Revolution Medicines, Inc.

Good day. My name is Katherine, and I'll be your conference facilitator today. Welcome to the Revolution Medicine's first quarter and 2022 earnings conference call. Today's call is being recorded. At this time, all participants are in a 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 1 on your touch-tone telephone. If anyone has difficulty hearing the conference, please press star zero for operator assistance. I would now like to hand the conference over to David Arrington, Revolution Medicine's SVP of Investor Relations and Corporate Affairs, for opening remarks. David, you may begin.

Thank you, and welcome everyone to our first quarter 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, research and development, and Jack Anders, our SVP of finance and principal accounting officer. Today, we will be referencing selected slides from our corporate presentation. The complete set is available for you to view and download on revmed.com. 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 any forward-looking statements. I encourage you to review the legal disclaimer slide of our corporate presentation or the earnings press release, as well as all of the company's filings with the SEC concerning these and other matters. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer.

Thanks, David. Good afternoon, everyone. Thank you all for joining us today. I'll start with a few top-line comments. We've made great progress in the first quarter. We continue to advance what we believe is the deepest portfolio of RAS-targeted therapeutics in the field, led by our RAS-on inhibitors in development, with significant opportunity for patient impact. Excessive RAS-on signaling drives some 30% of all human cancers. Today, I am very pleased to let you know that we have submitted the IND for RMC6236, our RAS multi-on inhibitor, and expect to dose the first patient in mid-2022. Preparation of the IND for RMC6291, our KRAS G12C-on inhibitor, is also on track with our original guidance, and we expect to dose the first patient in the second half of 2022. These two RAS-on inhibitors approaching the clinic and an exciting pipeline behind them represent a wave of RAS-on inhibitor drug candidates that could address the majority of RAS-addicted cancers that lack effective targeted drugs. Concurrently, we continue clinical evaluation of the class-leading RAS companion inhibitors, RMC-4630 and RMC-5552, that are intended as combination agents with direct RAS inhibitors, including our own RAS-on inhibitors, to maximize patient benefits. Regarding our development stage compounds, we are transitioning our communication schedule. Going forward, we plan to focus milestones for development stage programs on clinical initiation rather than IND submissions. Investors should look to our postings on clinicaltrials.gov for indications that an IND is open and that clinical investigation sites are being activated to enable study initiation. We also plan to communicate after we've begun dosing patients in each program. Slide five. Revolution Medicines has a deep science-driven pipeline of targeted therapies for RAS-addicted cancers. We have four RAS on drug candidates that are supported by robust and growing data sets that have large clinical opportunities with the potential to serve patients with a wide range of RAS-addicted cancers. Further, we expect that our pipeline will continue to grow with highly distinctive new assets deriving from our RAS cancer innovation engine, which should expand our reach to other key oncogenic mutations on RAS proteins. Although RAS-addicted cancers are induced primarily by mutations that cause RAS-on proteins to behave as cancer drivers, 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 companion inhibitors to suppress the cooperating proteins while deploying RAS-on inhibitors to suppress the primary RAS drivers. Lastly, I note that in many instances, we expect drugs of these two types may be combined to deliver the greatest clinical benefit. In the next few minutes, I'll highlight examples of three specific themes that are important to our strategy. First, Ras-on inhibitors demonstrate compelling monotherapy antitumor activity in diverse preclinical models of genetically defined Ras cancers. Second, Ras-on inhibitors can be combined with Ras companion inhibitors to improve antitumor activity in preclinical models that are less sensitive to monotherapy. And third, Ras-on inhibitors as monotherapies reverse the immune suppressive tumor microenvironment in Ras-driven cancer models and can unlock profound anti-tumor immunity when combined with immune system modulators such as PD-1 checkpoint inhibitors. Now I'll turn to specific comments about our portfolio progress. The first theme is RAS-on inhibitors as highly active monotherapy agents preclinically. We have produced a large collection of tricomplex inhibitors targeting diverse oncogenic RAS variants through highly differentiated chemical and pharmacologic profiles Slide 9. As a first example, RMC6236 is a potent oral RAS on selective inhibitor with broad potential across cancers driven by a variety of RAS mutations. To date, it has been shown to be active in three histotypes, including pancreatic, colorectal, and non-small cell lung cancer models, and across mutations, including KRAS G12D, KRAS G12V, and KRAS G12R. Cancer drivers for which patients whose tumors bear these mutations lack targeted therapy options. Slide 12. We are on the path to clinical data now that the IND has been submitted. We expect to announce dosing of the first patient in a monotherapy dose escalation study in mid-2022. And in 2023, we plan to provide evidence of first-in-class single-agent activity for RMC6236. I also note that RMC-6236 may also be deployed as a RAS companion inhibitor in combination with mutant selective RAS-on inhibitors, something I will say a bit more about later. Slide 14. As another example, RMC-6291 is a potent oral selective covalent inhibitor of KRAS G12C-on with a differentiated preclinical profile designed to serve patients with cancers driven by the KRAS G12C mutation, including lung, colorectal, and pancreatic cancers. 6291 has demonstrated best-in-class potential for treating KRAS G12C-driven lung cancers, non-small-cell lung cancers, based on superior outcomes in a mouse clinical trial with KRAS G12C lung cancer models. Slide 17. Our IND preparation is on track for submission in the first half of 2022, and we anticipate RMC6291 will be our second RAS on inhibitor program to enter the clinic this year and expect to disclose preliminary evidence of superior activity over the first generation KRAS G12C off inhibitors in 2023. Slide 19, as a third example, RMC9805 is an oral selective covalent inhibitor of KRAS G12D-ON, the primary tumor driver for more than 50,000 new patients annually in the United States, predominantly patients with colorectal, pancreatic, or non-small cell lung cancer. RMC9805 exhibits a highly differentiated profile, and we believe it is one of our most technically sophisticated RAS-ON inhibitors to date. It uniquely engages the KRAS G12D cancer variant covalently through the oncogenic aspartic acid residue by taking advantage of a proprietary chemical warhead, a bespoke linker, and our tricomplex binding modality. These design elements deliver a highly distinctive preclinical profile that includes oral bioavailability and selective and irreversible inhibition of this important cancer target. When administered orally to mice and grafted with the KRAS G12D tumor, RMC 9805 achieves favorable plasma exposures and dramatically suppresses DUSP6 mRNA, a molecular biomarker of RAS pathway signaling, for over 24 hours due to its irreversible inactivation of the target. Slide 20. We believe RMC 9805 is the first-ever drug candidate described that can covalently modify an aspartic acid residue in a targeted protein. drives deep and durable antitumor responses in pancreatic and colorectal cancer models in vivo upon oral dosing, and it is well tolerated. Slide 22, as a fourth example, RMC8839 is an oral selective covalent inhibitor of KRAS G13C on. We believe it is the first compound to directly inhibit KRAS G13C a target primarily for lung and select colorectal cancer patients who are currently not served by a targeted RAS inhibitor. Slide 24. Lastly, in our pipeline expansion programs, we continue leveraging our RAS innovation engine to identify additional orally bioavailable tricomplex RAS-on inhibitors to target RAS variants driving RAS-addicted cancers that are unserved by current targeted drugs. As illustrated on this slide, our tricomplex inhibitors bind to Ras-on proteins at a site that provides the opportunity for direct chemical interaction with amino acids at each of the three well-recognized mutational hotspots affecting residues G12, G13, or Q61. This binding geometry is leveraged in each of our programs to design compounds that are selective in engaging mutant amino acids at these positions that are responsible for most RAS-addicted cancers. Today, I'll share compelling initial data about RM043, a representative mutant-selective non-covalent inhibitor of KRAS Q61H-ON that was shown for the first time at the recent AACR Annual Meeting. shows nanomolar activity in cells driven by the KRAS Q61H variant, is selective for KRAS Q61H over wild-type RAS, and drives deep regressions in a KRAS Q61H xenograft model of lung cancer. To our knowledge, this is the first-ever example of a targeted RAS inhibitor directed to an oncogenic RAS variant at the Q61 mutation hotspot. This compound not only represents proof of principle for selective targeting of codon 61 by tricomplex inhibitors, but also demonstrates that this modality can be leveraged to develop highly mutant selective inhibitors even when covalent bonding is not possible. Slide 26. The second theme and parallel approach that I'll talk about today is that our RAS companion inhibitors in development may be combined with RAS-on inhibitors to improve anti-tumor activity in preclinical models that are less sensitive to monotherapy. These RAS companion inhibitors are 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 RAS-on inhibitors with best-in-class RAS companion inhibitors offers the greatest chance of pathway suppression and durability of response to deliver the best clinical outcomes. Ultimately, the optimal RAS on and companion inhibitor strategy will likely be disease specific. I will highlight here two clinical stage assets that support combination treatment approaches. Slide 28. First, RMC4630 is a potent oral small molecule that is designed to selectively inhibit the activity of SHP2, an upstream cellular protein that plays a central role in modulating cell survival and growth by facilitating RAS pathway signaling. Amgen continues its initial evaluation of dosing RMC4630 in combination with Sotiracib in second-line treatment of various KRAS G12C tumors in the U.S. Code Break 101 C study and recently announced it has submitted initial data from this study to a medical congress for late summer. Revolution Medicine's clinical study called RMC4630-03 is progressing and continues to enroll. This is a global phase two study of RMC4630 in combination with Sotiracib in patients with advanced non-small cell lung cancer with a KRAS G12C mutation who have failed prior standard therapy and who have not been previously treated with a Ras-on inhibitor, with a Ras inhibitor. We are on track to enroll the study fully this year and have sufficient data by the end of the year to share some of the high-level findings. Slide 29. Second, RMC6236, the exciting Ras multi-on inhibitor I described earlier, is notable within our broad Ras-on inhibitor portfolio because it, in particular, has the potential to be deployed as a RAS companion inhibitor as well as a primary cancer driver targeted agent. In some clinical context, patients may gain maximal clinical benefit from the broad activity of this RAS multi-on inhibitor in combination with the deep and sustained target coverage provided by a mutant selective RAS on inhibitor such as RMC6291. Slide 30, at the AACR meeting, We reported that RMC6236 in combination with RMC6291 demonstrated enhanced anti-tumor activity in KRAS G12C non-small cell lung cancer and colorectal cancer models that are relatively resistant to single agent treatments. An example shown on this slide, CRC022, is one such KRAS G12C colorectal cancer model in which either the G12C-ON inhibitor RMC-6291 or the RASP-MULTI-ON inhibitor RMC-6236 as a single agent slows tumor growth but fails to induce tumor regressions. In contrast, combining these two agents converts the impact into significant tumor regression. Slide 32. Lastly, RMC-5552 continues to advance. This drug candidate is a potent, first-in-class, biesteric mTORC1 selective inhibitor designed to suppress phosphorylation and inactivation of 4-EBP1 for cancers with hyperactive mTORC1 signaling, including certain RAS-addicted cancers. We aim to combine RMC5552 with RAS-on inhibitors in patients with cancers harboring RAS and mTOR pathway commutations. We are making progress in our ongoing Phase I-1B clinical trial, evaluating RMC5552 as a monotherapy, and are now focused on dose optimization in preparation for accommodations with RAS on inhibitors. Slide 11. Our third theme is unlocking the anti-tumor immune response by targeting RAS cancer drivers within tumors. We've seen examples, multiple examples, in which Ras-on inhibitors as monotherapies reverse the immune-suppressive tumor microenvironment in Ras-driven cancer models and can unlock profound anti-tumor immunity when combined with immune system modulators such as PD-1 checkpoint inhibitors. In particular, both RMC-6236 and RMC-6291 alone can favorably transform the immune microenvironment in RAS tumors and are highly additive with a checkpoint inhibitor. RMC6236 favorably transforms the tumor immune microenvironment by modulating both the adaptive and innate immune cells infiltrating these RAS-addicted tumors. And these changes significantly increase the sensitivity of such tumors to immune checkpoint inhibitors. Hence, the combination of RMC6236 with a checkpoint inhibitor causes profound, durable, and even complete anti-tumor responses in some preclinical models in mice with intact immune systems. Slide 16. RMC6291 is able to modulate the immune microenvironment via tumor intrinsic effects that prime cancer cells for anti-tumor immunity in the presence of a checkpoint inhibitor. Here, we show this combination is also able to drive complete responses in an immunogenic model of KRAS G12C cancer. In summary, these prepared comments have provided an update on our portfolio across three core themes that are important to our strategy. First, RAS-on inhibitors demonstrate compelling monotherapy antitumor activity in diverse preclinical models of genetically defined RAS cancers. Second, RAS-on inhibitors can be combined with RAS companion inhibitors to improve anti-tumor activity in preclinical models that are less sensitive to monotherapy. And third, Ras-on inhibitors as monotherapies reverse the immune suppressive tumor microenvironment in Ras-driven cancer models and can unlock profound anti-tumor immunity when combined with immune system modulators such as PD-1 checkpoint inhibitors. These concepts in conjunction with preclinical data sets behind each of the development stage assets in our R&D portfolio, underlie our belief that we may be able to serve significant unmet clinical needs for patients with a wide range of RAS-addicted cancers. I'll now turn to Jack Anders, our Senior Vice President of Finance, to report on our financial condition. Jack?