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spk00: Good day, ladies and gentlemen, and welcome to the Revolution Medicine's third quarter fiscal 2021 financial results conference call and webcast. At this time, all participants are in listen-only mode. Following management prepared remarks, we will hold a Q&A session. To ask a question at that time, please press the star followed by the number one on your touchstone phone. Please be advised that today's conference call is being recorded. If anyone has a 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.
spk05: 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 our Principal Accounting Officer. As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meaning 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 and other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted on our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolutions Chairman and Chief Executive Officer. Mark.
spk12: Good afternoon and thank you for joining us. We're very pleased to report that during this quarter, Revolution Medicines continued building momentum with our targeted therapeutics pipeline, advancing our mission to improve treatments on behalf of patients with a wide range of RAS-addicted cancers representing some 30% of all cancer patients. Our ambition is first to serve the significant unmet needs that remain for patients with KRAS G12C-bearing tumors despite first-generation targeted inhibitors coming online, and second, to deliver first-in-class or best-in-class solutions to benefit even larger numbers of patients with cancers driven by other RAS variants beyond KRAS G12C. RevMed continues making excellent progress reinforcing our belief that the company's innovative and integrated asset portfolio can drive rational mechanism-based combination treatments for the benefit of patients with diverse RAS-addicted cancers. Today, rather than providing a comprehensive overview of RevMed's entire pipeline, I would like to take you through a few highlights of several recent significant scientific presentations made by our R&D organization. As a reminder, represented on slide five of our November corporate slide deck, our primary R&D strategy is to advance our emerging RAS-on inhibitors to suppress RAS cancer drivers through innovative compounds with superior potential, deriving from their unique mechanisms of action and highly differentiated chemical and pharmacologic profiles. I'll update you on these exciting programs momentarily. We also recognize that RAS-addicted cancers are often supported and sustained by various cooperating proteins and cell regulatory pathways that limit the rate or durability of initial responses to targeted therapies. To defeat these oncogenic contributors, we are advancing our collection of high-quality targeted RAS companion inhibitors to deploy in combination with targeted RAS inhibitors in order to enhance clinical benefit. I'll touch on progress we've made in this part of our portfolio as well. RMC6291 is our potent, oral, and selective tricomplex inhibitor of KRAS G12C On with an exciting preclinical profile designed to address persistent unmet needs for patients with cancers driven by KRAS G12C. Shown in slide 8 is 6291's high potency and selectivity for KRAS G12C tumor cells and its favorable comparison to leading members of the KRAS G12C OFF inhibitor class. As shown on slide 9, our scientists recently disclosed data from a mouse clinical trial that was run with 19 KRAS G12C bearing non-small cell lung cancer models to compare the impact of RMC6291 head-to-head, in vivo, with a representative of the KRAS G12C off-inhibitor class. Consistent with findings we've reported in the past from previous experiments in individual tumor models, 6291 performed very well in this larger survey, showing broad antitumor benefit, evidenced by shrinking many tumors, inducing many regressions, including CRs, and demonstrating an overall response rate of 68% in this tumor set. The results of this study as shown on the previous slide and here on slide 10 point to specific advantages in terms of rate, depth, and or durability of response in the preclinical setting and establish an exciting best-in-class thesis for RMC6291 that we look forward to testing in the clinic. Additional data were presented just this week that extended the evaluation of 6291 into gastrointestinal cancers. Slide 11 shows a mouse clinical trial with 13 KRAS G12C-bearing colorectal cancers, demonstrating an objective response rate of 31% and disease control rate of 54%. Further, 6291 showed compelling durability of effect and delayed resistance development. Overall, these findings provide a broad foundation for our best-in-class thesis for RMC6291 that we expect to assess in the clinic. The company remains on track to submit an investigational new drug or IMD application for RMC6291 in the first half of 2022. I'd also like to highlight recent findings with RMC6236 are first-in-class oral RAS selective RAS multi-on inhibitor designed to treat cancers driven by a variety of KRAS mutations, including those that have emerged in patients following treatment with KRAS G12C off inhibitors. As shown on slide 15, our recently reported findings showed significant, broad, and durable activity of RMC6236 in vivo against numerous RAS-addicted tumor models driven by diverse RAS or RAS pathway mutations. In particular, as shown on the right, 6236 drove significant tumor shrinkage across multiple non-small cell lung cancer models with various mutations at the G12 position in KRAS, including G12D, G12V, and G12C. In addition, slide 16, shows a deeper dive specifically into the performance of 6236 in preclinical models of pancreatic cancer with mutations at KRAS position G12. This updated mouse clinical trial data set shows an objective response rate for RMC6236 of 57% across tumors with G12V, G12D, or G12R mutations with nearly complete disease control and sustained antitumor benefits. Likewise, data disclosed this week, as represented in slide 17, show significant antitumor benefit of 6236 across colorectal cancer models carrying either KRAS G12V or KRAS G12D in vivo, characterized by regressions, encouraging disease control, and highly durable antitumor effects. Overall, these data represent a very large and strong body of preclinical evidence that is a robust foundation for advancing RMC6236 to the clinic. The company remains on track to submit an IND for RMC6236 in the first half of 2022 to enable clinical evaluation for patients with these common, serious, and poorly served cancers. In addition to progressing 6291 and 6236 through IND-enabling programs, our RAS innovation platform enables the generation of additional new mutant-selective inhibitors of diverse oncogenic RAS mutants. As examples, on slide 23, which was initially disclosed last quarter, we described breakthrough work on crafting unprecedented potent RAS-on inhibitors that use highly mutant-selective covalent attachments to the KRAS G13C or KRAS G12D variants, respectively. Building on this important progress in drug discovery, recently we reported initial in vivo evaluation of two representative covalent KRAS G12D inhibitors labeled in slide 24 as RM036 and RM037. Both compounds administered orally drove deep regressions in this KRAS G12D dependent pancreatic cancer model, achieving CRs in nearly all animals. With this momentum, we remain on track to select a third development candidate from our lead optimization pipeline to advance into development by the end of this year. We will likely provide an update on this at an investor conference in early Q1. We also expect additional mutant selective RasOn inhibitors to mature out of our ongoing RasOn programs in the coming 12 to 24 months. The second key element of our R&D portfolio is developing targeted RAS companion inhibitors to counter other proteins and biochemical pathways that often cooperate with RAS mutants in driving or sustaining tumors. Today, I'll focus on certain aspects of our SHIP2 inhibitor, RMC4630, which we are developing in partnership with Sanofi, our global development and commercialization partner for SHIP2 inhibitors. RMC4630 is being evaluated in multiple combination studies with approved or late-stage drugs in development. Amgen's CodeBreak 101C study continues evaluating RMC4630 in combination with Sotiracib across multiple KRAS G12C-bearing tumor types. To date, this combination has demonstrated acceptable tolerability. RMC-4630-03 is a new study we announced in August evaluating the efficacy, safety, and tolerability and pharmacokinetics of RMC-4630 in combination with Sotiracib specifically in subjects with advanced lung cancer bearing the KRAS G12C mutation with or without additional mutations. Revolution Medicines is sponsoring the RMC-4630-03 study under its global partnership with Sanofi and conducting the trial in collaboration with Amgen. This study is now recruiting. In addition, under its global partnership with RevMed, Sanofi plans to sponsor a combination study evaluating 4630 in combination with Mirati's KRAS G12C inhibitor, Adagracid, to expand the evaluation of the potential benefit of adding this SHIP2 inhibitor to the KRAS G12C OFF inhibitor class. and we also anticipating evaluating 4630 in combination with RAS on inhibitor assets from our own portfolio as these progress. Finally, the TCD16210 study sponsored by Sanofi continues evaluating 4630 in combination with pembrolizumab, a PD-1 inhibitor, and Sanofi is planning an expansion cohort with this combination in first line PD-L1 positive lung cancer. With these prepared comments, I have tried to convey the status of our development stage assets represented by exciting and robust new data sets that suggest large clinical opportunities ahead for us to address in a wide range of RAS-addicted cancers. Further, our pipeline continues to grow with highly distinctive new assets deriving from our RAS cancer innovation engine, including multiple targeted RAS-on inhibitors and RAS companion inhibitors as we pursue science-driven strategies to outsmart RAS-addicted cancers. Please take the opportunity to review the full corporate slide deck that you can download from our investor relations website. I'll now turn to Jack Anders to report on our financial condition.
spk09: Thank you, Mark, and good afternoon, everyone. We ended the quarter with $609 million in cash, cash equivalents, and investments. Turning to revenue, the company recorded a non-cash, non-recurring gap accounting adjustment that reduced collaboration revenue by $8.5 million during the quarter. This non-cash adjustment is the result of adding the RMC-4630-03 study and deprioritizing the RMC-4630-02 study under our Sanofi collaboration. As a result of these events, we revised our estimates of the accounting transaction price and percentage of work performed to date under the collaboration. These revised estimates resulted in a cumulative catch-up accounting adjustment that negatively affected revenue by $8.5 million. Total revenue including the effect of this non-cash revenue adjustment was $1.1 million for the quarter. Total operating expenses for the quarter increased to $54.3 million, largely driven by research and development expenses, which were $46.5 million. Net loss for the quarter was $52.9 million, or $0.72 per share. With regards to financial guidance, we continue to expect full-year gap net loss to be between $170 and $190 million, which includes estimated non-cash compensation expense of approximately $20 million. And with that, I'll turn the call back over to Mark.
spk12: Thank you, Jack. We believe that RevMed is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy, a growing set of exciting product assets, and a strong balance sheet. We are proud of the tireless commitment to patients by our organization and are grateful to our patients and their families and the many partners who work with us for providing RevMed with the opportunity to advance our unique pipeline of RAS-on inhibitors and RAS-companion inhibitors, which we believe may transform the treatment of RAS-addicted cancers in the future. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session. Operator?
spk07: Thank you, sir. As a reminder to all participants, if you have a question, please press star 1 on your telephone keypad. Again, it's star 1 on your telephone keypad. Please stand by while we compile the Q&A roster. Your first question is from the line of Michael Schmidt with Guggenheim. Your line is open.
spk01: Hey guys, thanks for taking my questions. I just had a couple ones. Maybe first on your KRAS-on inhibitors, my question there was if you could remind us perhaps what the KRAS wild-type inhibition is of your pan-KRAS inhibitor relative to the mutation-selective inhibitors. And related to that, how you envision clinical development next year of RMC6236 relative to the selective inhibitors like 6291 or the G12D inhibitor that you mentioned?
spk12: Hi, Michael. Thanks very much for your questions. First, with regard to the RAPS multi-inhibitor RMC6236, it is active on wild types. And there's really not a differentiation on mutants versus wild type, so it is a multi-RAS inhibitor. And as you know from previous conversations, we view this as a strength and a feature of the molecule in that we know that multiple forms of wild type RAS can contribute even to tumors that are driven primarily by a mutant form of RAS. And so the ability to suppress both of those does offer a potential therapeutic benefit, added benefit. But as you point out, or as you're implying, it also carries with it some liability in terms of the degree to which you can suppress RAS in normal tissues and still be tolerated. So I think we'll be operating with some sort of ceiling, but in the evidence that we've generated so far, including evidence that I just described and is covered in the new a corporate deck across many different model systems, we've seen quite dramatic anti-tumor effects at tolerable doses. So I think that's going to be the name of the game is to find the right dose and schedule in the clinic to maximize anti-tumor benefit without incurring intolerability. Your second question is about our clinical strategy for RMC 6036. It's a terrific question. It's about a month or two too early. I think we'll talk about that as we enter 2022 and as we're really wrapping up the activities around the submission of the IMD and moving into clinic, and we will try to share some sort of overview about how we'll approach both RMC 6091 and RMC6236 in the first half of 2022.
spk01: Okay, makes sense. And then the follow-up on the SHIP2 program 4630 regarding the pembrolizumab combination study, it looks like, as you said, Sanofi is advancing into an expansion cohort in lung cancer. Any visibility on when you or Sanofi might be able to disclose data from that arm of the study?
spk12: Well, as you point out, Sanofi is sponsoring that, and so they have the right to make that determination, and we will know about it since we're in close contact with them, but we can't communicate anything about that. You've got to go directly to Sanofi. But as you rightly indicated, You know, they are activating that expansion, and we're looking forward to seeing how that goes.
spk01: Okay, and then just one more. I'm not sure if you can answer, but on the trial collaboration around Miradi's KRAS inhibitor, I guess in addition to Amgen, is that – really just to, you know, hedge your bets, more or less, and cover any of the KRAS inhibitors out there, or is there more to it, to also adding that to the trial lineup?
spk12: Yeah. We've always anticipated that players with Rapsodon inhibitors would try to access a wide range of potential companion inhibitors. you know, there are differences between all these different molecules that are floating around. And so it makes sense if you own an important RAS inhibitor asset that you would make sure to keep open, you know, all potential lines of combination and to evaluate them. So I think this very much fulfills our expectation that the leading RAS inhibitors will look for a leading CHIP2 inhibitor to combine with. And in our view, RMC4630 is a leading SHIP2 inhibitor, and I think this suggests that others think so as well. You know, practically speaking, from our perspective, what it will do is to help expand the range of RAS inhibitors that the SHIP2 inhibitor can be combined with and to build a broader data set. But, of course, the Amgen study and the O3 study that we've announced will likely get to sort of the fundamental answer to the question earlier than the Adagracib data. But we're excited to see Adagracib pulled into this as well, and it's just lots of parties dancing with lots of other parties, and it'll all sort of fell out down the line.
spk01: Okay, great. Thanks for taking my question.
spk07: Your next question is from the line of Jonathan Chang with SVB Learning. Your line is open.
spk06: Hi, guys. Thanks for taking my questions. Can you talk about how you're thinking about a dose escalation strategy with the RAS-on inhibitors as you prepare to enter the clinic next year? Have you received any sort of regulatory input on this? And how might that inform how soon we could see initial proof-of-concept data from those programs?
spk12: Yeah, so I think, thank you Jonathan, nice to talk with you and thanks for your questions. As I mentioned, in the early part of 2022, we'll start to lay out more information about how we'll approach the development, the clinical development of RMC6291 and RMC6236. I'm not sure that there's something specific on the question of dosing and dose escalation that you're trying to ask about. Is there something kind of narrower that you could clarify?
spk06: Any more sort of granular thoughts on, you know, I guess just trying to back out when we might see initial efficacy data from those programs?
spk12: Okay, so it's really a timing question. It's a good question. I'd say hold that. You're, again, a couple of months ahead of us in terms of the question that you're asking, but we'll try to be forthcoming on that point in the early part of 2022 as we lay out the overall strategy for development.
spk06: Understood. And just maybe one last question from me. Can you discuss the considerations for choosing your next draft on development candidates? Thank you.
spk12: Right. Well, you know, our process here reflects the fact that we have multiple programs running in parallel. We sort of select some to talk about, but we certainly don't talk about all the things going on. It's a very leveraged drug discovery process, meaning that each of the programs is learning from each of the other programs, so as soon as one thing advances, we gain knowledge that gets fed into all the other programs. And there's just sort of a constant shuffling going on, particularly in lead optimization, where you're trying to optimize against a variety of different parameters. It's always hard to predict on a given day when those parameters will all come together in the optimal molecule. And so we don't really make a decision about a molecule until we make a decision. So we have all the data, and it's up to the teams to determine the pace of that based on the data packages that are brought forward. So to a large degree, it's driven really by you know, if you will, a bit of an internal competition, but really a set of standards that each program has to meet. And when it meets those standards, the packages get presented, and we make a decision about whether to move something forward or not. So far, we've not made decisions where we've decided to sort of hold one thing back and move something else forward. We've just been fortunate to be able to advance the molecules that are being proposed to advance, and it just happened to be RMC69-1 and RMC63-6 which were proposed on the very same day last year and accepted on the very same day. But there isn't sort of a hyper strategy to prioritize in terms of advancing molecules. That's not to say that there isn't a strategy around which targets we prioritize in the discovery process. We, of course, can't work on 36 targets simultaneously. We work on a smaller number than that. So there is some prioritization that's going on there. But at the end of the day, it's just when the data packages become available and we evaluate them quite quickly and make a determination about whether something qualifies to advance.
spk06: Got it. Thanks for taking the questions.
spk07: Your next question is from the line of Eric Joseph with JP Morgan. Your line is open.
spk08: Hi. Good afternoon and thanks for taking the questions. Maybe just to follow up on Jonathan's, I'm wondering whether from your dose ranging, dose range finding studies or pre-IND work with 6291, whether you can sort of talk a little bit about sort of the anticipated dosing interval or PK profile, whether you anticipate any, having to evaluate intermittent dosing when the phase one gets underway. And then following up on the Sanofi-Mirati collaboration, do you have a sense of how much of the focal indications in their phase 1-2 study might overlap with your O3 trial or with Amgen's code break 101c?
spk12: Okay. Hi. Nice to talk to you. Thanks for your questions. With regard to SPARM C69-1c, do you want to comment? The question was about Are we planning daily dosing versus intermittent dosing, and have we learned any quotes? For RMC-6291. For RMC-6291, that was the question.
spk11: Yeah, sure. I think what we're learning from the current information coming in, particularly from the sotiracid and advogracid programs, is that you need to really continuously cover the mutant G12C for as long and as hard as you possibly can. And so in that respect, it is unlikely that some form of intimate and dosing schedule will be deployed with IMC6291, which has at least as good selectivity against G12C, the mutant G12C as it does against wild-type RAS. So we're not anticipating having to deploy an intimate and dosing strategy with IMC6291, or indeed with any of our truly mutant-selective RAS-on inhibitors that we bring forward to be up behind IMC-6291. It's a strategy that I think works very well for inhibitors that inhibit wild-type RAS pathway signaling. I'm not sure that it's either necessary or even desirable for the mutant-selective RAS-on inhibitors.
spk08: Okay, that makes sense. From the PK profiling work that you've done, do you have a sense of whether you have coverage for once daily dosing versus twice daily?
spk11: The PK profile of RMC69-1?
spk08: Correct.
spk11: Yeah, it's very difficult to predict that. I mean, we've run the usual sort of allometric scaling and what have you. We're still waiting for some data to come in, so it's not complete yet. You know, the default, I suspect, will be once daily dosing, but once we get some PK in the clinic, we'll have to revisit that and see whether that's still the best thing to do. I mean, you know, we have quite a lot of flexibility there. But for now, I think it would be safe to assume that that's a good starting position. But we, of course, reserve the right to change our mind as information becomes available to us in the clinic.
spk08: Understood. And just coming back to the Sanofi-Miradi collaboration, what is, yeah, if you could just kind of talk about what's complementary to the Lumicrast combination with RMC4630 versus potentially redundant.
spk12: Yeah, if I might just add something on the issue of QD versus PID dosing on RMC6291, just to return to that briefly. And that is just keeping in mind that the RAS, the dynamics of inhibiting RAS on versus the dynamics of inhibiting RAS off may be very different. And I know, Eric, you and I have talked about that in the past, that, you know, we have this immediate and complete cessation of RAS signaling from KRSG12C when we hit it with a RAS on inhibitor as opposed to the requirement for sustained accumulation of RAS off in the compound bound form which is required for RAS off inhibitors to work. So it's really, it's not really an apples to apples comparison if you're sort of thinking about the paradigm for adagraphic and sotiraptive and the other RAS-off inhibitors versus RMC69-1, it's a different paradigm. Nonetheless, I think Steve's answer was very clear about what we believe is the default assumption here, and if we're informed otherwise in the clinic, we'll react to it. I think with regard to CodeBreak 101 and Mirati, well, he's asking sort of both questions, so maybe you could comment on this, Steve. Part A was How does it differ versus, how is it complementary to CoBreak 101C? And then the second question was, what about the .
spk11: Yes. The RMC46303 study, which is the combination study with soteroacid, was deliberately designed to be different but yet complementary to the lung cancer component of CoBreak 101C. It is different. We learned from some of the, you know, the public data with regards to how to divide up the cohorts. As you know, I mean, there are essentially two predefined cohorts in that study. One which is essentially restricted to patients who have G12C mutations and commutations in in other genes that might alter the response to either citric acid or even RMC4630. So that allows us to evaluate those arms separately. There are some other subtle differences as well, which may become important. Firstly, the number of lines of cryotherapy is restricted in the O3 study, which is not in Cobrate-101C. And then the probably the more obvious operational difference is that the lung cancer arm of COBRE 101C is restricted to the United States, whereas the O3 study will involve a substantial portion of patients outside the United States. I don't think that's going to make any difference to the ultimate evaluation or evaluability of the data set. The Mirati combination is, we see it as hugely complementary. Firstly, as Mark said, it's inevitable, because RMC464 is a companion inhibitor for all RAS inhibitors, and adverteracid is one of those RAS inhibitors, and it's complementary, and it's both enabling as well, because at the very least, safety data from that study will enable us, if we wish, to move very quickly into more advanced trials, should that become desirable in combination with adiproacid. So I think it's all part of the rich tapestry of using ions in 463L as a companion for RAS inhibition. I think we're very focused right now on G12C because, of course, those are the two, you know, the more obvious clinical RAS inhibitors inhibit G12C. But this, of course, is going to become incredibly important later as we get inhibitors against RAS mutations that are not G12C. And we very much hope to be first into the clinic with those at some future date.
spk08: OK, great.
spk07: Your next question is from the line of Mark Fram with Cowan & Company. Your line is open.
spk03: Yes, thanks for taking my questions. Maybe just on your last comment about safety read across from trials and that that's very much an ongoing process. Are you able to state the code break trial, has it now selected a recommended phase two dose or with that target dose of 200 milligrams day one, day two, or is that still not quite finalized yet? And then related to that, is in the O3 trial, because the recommended phase two dose hadn't been selected when you were opening that up, there's a safety run-in period. Has that safety run-in period been completed on your end, or are you able to skip it given the evolving safety data within CodeBreak?
spk12: Hi, Mark. Thanks for your question. So with regard to Lumicraft, As you know, we're not the sponsor of that Code Break 101c study, so that disclosure needs to come driven by Amgen, so we don't have any update on that. And then with regard to the O3 study, you know, we just started that. We announced the study in August, and we just, you know, today are now indicating that it's actively recruiting It would be fantastic if we could tell you that we had already recruited and dosed enough patients to have selected a dose or to complete the dose run-in, but that wouldn't be true. So I can't say so. But, you know, I think we'll be informed by the selection of that dose when Amgen is able to disclose. If they do not disclose the dose, publicly while we're dosing in the running. We'll dose at 140 milligrams and then we'll bump up to 200 milligrams. So I think we're still in the same paradigm that we were in, you know, a few weeks ago or a couple of months ago, and we'll update you when we are able to give you a material update on that.
spk03: Okay, that's helpful. And then just in terms of the guidance from the O3 trial to potentially disclose some results the back half of next year, is that your mind likely to be just kind of the data from that safety run-in period, or should we think broader than that?
spk12: Oh, yeah, that's a good question. I mean, what we intended to communicate was that our ambition, our aspiration, is to have high-level findings from the activity of the combination, anti-tumor activity, by the end of next year. Obviously, that depends on how quickly we ramp up enrollment, but I don't think it's really strictly going to be driven by that short run-in. I think it's driven by the desire to have a larger number of patients, which is really the whole purpose of that study is to get to that kind of range of N equals 46 split between the cohort without co-mutations and the cohort with mutations, not necessarily split evenly, but split between those two. So that's the kind of data we're really looking for. I think the run-in to us is a relatively modest kind of early piece, but we hope to generate, you know, more substantial data throughout the year. But, of course, everything depends upon enrollment, and, you know, it's very hard to predict exactly enrollment rates before you've enrolled patients, so our best guess is by the end of 2022 we'll be in a position to share some. All right.
spk03: Thank you. Very helpful.
spk07: Your next question is from the line of Chris Shibutani with Goldman Sachs. Your line is open.
spk10: Thank you very much, and apologies in advance. Hopefully there won't be too much background noise off the train station. Mark and Steve, there were two questions that I had, one on colorectal cancer opportunities. I believe this is some new data that you're sharing preclinically in terms of 6291 and 6236. I'm curious to know how you're thinking about the opportunity set and the strategy, particularly in view of clinical data that's been unfolding, particularly, for instance, with the EGFR combinations that are ongoing. What's your view on the opportunity? What's the strategy looking like?
spk12: Yeah, thanks, Chris. Appreciate your going to trouble calling in despite being on the road. Thank you so much. Colorectal cancer, Steve, I think you probably will want to comment about this. Yeah.
spk11: Yeah, I mean, firstly, Chris, you know, as you know, just under half of colorectal cancer is RAS mutant, and it's a really nasty disease to have. So in the context of, you know, serving an unmet medical need, it's a really high priority for us. We are encouraged by the 6291 data in RAS mutant colorectal cancer, and whether or not RNC 6291 as a single agent has enough punch there to really do justice to patients, we'll wait and see. But I think what you're angling at is ultimately, you know, that we are prospectively planning to combine RMC69-1 with companion inhibitors in colorectal cancer. And, you know, we have a number of those in our portfolio, but we're certainly not afraid to do a clinical trial in combination with one of the anti-EGFR antibodies if it comes to that. But, you know, it's a very We expect RMC69-1 to have a reasonably clean selectivity profile, so we don't anticipate there being overlapping toxicities with EGFR inhibitors, and that's a completely legitimate path forward for G12C mutant colorectal cancer. Now, of course, the big unmet medical need in colorectal cancer is in the other G12 mutations because most RAS mutant colorectal cancer is either a G12D mutation or a G12B mutation, and I think that's where the impact of the RMC6236 data comes in. You know, we've seen very impressive responses in RAS mutant colorectal and pancreatic cancer with single agent RMC6236, and we have no hesitation in testing IMC 6236 as a single agent in RAS mutant pill on cancer once we get to that point. Because IMC 6236 has RAS wild type activity, it does restrict the combinations that we may be able to use a little bit, but nevertheless, you know, there is a very active combination preclinical program ongoing, which we haven't disclosed yet and will do in due course. But I think in general what you can expect to see is pretty much what we have already observed with the KRAS-OF inhibitors, which is there will be some single-agent testing. If it packs a punch, then that will be great, and then the combinations will move forward to try to optimize on the clinical benefit. Okay. Great.
spk10: And a second question, if I may, one on strategy. Oh, I'm sorry, Mark, but did you want to add some comments? Please do.
spk12: Yeah, I was just going to build on Steve's good comments there. You know, there probably is also an advantage to 6236 in its wild-type antirast activity, which I alluded to earlier with Michael's question, and I think that could come into play in colorectal cancer and the where we know that other forms of RAS do step in and contribute. That's, I think, quite well established now. So we're quite excited about the data sets in colorectal cancer for 69.1 and 63.6, and I appreciate your highlighting that, and I think there's real opportunity there.
spk10: Great. And then if I could follow with a strategic question. You guys have a truly strict strategy and capacity. So in the past, you've done a number of partnerships, including with Amgen, Sanofi, for instance. There's pros and cons of doing these approaches. Maybe somebody else gets to pay the bill, but then they also have control, perhaps better, of communication, particularly with shareholders or pacing and whatnot. As you sit here in November of 21, the rash on portfolios certainly seems to be coming into its own. And some of the earlier questions also We're trying to contemplate how much you guys felt you could do on your own versus do with others. If you did a partnership, what's the most important priority for you? Or are you thinking now that you're going to go it alone for a while as we, for instance, head into that notorious competitor conference in January?
spk12: Thanks. Great set of comments, Chris. I appreciate everything you said and agree with it all. As to our posture, I think we are fundamentally viewing the RAPs on inhibitor opportunity as being a RevNet opportunity. I think, you know, we're leaders there. We're pumping out these molecules at an astonishing rate and at high-quality molecules, and the preclinical data are continuing to kind of affirm the commitment for us because of the kinds of success we're seeing. particularly anxious to get into the complexities of partnerships around these assets. If we do it, it would be very narrow. I could imagine a single asset, a partnership, but I don't think it's necessarily likely that we would do it, but I can imagine it. But I think a big feature here, and you alluded to this in your remarks, is that it does actually take extra bandwidth for us to enter partnerships. It can complicate our own strategic activities because we have to now make decisions in concert with somebody else's strategic vision, which almost inevitably is not the same as ours. That's just the nature of two companies. They will have different views. And so there is a certain amount of heat that just gets generated that we have to support just in doing a partnership. And so at some point, you then wonder whether or not the net benefit is there. At the same time, we are expanding our programs. We have two more compounds going into the clinic, but we'll have, you know, four in the clinic in 2022, and I expect there will be more after that. And so our pipeline is getting very big, costly, and if we talk about the combinations which can offer that, you know, add another level of complexity. So there is always going to be a voracious appetite for supporting that with personnel and, you know, things that cost money. So we'll see. But I would say our default assumption is that there would not be a partnership anytime soon. But there has been significant interest inbound, and we'll see if we can design something that's optimized for us rather than for somebody else.
spk10: Great. Thank you both for your thoughtfulness and candor. Talk to you soon.
spk07: And your last question is from the line of Ben Burnett with C4. Your line is open.
spk02: Hey, thank you very much. I was wondering if you could just offer maybe just a little bit more color on some of the strategies that you might be able to employ with regard to the RAS multi, RMC-636, just what you can employ clinically to optimize the therapeutic window if needed. And then I have a quick follow-up.
spk11: Maybe Steve wants to comment on that. For 6236, yeah. We've tried hard to message this because of the initial wave of concerns that we had over anything that hits wild-type rasping toxic. There are a number of ways that we are going around optimizing the therapeutic index around C6236. The first and most obvious is that we think it's inherent in the fact that tumors with RAS mutations are addicted to mutant RAS, that there will be a therapeutic index. And I think that the more information we see from sartoracid and adagracid, that that becomes increasingly clear. You know, tumors with mutant RAS seem to be highly dependent on it, and if you switch that off, then they tend to implode to at least to some extent. So we do expect the tumor to suffer more under exposure to RMC6336 than normal tissue. There are, as we've alluded to in some of our previous disclosures, certainly recent disclosures, ways of scheduling RMC6236 that can improve the therapeutic index. I think it gets back to this concept of intermittent dosing. But I think it's important to point out RMC6236 is a very unique molecule in as much as the pharmacokinetics in tumors seems to be different from the pharmacokinetics in normal tissue. And I think that has something to do with the binding of RMC6236 to the intracellular chaperone cyclophilin A, which on a net basis across tumors seems to be more abundant than in normal tissue counterparts. So what you see is a sort of residence time of RMC6236 in tumors, which greatly outstrips the residence time in normal tissue. And what that ultimately results in is that the intermittent dosing that may be deployed in the clinic actually only results in intermittent inhibition of RAS in normal tissues and not intermittent dosing of RAS in tumor tissue, which ultimately creates quite a significant therapeutic index because the dynamics of RAS within tumors and the way that the RAS pathway signaling is inhibited diverge very dramatically with quite subtle changes in the intracellular exposure. So on top of that, I think we can harness the immune system. We've already disclosed some data on how RMC6236 significantly changes the tumor microenvironment in a way that would favor the anti-tumor effect versus any inhibition on normal tissue. And then ultimately, if we need to preferentially enhance the anti-tumor activity of RMC6236. We can combine it with something that has a selective anti-tumor effect and something which even potentially has a synergistic effect. And there are a number of things that we're testing right now in that respect. So I think that the direction in which we're heading, we're confident that we will achieve a therapeutic index for RMC6236. And that clearly, the nature about how it's manifest is going to vary probably from patient to patient and from patient population to patient population. But there are a number of strings we can pull and we're pulling all of them.
spk02: Okay. That's super helpful. Fascinating. Just one other quick question. Is there, like what is the relevant potency? KRAS inhibition between the 6236, the multi-RAS inhibitor with the G12C specific inhibitor. And I guess what's motivating that, you showed some preclinical data of the multi-RAS inhibitor that looks like it was done at a lower dose to the G12C inhibitor. I think 25 mg per kg versus 200 mg per kg. And so I guess I was just wondering, is the multi-inhibitor more potent than the G12C? And if not, I guess, could you just comment on the choice of dose for those assays?
spk11: Yeah. The potency as measured in the sort of the classical in vitro systems against G12C is not terribly different between RNC69-1 and RNC63-6. In the context of how you might deploy RMC6236, there is still some possibility that it would have utility in patients who have tumors harboring the G12C mutation. It's not entirely clear to us at this stage how we will develop RMC6236 in patients with G12C mutations as opposed to the other G12 mutations or indeed the other KRAS mutations. And as Mark said, we'll go into that in a bit more detail in the early part of next year. With regards the dosing paradigm, I mean, right now we are dosing RMC6236 in our preclinical models at a dose and schedule which is well tolerated. and which has profound anti-tumor activity against all of the RAS mutations that we've shown you in the slide deck today, it is quite possible that some of the anti-tumor activity that we are seeing with RNC6236 is due to the inhibition of feedback through wild-type RAS. It is not completely restricted to its profound inhibition of the mutant RAS. And so it's very hard to compare RMC6236 and RMC6291. They're very complementary compounds. And in fact, you know, in the long-term strategy, it is quite possible that RMC6236 could be a very useful companion inhibitor for a RAS mutant selective inhibitor like RMC6291. So I don't think, you know, we see these as very complementary compounds. compounds marching forwards together. And for all we know, they may well be useful in combination in G12C mutant tumors.
spk12: And if I could add to that, I think that's really well put, Steve, with regard to G12C. And as you mentioned earlier, as Steve mentioned earlier, that concept extends to other mutant selective inhibitors of other targets. And we just shared with you today and recently data, for example, on our oral highly mutant-selective KRAS G12D inhibitor, which is coming just behind RMC6036. And we really don't see those as mutually exclusive. They could end up converging. It's quite a remarkable bit of biology that's going on here. We're trying to create a master clinical toolkit, if you will, of compounds that are that have special features. And sometimes those features are particularly useful for killing tumors. And if we can put them together in the optimal way, we'll have the greatest impact for patients.
spk02: Interesting. Thank you.
spk07: I see no further questions at this time. That concludes the question and answer session for the call. And I'll hand the conference back to Dr. Mark Goldsmith for final comments.
spk12: Well, thank you, Operator, and thank you to everyone for participating today. We appreciate your continued support of Revolution Medicines.
spk07: This concludes today's conference call. Thank you for joining Humana Disconnect. Stay safe and well.
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