Revolution Medicines, Inc. (RVMD) Earnings Call Transcript & Summary

Good afternoon, everyone, and thank you for joining the H.C. Wainwright 2021 Global Life Sciences Conference. [Audio Gap], and I'm an equity research associate here at H.C. Wainwright. While we are virtual this year, we are confident that we are going to be able to provide value to you with over 425 companies presenting at this conference. H.C. Wainwright is a full services investment bank dedicated to providing corporate finance, strategic advisory and related services to public and private companies across multiple sectors and regions. We have a total of 18 publishing senior analysts and 493 companies across all sectors. Please visit hcwco.com for more information. From a logistics standpoint, please make sure to reference your virtual conference online portal that provides your individual [Audio Gap] to our meetings and all presentations. Panels and all presentations are live and on-demand online for March 9. With that said, have a productive and enjoyable day, and I'd like to introduce our first presenter. I'd like to welcome Mark Goldsmith, the CEO and Chairman of Revolution Medicines, a clinical stage precision oncology company focusing on developing novel targeted therapies to inhibit frontier targets in RAS-addicted cancers. Over to you, Mark.

Thank you, [ Chate ], for this opportunity to present Revolution Medicines. Revolution Medicines is, as you mentioned, a clinical stage precision oncology company focused on large unmet medical needs in RAS-addicted cancers, representing a very significant share of all human cancers. Our science-driven strategy includes targeted therapeutics organized into 2 portfolios. Our RAS(ON) inhibitors deriving from an innovative technology platform are unique compounds that target diverse oncogenic RAS variants through highly differentiated profiles. In January, we announced that our first 2 RAS(ON) inhibitor programs have entered development, RMC-6291, targeting the KRAS G12C oncoprotein; and RMC-6236, a multi-RAS inhibitor for a range of diverse RAS proteins that cause cancer. Our RAS companion inhibitors directed against key nodes and RAS-signaling circuits are potential backbones of targeted combination treatments to maximize clinical benefit. RMC-4630, our SHP2 inhibitor, exhibits clinical activity and is advancing in a broad clinical program. RMC-5552, our innovative mTORC1-selective inhibitor, has been cleared by the FDA for a Phase I study that has now begun recruiting. And we also announced in January that RMC-5845, our SOS1-selective inhibitor, has also entered development. Hence, we now have 2 clinical stage programs and 3 new development programs. RAS proteins are the primary cause of many cancers and these same proteins also induce oncogene addiction by cancer cells and elicit their own drug resistance mechanisms. Our goal is to outsmart RAS-addicted cancers by understanding and overcoming these fundamental complexities. Our product strategy specifically addresses 3 key features: One, many distinct variants of the RAS family of proteins cause cancer and underlie addiction; two, it's the activated or RAS(ON) form of these proteins that drives oncogenic signaling; and three, complex natural circuits within human cells can be exploited by cancer cells as drug resistance pathways, and these pathways require carefully chosen companion drugs for combination strategies in order to achieve deep and durable clinical responses. The scope of the unmet need in RAS-addicted cancers is enormous, including 30% or more of human cancers in the U.S., causing severe morbidity and mortality. There are many different RAS variants that can cause cancer and each RAS-addicted tumor can be defined by its genetics. Shown here is our estimate of the new RAS-addicted cancers diagnosed each year in the U.S. organized into convenience groups based on these genetics that also provide a road map of which types of RAS inhibitors are needed. For example, at the bottom of the graph is the G12C mutation responsible for 30,000 new cancers each year. Although it is the best-known RAS mutation, it is certainly not the most common as both G12D and G12V are more common. In aggregate, some 230,000 new cancers could be served by RAS inhibitors in the U.S. alone each year. These are quite large numbers. We believe that Rev Med is uniquely positioned to serve these enormously important clinical needs, and we have tremendous momentum toward doing so with our rich cohesive pipeline of complementary development stage assets as shown here. Our RAS(ON) inhibitors are highly innovative and sophisticated compounds that are engineered to enter a cell, bind to an abundant chaperone protein known as cyclophilin A and then engage a particular RAS(ON) target to form a tri-complex that quickly inactivates RAS signaling by sterically preventing activation of effectors. We've shown compelling single-agent activity for examples of these inhibitors in preclinical in vivo models of human cancer, representatives of which we'll highlight today, as well as combination benefits. We've observed preclinical features of these inhibitors that suggest potential clinical benefit in terms of breadth, depth and/or duration for antitumor impact that will deserve to be evaluated in patients, and we've proven the broad reach of our inhibitor collection across a wide array of oncogenic variants. Indeed, our outstanding research organization has produced a vast collection of novel compounds, some examples of which are shown here bound to various RAS(ON) targets. We have potent and cell-active RAS inhibitors that cover the vast majority of oncogenic variants of RAS. Today, we'll focus on the first 2 inhibitors from this unique collection that have entered development. RMC-6291 shown in the crystal structure on the left is our first-in-class highly potent selective oral tri-complex inhibitor of KRAS G12C in the ON form with excellent drug-like properties. It exhibits subnanomolar potency for suppressing RAS/MAP kinase signaling through phospho ERK and causing growth inhibition in KRAS G12C-driven tumor cell lines and for NRAS G12C-driven cells as well. It's engineered to exhibit very high and specific reactivity to cysteine 12 on the mutated RAS G12C target to be highly selective for RAS G12C-driven cell lines over RAS independent tumor lines and have a low-risk profile as determined in an expansive off-target safety panel and cysteinome screen. It shows good oral availability across small and large species. And in sum, this profile is highly favorable compared to the current class of KRAS G12C OFF inhibitors and it's differentiated from others by acting through the direct inhibition of RAS G12C ON. RMC-6291 induces profound antitumor effects in vivo and preclinical xenograft models. In this example, a well-known human lung cancer cell line bearing a KRAS G12C mutation is engrafted into mice and followed over time for tumor growth or regression. 6291 caused deep and consistent tumor regressions at all 3 doses shown here, 25, 50 or 100 milligrams per kilogram per day. These effects compare well to the benchmark used in this experiment, MRTX849 at 100 milligrams per kilogram, the standard dose used by Mirati, despite dosing 6291 with as low as 1/4 the dose of MRTX. All animals and all treatment arms tolerated treatment well. A closer comparison reveals potentially important differences between these treatments. The end of treatment measurements on the left show that 6291 in all 3 dose groups actually induced deeper regressions than the MRTX849 benchmark with 10 of 10 animals in each group scoring as complete regressions or CRs defined by a reduction in tumor volume of greater than 80% compared to the starting volume compared to 7 of 10 in the MRTX849 group. Furthermore, after discontinuing treatment and tracking tumor regrowth over time as shown on the right, it's clear that 6291 induced a more sustained antitumor response compared to the comparator. Together, these results show the superior antitumor efficacy of 6291 in this preclinical model. In a second example, we tested the 2 compounds side-by-side in LUN092, a patient-derived lung cancer carrying a G12C mutation engrafted into a mouse. Both 6291 and the comparative compound, given at 100 milligrams per kilogram per day, drove regressions in this PDX model and both were well tolerated. But again, as shown previously in the CDX model, in this PDX model, 6291 induced deeper and more consistent responses. Based on these data and additional findings we'll report at a scientific meeting in the future, RMC-6291 has a best-in-class preclinical profile that we believe predicts a best-in-class clinical profile. It is currently in IND-enabling development with IND submission projected for the first half of 2022. Our clinical superiority thesis, which, of course, must be tested in patients, is that 6291 will exhibit advantages in terms of range of sensitive tumor types, response rate, depth and/or duration and monotherapy effects as well as potentially beneficial combinations with our RAS companion inhibitors. Our second distinguished RAS(ON) inhibitor to enter development, RMC-6236, is a first-in-class, potent, RAS-selective oral tri-complex multi-RAS inhibitor that we expect to be used -- useful in multiple RAS-addicted tumor types. RMC-6236 drives multiple diverse oncogenic forms of RAS into inhibitory tri-complexes, including, as shown here, KRAS G12V and G12D, both in the ON form. These are the 2 most common mutant drivers of the RAS drivers of human cancer, together causing 100,000 new cases of cancer each year in the U.S. alone that remain unserved by targeted therapies. 6236 exhibits low nanomolar potencies across a range of RAS-dependent tumor cell lines, yet it is highly selective for RAS-dependent tumors. It scores us a low-risk in a broad off-target safety panel and it has good drug-like properties, including oral bioavailability across multiple species. This very attractive compound is now in formal development. As mentioned, the key feature of 6236 is that it potently inhibits RAS-dependent tumor cells in vitro. It exhibits single-digit nanomolar potency for growth inhibition across multiple cells carrying various specific RAS mutations, including G12V and G12D as shown here as well as excellent potency against a broad array of other RAS mutants. Importantly, it shows virtually no pharmacologically relevant impact on cells with downstream pathway mutations that function independently of RAS. With such a range of activity, RMC-6236 has the opportunity to address the majority of unserved RAS-addicted cancers. In vivo, RMC-6236 induces impressive dose-dependent antitumor effects as represented in xenografts of human tumors. In this model of human lung cancer driven by the KRAS G12D mutation, RMC-6236 administered orally caused obvious tumor regressions as shown on the left. The 10 milligrams per kilogram group showed 8 of 10 regressions as measured at the end of the study, while the 25-milligram per kilogram group showed 10 out of 10 complete regressions. And importantly, both daily doses were also well-tolerated. Marked antitumor effects were also seen in other human cancer models carrying the KRAS G12V mutation. For example, as shown on the left, a pancreatic ductal adenocarcinoma cell line, and on the right, a colorectal cancer of PDX engraftment, both showed significant tumor regressions in response to 6236 and, in some cases, complete regressions. These results clearly show the great promise of 6236 for treating KRAS G12V-bearing cancers. Earlier, I also showed the inhibitory effect of 6236 on KRAS G12D in vitro. And here, we display the antitumor effects in vivo in HPAC, a human pancreatic cancer cell line carrying a KRAS G12D allele and engrafted into mice. 6236, again administered orally, induced profound antitumor responses as shown on the left. Indeed, at the end of the experiment, all of the animals in both treatment arms showed complete regressions, and again, treatment was well tolerated. Hence, this exquisite compound can turn RAS addiction into a profound vulnerability for these tumors. Based on these findings and extended additional findings, we expect RMC-6236 to be able to serve very broad clinical opportunities for large unmet needs. It is currently in IND-enabling development and we project IND submission in the first half of 2022. Our broad clinical thesis is that numerous RAS genotypes across multiple cancer patient segments will show sensitivity to 6236 either alone or as well as with beneficial combinations with RAS companion inhibitors. Let's briefly review the status of our RAS companion inhibitor portfolio, starting with RMC-4630, our potent selective and oral inhibitor of the SHP2 protein, a master regulator of the RAS-signaling pathway. We've reported multiple times on our broad clinical development program conducted under our global partnership with Sanofi. We've described monotherapy activity in multiple cancers and genotypes and are currently conducting expansion work at the recommended Phase II dose and schedule that we selected this fall. We've also reported preliminary activity in combination with a MEK inhibitor, cobimetinib, in RAS mutant colorectal cancer and are currently conducting expansion work at the recommended Phase II dosing schedule for that combination. We've also reported evidence from paired tumor biopsies from patients, supporting enhancement of the tumor micro -- of the tumor immune microenvironment in patients who have been treated with RMC-4630. Importantly, though, our central clinical thesis remains that RMC-4630 should serve as a backbone of rational mechanism-based combination strategies. And this table summarizes the combination strategies that we're currently evaluating. Four clinical experiments are currently underway testing various combination hypotheses and additional clinical experiments are planned but have not yet begun. These studies involve 5 institutional collaborators, including 4 big pharma partners. Our second RAS companion inhibitor is RMC-5552, a highly innovative and potent mTORC1-selective inhibitor. We are currently activating clinical sites and expect to begin enrolling patients into a Phase I monotherapy dose escalation study imminently. Once we have initial single agent experience in patients, we expect to test RMC-5552 in combination with RAS inhibitors for patients harboring RAS and mTORC-signaling co-mutations. Our third RAS companion inhibitor is RMC-5845. It's a potent and oral inhibitor of SOS1, a major switch for RAS(OFF) to RAS(ON). This compound is highly selective for inhibiting SOS1 over SOS2, and it's well-tolerated preclinically. It's intended for select combination therapies for certain genetically defined RAS-dependent cancers. RAS-5845 is now in IND-enabling development, and we will share more information about it at a scientific meeting later in 2021. In summary, despite the menacing COVID-19 pandemic and chaotic macro environment, Revolution Medicines has continued to be highly productive on behalf of patients, and we're proud of our expansive pipeline and strategy to outsmart RAS-addicted cancers as shown here. From our RAS(ON) inhibitor collection, we have 2 assets in development, RMC-6291 and RMC-6236, with additional assets in lead optimization as shown here. In our RAS companion inhibitor portfolio, our SHP2 inhibitor RMC-4630 is progressing through the clinic. Our RMC-5552, our mTORC1-selective inhibitor, should begin treating patients shortly. And our RMC-5845 SOS1-selective inhibitor is now in IND-enabling development. We look forward to reporting on a number of aspects across this portfolio in 2021 and beyond. And having raised an additional $281 million in net proceeds in our recent follow-on financing, we have a very strong balance sheet. We will continue our tireless commitment to patients. And thank you very much for your interest in Revolution Medicines.

Excellent, Mark. That was a very informative presentation, and I'm sure we'll all be watching your story very keenly. So with that, we'll wrap up in the interest of the time. I want to thank Mark and Revolution Medicines for taking part in what has been a very productive and informative series of presentations. We appreciate the time and effort that you did in preparing them. Hopefully, our next conference will be one that we can be -- that can be held in person rather than virtually. But in the meantime, we are very grateful for your flexibility and your presence online. Thank you again from the H.C. Wainwright team.