Revolution Medicines, Inc.

Good day, ladies and gentlemen, and welcome to the Revolution Medicine's fourth quarter and full year 2021 Financial Results Conference Call and Webcast. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a Q&A session. To ask a question at that time, please press the star key followed by one on your touchtone telephone. Please be advised that today's conference is being recorded. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Good afternoon, everyone, and thank you all for joining us today. Joining me on today's call are Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer. Dr. Steve Kelsey, the company's president of R&D, and Jack Anders, our senior vice president of finance and principal accounting officer. As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meanings of the Private Securities Litigation Reform Act regarding the current beliefs of the company with respect to our business. 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 we are presenting today, as well as all of the company's filings with the SEC concerning these other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Oldsmith, Revolutions Chairman and Chief Executive Officer. Mark.

Good afternoon, and thank you for joining us. We're very pleased to report that during the fourth quarter of 2021, Revolution Medicines continued building momentum with our targeted therapeutics pipelines. advancing our mission to improve treatment on behalf of patients with a wide range of RAS-addicted cancers, representing some 30% of all cancer patients. As depicted on slide five, RAS-addicted cancers are induced primarily by mutations that cause RAS-on proteins to behave as cancer drivers. But often these cancers are also supported and maintained by other cellular proteins we call RAS cooperating targets and pathways. We believe it is important scientifically to match our treatment strategies to this biological cooperativity by developing RAS-on inhibitors to suppress the primary RAS drivers, as well as RAS companion inhibitors to suppress the cooperating proteins. In many instances, we expect drugs of these two types may be combined to deliver the greatest clinical benefit. I'll spend the next few minutes briefly recapping four drug candidates that constitute our development stage RAS on inhibitor portfolio directed against RAS variants that are the primary drivers of RAS-addicted cancers. Dr. Steve Kelsey, our president of R&D, will then highlight recent updates on our clinical stage RAS companion inhibitors, RMC4630, SHP2, and RMC5552, mTORC1. Our first RAS-on inhibitor, RMC-6236, is an innovative and exciting drug candidate, a first-in-class RAS multi-on inhibitor with potentially very broad utility across many RAS cancer variants. As shown on slide 12, initially we are particularly interested in the more than 130,000 new pancreatic, colorectal, and or lung cancer patients in the U.S. each year with tumors bearing one of various mutations at amino acid 12 in KRAS, the dominant hotspot for KRAS cancer mutations. We refer to these collectively as G12X mutations. RMC6236 has demonstrated strong single agent activity across numerous cancer models with such G12X driver mutations derived from non-small cell lung, pancreatic, and colorectal cancer patients. We believe this compound has the potential to be the first RAS targeted therapy for many patients still reliant upon chemotherapy, including those with tumors bearing KRAS G12D or KRAS G12V mutations. This compound is in the late stages of IND preparation and we are on track to submit an IND in the coming months and then to begin single agent dose escalation with an initial focus on patients with various tumors carrying KRAS G12X mutations. During dose escalation, we plan to deploy a dynamic below MPD expansion strategy to help us both find the right dose and schedule and discover the most sensitive tumor types as efficiently as possible. The next compound, RMC6291, is our first mutant selective inhibitor planned to enter the clinic. This one focused specifically on the KRAS G12C target. RMC6291 is differentiated from first-generation KRAS G12C off inhibitors, which sequester the KRAS G12C off form, by its mechanism of directly inhibiting the KRAS G12C on, or active, protein form. We believe direct inhibition of the ON form of RAS cancer variants offers important biological advantages that could translate into meaningful increases in patient benefit relative to KRAS G12C OFF inhibitors. Based on extensive preclinical characterization showing compelling response rates, depth, and durability, we believe RMC6291 has best-in-class potential for treating KRAS G12C cancers addressing approximately 29,000 new U.S. patients per year, primarily with lung or colorectal cancers. As with the 6236 compound, as shown in slide 16, we expect to submit an IND for RMC6291 in the first half of this year, followed by beginning single-agent dose escalation in patients with various tumors carrying KRAS G12C mutations. Likewise, we plan to deploy a dynamic below-MTD expansion strategy to help us both find the right dose and obtain anti-tumor activity data in select populations as efficiently as possible. Our overall ambition is to demonstrate clinical superiority to the first-generation KRAS G12C off inhibitors. In addition to progressing 6236 and 6291 through IND submission, as expected in the first half of this year, We recently announced two new RAS-on inhibitors from our RAS innovation platform that have advanced into IND-enabling development. The first is RMC9805, summarized on slide 17, a remarkable mutant selective inhibitor of the KRAS G12D cancer driver. It's highly potent and benefits from what we believe to be the first ever highly selective covalent engagement of the oncogenic aspartic acid in this clinically important RAS variant. Indeed, it appears to be the first drug candidate ever to deploy this sort of selective target-binding mechanism directed against an aspartate-containing disease target. Like our other development stage assets, it is also orally bioavailable, promoting effective target coverage in cancer cells. We recently showed that RMC9805 drives deep and durable anti-tumor responses as a single agent in preclinical KRAS G12D pancreatic and colorectal cancer models in vivo. We aim to file an IND for this highly innovative compound in the first half of 2023. Our second new development candidate is RMC8839, summarized in slide 20, an exciting mutant selective inhibitor of the KRAS G13C cancer variant that forms a selective bond with the oncogenic cysteine in this RAS target. that has not been previously drugged. Like our other development stage RAS on inhibitors, RMC8839 exhibits attractive potency, selectivity, and oral bioavailability, and was shown recently to drive significant antitumor responses as a single agent in preclinical KRAS G13C lung cancer models in vivo. We aim to file an IMD for this novel compound in the second half of 2023. Beyond these four groundbreaking development stage RAS-on inhibitors, I mentioned earlier that our strategy also includes developing specific RAS companion inhibitors as illustrated on slide 24. Targeted drugs that suppress cooperating targets and pathways known to work in coordination with RAS cancer drivers to sustain RAS-addicted cancers, and in some instances, confer drug resistance. We believe that combining best-in-class GRAS inhibitors with best-in-class companion inhibitors offers the greatest chance to deliver the best clinical outcomes. In that context, Dr. Kelsey will review briefly two clinical stage assets that are designed to support combination treatment approaches. Steve?