitive Intelligence – Revmed has assets targeting SHP1 (PTPN6), a tyrosine phosphatase that regulates multiple arms of the immune response, and 4EBP1, a regulator of oncogene translation in the PI3K/AKT/mTOR pathway.

Goldsmith was circumspect about the company's long-term business approach.

"We continuously explore both equity financing options as well as business partnerships," he said. "We're open to the possibility that a collaboration with a larger company may increase the scope and/or probability of success of our SHP2 program in order to maximize clinical impact on behalf of our patients and value creation for our shareholders. If a synergistic relationship can be forged that fulfills these objectives, we will pursue it."