Revolution Medicines, Inc.

Good day and thank you for standing by. Welcome to the Revolution Medicine Q4 and year-end 2022 earnings conference call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1-1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Peg Horn, Chief Operating Officer. Please go ahead.

Thank you and welcome everyone to the fourth quarter and full year 2022 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer, Dr. Steve Kelsey, the company's President of Research and Development, and Jack Anders, our Chief Financial Officer. As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act. These statements are subject to a number of assumptions, risks, and uncertainties. Actual results may differ materially from these statements, and except as required by law, the company undertakes no obligation to revise or update any forward-looking statements. I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings release, press release, as well as all of the company's filings with the SEC concerning these and other matters. During this presentation, we will be referring to a number of slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark?

Good afternoon, and thank you for joining us. Today, I'll provide an update on our company progress. Steve Kelsey will provide additional information about our RMC6236 clinical program, and Jack Anders will provide highlights of our financial results. Revolution Medicines is advancing our pipeline of groundbreaking RAS-on inhibitors and RAS-companion inhibitors on behalf of patients with a wide range of RAS-addicted cancers, setting up an exciting and data-rich year. We have advanced into clinical development the first two drug candidates from this highly innovative RAS-on inhibitor portfolio. RMC6236 is a groundbreaking RAS inhibitor with the potential to treat all or nearly all RAS cancer patients due to its highly differentiated mechanism of action, facilitating broad activity across major RAS variants. RMC6291 is the vanguard of our mutant selective RAS-on inhibitor portfolio, which also includes our oral and covalent KRAS G12D inhibitor, expected to enter the clinic mid-year, and a second wave of inhibitors designed to treat a range of RAS mutant cancers. Together, the two Phase I programs will provide key insights into the potential of each exciting drug candidate and initial information to validate our tri-complex RAS-on inhibitor platform as a whole. RMC-6236 and 6291 have been well behaved so far in the dose escalation portions of the RMC-6236-001 and RMC-6291-001 clinical studies, respectively. Both compounds have exhibited oral bioavailability, leading to increasing exposure levels with increasing dose, consistent with our preclinical projections. They've both been generally well tolerated, We've cleared several dose levels for each compound with a once daily dosing schedule, and we have not yet reached a maximal tolerated dose or defined a recommended phase two dose for either compound. Today, we'll expand further on the findings related to RMC-6236 in particularly. Momentarily, Steve Kelsey will share with you additional information coming from the RMC-6236-001 trial. You'll hear about initial pharmacokinetics, molecular and radiographic findings from the early stages of this study supporting our belief that we are dosing this compound in a pharmacologically active range and observing anti-tumor activity consistent with clinical benefit with acceptable safety and tolerability. Although the data Steve will describe today are early, we believe these findings are quite encouraging for RMC6236 itself as a drug candidate. They are insufficient to define the full profile and potential of 6236, including response rates or long-term durability in any tumor type, which will require more data and time. Nevertheless, we feel these data are important as they significantly de-risk key aspects of our broad portfolio of multiple clinical and preclinical Rason inhibitors that all share a number of fundamental properties. Let me offer additional context by reminding you of some key elements regarding the compound RMC-6236. Our description of 6236 as a RAS multi-on inhibitor has three components. It is designed to bind selectively to RAS proteins. It binds to and inhibits all or nearly all forms of RAS, including every known oncogenic mutant and wild type form we've tested. and it binds RAS exclusively in the on or activated state in contrast to first-generation KRAS G12C inhibitors that bind RAS in the off state. 6236 shows high potency in cellular assays, inhibiting RAS signaling typically at low nanomolar to sub-nanomolar concentrations, and frequently driving deep and sustained RAS pathway suppression in RAS-dependent tumor cells. And we've shown extensive preclinical evidence that 6236 induces deep and sustained regressions in diverse in vivo cancer models representing multiple tumor types and multiple RAS mutant genotypes, especially KRAS G12X mutants, a RAS inhibitor profile that is, to our knowledge, unprecedented. Overall, the design of RMC6236 as a RAS multi-on inhibitor not only chemically and pharmacologically breaks new ground in the field, but also serves the bold, biological goal of leveraging its ability to inhibit all or nearly all forms of RAS including both the primary mutant RAS driver and normal or wild type RAS forms to maximally suppress RAS signaling overall in cancer cells that are addicted to RAS. A fundamental question being evaluated in the RMC 6236-001 clinical trial is whether 6236 with this biological profile can be dosed in patients at levels that deliver clinical anti-tumor impact without also causing unacceptable effects on normal tissues due to the compound's intentional activity against wild-type forms of RAS that would also be anticipated in normal cells. The extensive preclinical evidence of dramatic anti-tumor activity in multiple animal models came from studies at dose levels that did not induce concomitant intolerability. and the RMC6236-001 clinical study is a first test of these aspirations for this drug candidate in patients. Steve Kelsey, our president of R&D, will present our first report of clinical experience with a Rasa on inhibitor, RMC6236. Steve?