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spk06: Good day and welcome to Revolution Medicine's first quarter 2023 earnings conference call. At this time, all participants are in 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 that your hand is raised. To withdraw your question, simply press star 1 1 again. Now, we ask that each participant limit their questions to one initial question and one follow-up question. After that, we just simply ask that you rejoin the queue, and we will address additional questions as time permits. As a reminder, today's conference is being recorded. I would now like to turn the conference over to your host, Aaron Graves, Senior Director of Corporate Communications and Investor Relations. Aaron, please go ahead.
spk01: Thank you and welcome everyone to the first quarter 2023 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine's chairman and chief executive officer, Dr. Steve Kelsey, our president of R&D, and Jack Anders, our chief financial officer. Peg Horn, our chief operating officer, will also join us for the Q&A portion of today's call. 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 press release, as well as all of the company filings with the SEC concerning these and other matters. During this call, we will be referring to a few slides from our corporate presentation, which was posted to our website prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark.
spk05: Thanks, Erin. It's good to be with you this afternoon and to provide an update on our first quarter 2023 earnings. On today's call, I'll provide a brief update on our company progress. Dr. Kelsey will cover a few highlights of our R&D progress, and Jack Andrews will provide highlights of our financial results before we open the line for questions. We're off to a strong start this year with two important steps that we shared in the first quarter. First, we communicated early findings from the Phase 1-1B study of RMC6236, our first-in-class RAS multi-on inhibitor, which showed encouraging anti-tumor activity, safety, and tolerability for patients with advanced solid tumors harboring a range of distinct KRAS G12X mutations, particularly KRAS G12D and KRAS G12V. While covering a relatively small sample size, this was an important update as it provided initial validation of the novel mechanism of action and potential clinical utility of RMT6236 and also carried positive implications across our pioneering and deep portfolio of RAS on inhibitors. A second important step was a successful public equity offering in March, which raised $345 million of gross proceeds and further reinforced our strong financial position. The additional capital is allowing us to consider additional near-term and long-term investments to strengthen clinical development of our first wave of RAS-on inhibitors and to prepare our organization for the advancement of RMC6236 through the hiring of additional senior leaders and staff. We'll now turn to Dr. Steve Kelsey to review several clinical and preclinical highlights from the quarter. Steve?
spk10: Thank you, Mark. Let me provide a few additional comments on our first wave of development stage RAS-on drug candidates beginning with updates on dose escalation of RMC6236, our RAS multi-on inhibitor in the RMC6236-001 trial. First, I am pleased to report an update on a case we highlighted in February of a patient with previously treated metastatic pancreatic cancer harboring a KRAS G12D mutation. We reported that this patient had an unconfirmed partial response at cycle five day one on RMC6236 at 80 milligrams daily. The partial response was subsequently confirmed by RASIST with an 82% reduction in tumor measurements on cycle seven day one. The CT scans are shown on slide 14 of the corporate deck, and this patient continues on treatment. Second, We have escalated the dose level through 160 milligrams daily and are now evaluating 220 milligrams daily while also continuing to backfill the 120 and 160 milligram dose levels. We are encouraged that we continue to accumulate clinical evidence of anti-tumor activity for RNC6236 at doses that appear to be well tolerated. We currently plan to provide additional updates on the program via multiple clinical updates this year. These will be a combination of corporate disclosures and presentations at scientific meetings beginning in Q3. We expect to be able to provide a more detailed schedule of these updates in connection with our Q2 earnings release. We'll next discuss RMC6291. our mutant-selected KRAS G12C ON inhibitor. At the recent AACR annual meeting, we presented new preclinical data and provided the first disclosure of the chemical structure of this drug candidate. This is the first structure disclosure of a drug candidate from our pioneering RAS ON inhibitor collection. RMC6291 exemplifies how we are able to bring favorable drug-like properties, including potency, selectivity, and oral bioavailability to these beyond rule of five macrocyclic compounds. We are continuing to dose escalate in the RNC6291001 study and are now focused on a twice-daily dosing schedule to maximize continuous drug exposures. RMC6291 continues to be well tolerated, and we have not yet reached the maximum tolerated dose or selected a recommended phase 2 dose. We remain on track to provide an update in the second half of this year. RMC9805, our mutant selective oral and covalent KRAS G12D on inhibitor, remains on track in support of the goal of beginning clinical evaluation of this groundbreaking compound in mid-2023. Hence, we'll shortly have our entire first wave of three Ras-on inhibitors under clinical evaluation. As many Ras mutant epithelial tumors have a propensity to metastasize to the brain, It is important to define the potential activity of these RAS1 inhibitors against tumors that have metastasized into the central nervous system. This may become particularly important if improvements in treatments of systemic or visceral disease allow more cases involving the central nervous system to emerge. Today, we highlight preclinical studies demonstrating anti-tumor activity in intracranial tumors by each of the three first-wave Ras-on inhibitors. As shown on slide 21 of the corporate deck, we used a well-validated intracranial xenograft model of human non-small cell lung cancer carrying the KRAS G12C mutation, the LU99 model, in which an embedded luciferase gene enables non-invasive quantitation of tumor size. The graph on the far left of the slide shows the bioluminescent signal intensity of tumors in untreated animals, and for validation, adjacent to it is a group of animals treated with adiposib at 100 milligrams per kilogram twice daily that showed a roughly 10 times lower signal representing significant tumor reduction. This model and results match those published by Mirati, an important point since Adagracid was reported last year to display anti-tumor activity against brain metastasis in patients with KRAS G12C lung cancer, consistent with the preclinical results. The next group in orange shows the signal from implanted brain tumors treated with RMC6236 at 25 milligrams per kilogram daily. showing encouraging anti-tumor impact that is essentially indistinguishable from that of adagressive. And the next group, in blue, is mice treated with RMC6G9-1 at 100 milligrams per kilogram twice daily, a dose selected to be identical to the adagressive treatment regimen, where a greater anti-tumor effect is observed. And finally, on the right, is an analogous study of RMC9805 versus control in an intracranial model of pancreatic cancer carrying KRAS G12D, showing a profoundly reduced signal, indicating a significant anti-tumor effect by this compound as well. Despite the limitations of these orthotopic models, collectively, these favorable preclinical results define a shared property of all three RAS-on inhibitors to potentially penetrate into central nervous system metastases, a property not shared by all anti-cancer agents. This will be evaluated in subsequent clinical trials. Finally, I'd like to provide a brief status update on our two clinical stage RAS companion inhibitors. First, our SHIP2 inhibitor, RMC4630. The Global Phase II RMC4630-03 trial evaluating RMC4630 in combination with Sotiracid for patients with KRAS G12C non-small cell lung cancer is fully enrolled, and we remain on track to read out top-line results in the second half of this year. Second, our mTORC1 selective inhibitor, RMC5552, continues its evaluation as monotherapy in patients with tumors carrying mutations associated with hyperactivation of mTORC1 signaling with the goal of advancing into combination studies with RAS-on inhibitors in select patients. Previously, we were focused on dose optimization in the six to eight milligrams a week range after observing dose-limiting mucositis in patients treated at higher doses, a side effect that is common with mTOR inhibitors. Since then, we have successfully piloted a revised prophylaxis strategy that appears to diminish both the frequency and severity of mucositis and has allowed dose escalation above 8 milligrams per week. We plan to provide a clinical update on RMC5552 at a scientific meeting in the second half of this year. Back to you, Mark.
spk05: Thank you, Steve. In conjunction with the clinical momentum described above, we've also continued building our organization with a particular emphasis on enhancing our late-stage capabilities to support further progression of assets such as RMC6236. I'm especially pleased to announce today several new executives who have joined the leadership group at RevMed and bring substantial experience and track records to our efforts. Dr. Wei Lin, an oncologist with academic and industry experience, has joined us as chief medical officer, a significant leadership addition to Dr. Kelsey's R&D organization. After completing medical training at Harvard Medical School and the MD Anderson Cancer Center, Wei led early stage and late stage cancer drug development programs during a career at Genentech, Nectar, and Eraska, and he now oversees clinical strategy and medical affairs at Revolution Medicines. Alicia Gardner has joined as Senior Vice President for Commercial. In her career at Genentech, Alicia held a variety of leadership roles across its oncology and hematology franchises, including life cycle management, commercial strategy, and launch planning. And we have also welcomed Nisha Brown as Vice President of Commercial Development, Zane Rogers as Vice President of Regulatory Affairs, and Sriram Naganathan as Vice President of Chemistry, Manufacturing, and Controls. With these highlights of our recent R&D and organizational progress, I'll now turn to Jack Anders, our CFO, to provide a financial update. Jack?
spk14: Thank you, Mark. During the first quarter, we strengthened our balance sheet with the upsized public offering of common stock, raising gross proceeds of $345 million. Net proceeds were approximately $324 million after deducting underwriting discounts, commissions, and estimated offering expenses. Including the financing, our ending cash and investments balance as of March 31, 2023, was $909.8 million. which is now expected to fund planned operations into 2025. Revenue from our collaboration agreement with Sanofi was $7.0 million in the first quarter of 2023. Total operating expenses for the first quarter of 2023 were $82.2 million and increased by 25% over the prior year period. The increase in operating expenses was largely due to R&D expenses related to the advancement of RMC-6236 and RMC-6291 into clinical trials, as well as an increase in personnel-related expenses related to additional headcount. Net loss for the first quarter of 2023 was $68.1 million, or 72 cents per share. We are updating our financial guidance for 2023 and now expect full year 2023 gap net loss to be between 360 and 400 million, which includes estimated non-cash stock-based compensation expense of 40 to 50 million. The increase in expected gap net loss is a result of increased investments to support and strengthen clinical advancement of our first wave of Rasson inhibitors. including expanded clinical supply and additional senior leaders across late-stage development, manufacturing, and commercial planning for RMC 6236. And with that, I'll now turn the call back over to Mark. Thank you, Jack.
spk05: We are highly energized by the exciting pipeline and organizational progress so far this year, with ambitious plans to continue amplifying this momentum. We look forward to sharing further clinical updates on our first wave of RAS-on inhibitors and RAS-companion inhibitors in the second half of the year. We deeply appreciate the support of our patients, clinical investigators, scientific and business collaborators, advisors, and shareholders, and the tireless efforts of our RevNet employees in pursuit of our mission to outsmart RAS-addicted cancers. This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session.
spk06: Thank you. At this time, we'll conduct the question and answer session. As a reminder, to ask a question, you'll need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, simply press star 1-1 again. We ask that each participant limit their questions to one initial question and one follow-up question. And after that, we'll ask participants rejoin the queue and we'll address additional questions as time permits. Please stand by while we compile the Q&A roster. Our first question comes from Mark Fromm with TD Cowan. Mark, your line is open. Please go right ahead. Mark? Your line is open. Mark Fromm?
spk09: Yes. Sorry. Thanks for taking my questions and congrats on the progress and a little bit of data update, Steve, that you dropped in there. Just looking forward to the additional 6236 updates. Maybe to start off, just can you give some context for the patient numbers? Right now, most of the data has been in G12D patients, in part from the epidemiology. Should we you know, expect in these next updates to see, you know, the POC kind of get broadened out to other mutations in histologies? Or, you know, is this really staying, given the epidemiology, just very focused on G12D? And then I'll probably have a follow-up there.
spk05: Thanks, Mark, for your question. I don't think we can really give you a lot more color on that right now. Obviously, we're still accumulating data. We're still following patients who have been on study. We are enrolling into escalation cohorts, and then we're backfilling at doses below the escalation dose. So, you know, we'll certainly have a larger N. As you know, to a large degree, we think that the patient population represented the epidemiology broadly. which is that KRAS-GCOV is the most common mutation. And that's what we're seeing in the study. But we are seeing additional genotypes. In terms of histology, you know, clearly we continue to see most patients in the pancreatic cancer and non-small cell lung cancer tumor types. But there are some others as well. So it's hard to say from where we are today. We'll know better. as we get closer to that disclosure point.
spk09: Okay, that's helpful. And then, you know, obviously the net loss guidance implies, you know, a significant growth in expenses kind of here over the remainder of the year. Can you just kind of walk through what some of those priority trials are that you're looking to start? You know, is that really monotherapy expansion for the multi-RAS and maybe the G2LC, or is this really the combo work getting underway and, you know, what's the priorities there?
spk05: Yeah, I don't think today we're necessarily announcing new new studies. I think it's more along the lines of plans that we've already had. But the probability for those plans, of course, has gone up because of the progress. And we do feel that there it is justified to increase our commitment to supply, which will supply both this year and continue providing support into studies that extend into next year as well, as well as expanding the personnel, the senior leadership that we talked about and so on. So, I don't think it's really today a point for us to start disclosing the broader development plan around RMC 6236 specifically. You can certainly expect that we're continuing monotherapy and expanding there and that a priority as well. to run in parallel is to get into the combination studies, but no specific update today on that. I think as we get later into the year and after we've unveiled more clinical data, then I think it will be more appropriate to sort of combine that with projections about what's coming next. Okay. Thank you.
spk06: You're welcome. Please stand by for our next caller. And our next question comes from the line of Eric Joseph with JP Morgan. Eric, your line is open. Go ahead.
spk12: Thanks for taking the question. Just on the dose escalation update now at 220, can you talk a little bit about what you saw in terms of tolerability at 160 that you're comfortable with widening the dose interval? And I guess, do you think currently We know right now that there's perhaps headroom to further dose escalate.
spk05: I think Steve will comment on that.
spk10: Sure. The tolerability profile of RMC6236 continues to be what we consider favorable. There have been no qualitative changes in the tolerability profile around C63-6 since our last update. And so we feel comfortable in continuing to dose escalate. And as we somewhat laboriously waded through back in February, even though rash is the most frequent toxicity and remains the most frequent toxicity, it really is difficult to predict ultimately what is going to become dose limiting. We had previously articulated, I believe, that we would expect on the basis mechanistic studies and nonclinical toxicity studies that maybe GI toxicity would ultimately become dose limiting. As of now, that's not happening. And so we're continuing to dose escalate. It's very difficult to, Eric, to predict where we're going to stop with this. I honestly cannot give you color on that. I may do even if I was. Other than that, you know, the program continues pretty well.
spk12: Okay. I don't know if you have visibility on this, but just having highlighted the expectation of being at a medical conference in third quarter, I guess, should investors expect sort of a meaningful difference in the scope of data reading out sort of mid-year from what you might present at a medical meeting with this program?
spk05: Well, I think what we're communicating, Eric, is that our mid-year update will be a set of multiple updates including corporate and scientific meeting presentations that begin in q3 i don't think we're going to be having an update next week followed by an update uh that you know series that starts in q3 i think those are all those are all part of the same the same series that will begin in q3 got it okay thanks for clarifying appreciate you taking your questions yeah thank you stand by for our next caller
spk06: And we have Michael Schmidt from Guggenheim. Michael, your line is open. Please go ahead.
spk11: Hey, guys. Thanks for taking the questions. Question on 6291, now that we've seen a few more clinical data sets from other G12C inhibitors at ACR, I guess, what are you looking for in the clinic for your program? I guess, what degree of differentiation, be it either on efficacy or safety, are you looking for at a minimum relative to the others, which look rather comparable? And then a follow-up question on the, to switch to the BID dosing, just to help us understand a little bit more, you know, what drove that decision to move into twice daily from the originally planned once daily dosing. Thank you.
spk05: Yeah. Hi, Michael. Thanks for your questions. I might just take both of those, and Steve can add to it if there's anything to add. So the question of BID dosing, really nothing specific drove it, other than the fact that the PK and the daily dosing turns out to be consistent with what we saw preclinically. And preclinically, we saw and have reported that that half-life of RMC6291 in animals, and now we've seen in people, is shorter than a full 24-hour type of coverage from daily dosing. We didn't really see much impact of that, adverse impact of that preclinically. In fact, almost all of the preclinical data we reported were from daily dosing. And so the preclinical differentiation that we reported was supported by that daily dosing. But nonetheless, in humans, we want to have every opportunity to be successful here. And there's really not a good argument for going to staying at daily dosing. Twice daily dosing will give us more continuous coverage. And, you know, if there's a benefit that comes from that, we'd like to have that on behalf of patients. So that's really all there is. There's nothing else from the clinic that drove that decision. And the first question was?
spk11: I was just asking about... The degree of differentiation you're sort of looking for in the clinic relative to the other T12C inhibitors out there, which you're fairly comparable so far.
spk05: Yes. Well, I think that's sort of the key point, is that the entire RAS-off inhibitor pool of drug candidates, they look relatively similar. And we, that's what we've expected based on the biology of inhibiting the reserve pool of RAS that's in the off state. And that you're always going to be chasing, trying to get a leg up, but without much biological ability to do so. So, ultimately, we'd like regimens that incorporate RMC6291 to give us greater clinical benefit. And as we've talked about in the past, we're not exactly sure whether that's going to be in higher response rates or greater durability response and or greater tolerability. Those are all features that we've, you know, that we've seen preclinically, and any or all of those could be manifest in humans. I think you're asking, though, how much of that do we need to see in monotherapy before we start our combination studies, since we've indicated pretty explicitly multiple times that our strategy around RMC6291 is, to move it into combination studies as quickly as we can and to focus the long-term plan on combinations because I think the puck has already moved past monotherapy and so we're trying to play where the puck is going to be in the future on behalf of patients. And the answer to that is we're not really prepared to define for you an answer to that. We're going to move into combination studies as quickly as we can and we need to get sort of the basic profile in monotherapy, and we need to compare that to the benchmarks. And how much superiority or differentiation we see relative to those benchmarks, we don't know. And we're not too concerned about it because we know mechanistically it is going to be qualitatively differentiated. So we're not too hyped up about exactly what we see in a relatively small number of patients. So I think if we're in the ballpark of the benchmarks, we'll be going into those combination studies. If we are vastly superior in a way that one could draw such conclusions from a relatively small study, you know, that might allow us to continue down a monotherapy pathway. But, you know, we don't really anticipate that from a phase one dose escalation study. Great. Thank you, Mark.
spk06: Yep. Stand by for our next question. Chris Shibutani joins us from Goldman Sachs. Chris, your line is open. Go ahead.
spk13: Hi. Good afternoon, everyone, and thank you for taking our questions. This is Charlie on for Chris. It's nice to see the CNS activity that we're seeing across the Rasson platform at this point, so I just wanted to get your take in terms of the potential for that intracranial activity to translate into the human subjects as we proceed and advance further into the clinic. Is there anything that in particular that you would call out about the tricomplex mechanism of action that might influence the translatability of that intracranial activity that you're seeing in mouse models so far?
spk10: I don't think so. I think the impact of penetrating into CNS nets is going to be determined to a very large extent by the patient population in which these drugs are being tested. So ultimately, And as we get into earlier lines of therapy, if we have the opportunity to control the visceral disease more effectively, then I think that brain metastases are going to be an increasingly large part of the unmet medical need. And that's when you will see the impact, the translatability, so to speak, of the of compounds getting into CNS metastases. With regards to the tricomplex technology per se, particularly the mutant selective compounds which cause these regressions in these implanted tumors, they're highly selective for mutant rats. there's unlikely to be any translation into CNS-based toxicity from any impact in penetrating the normal CNS. We honestly really don't have a very good handle on how much of these compounds gets into normal CNS. All of the evaluations to date have been done in tumors that are specifically growing within the central nervous system, and I think that's the message that we would like to convey at the moment.
spk13: Great. That's helpful. Thank you so much. And then maybe just a quick one on 6236 with the profile that's still emerging. Is there anything in particular in terms of combination partners that are you seeing a particular combination partner that's maybe more or less likely to be combinable with 6236 at this point? Or are you really seeing a relatively tolerable profile thus far that's leaving all potential combination partners on the table at this time?
spk05: Yeah, I mean, I think at this point, everything is open. Obviously, with the RAS multi-inhibitor that is suppressing, to some degree, suppressing normal or wild-type RAS in normal tissues, there would, in principle, be overlap with other inhibitors that also suppress RAS signaling in normal tissues. So, for example, a SHIFT2 inhibitor and an RMC6236, They may be combinable or they may not be, but you would worry more about that combination than you would about combining with something that's highly selective and has a non-overlapping, you know, mechanistic effect. And an example of that might be PD-1. So, 6236 mechanistically targeting RAS and PD-1 not mechanistically targeting it. You could imagine those might, in principle, be more combinable. Preclinically, we've combined a lot of things. and can see impact in the preclinical models. So, I just think it's hard to predict today exactly what will work out best, but we do have some priorities, and I've just given you some sort of guidance about how you might think about those priorities.
spk13: Yeah, I really appreciate it. Thank you so much.
spk05: You bet.
spk06: Stand by for our next caller. Alex Stranahan joins us from Bank of America. Alex, your line is open. Go ahead.
spk02: Hey, guys. This is John. I'm on for Alex. Just a quick one on 9805. Obviously, we saw some preclinical data at ACR. In terms of getting into the clinic that you dosed the first patient in your hormonal therapy dose escalation study, what's the kind of like patient baseline characteristics we can expect? And, you know, what tumor types are you going to go for in the study? If you could shed some light on that. Thanks.
spk10: Well, right now, the plan for RNC9805 is to identify a recommended phase two dose as expediently as possible and obviously convince ourselves that that's the right dose persuade other constituencies out there that we have the right dose. So apart from an obvious restriction for patients with tumors harboring a KRAS G12D mutation, I don't think you're going to see a lot of difference from the RMC6236 dose escalation, frankly. You know, we know the the histotypes in which KRAS G12D mutations predominate. And, you know, we have enough experience now with 6236 to get a handle on the types of patients that we're going to get in the phase one study. They're going to be predominantly patients with lung cancer, pancreatic cancer, and colorectal cancer. And I think that's pretty much all we can say right now. There is nothing unusual about the phase one plan for this compact.
spk02: Got it. Thanks.
spk05: Might be worth adding. I don't know if slightly underlying, it was a question about access to patients, which we sometimes get asked about. You know, there are 55,000, we estimate 55,000 new U.S. cases of KRAS G12D cancers each year. And given that, even across multiple companies, studies that might be underway at the same time, you're talking about dozens or at most hundreds of patients, I don't think there's going to be any impact of of either competition from others to the extent that there is any versus competition from ROMC6236. We'll have plenty of access to patients with KRES G12D tumors.
spk02: Okay. Thank you. And a quick follow-up to that. You mentioned that CRC is likely going to be one of the type of patients recruited. So, given the complexity of colorectal cancer in general, Other than screening for KRAS, the presence of KRAS G12D, are you also going to be screening for the absence of other mutations?
spk05: Well, I think just to build on Steve's comments, you know, the first thing to do with the compound is a phase one dose escalation. And that's not typically a time at which one wants to apply a whole bunch of restrictions. That comes later after you've seen how it behaves. have a good sense of where you might prioritize. So I think Steve mentioned that there will be relatively few restrictions other than sort of conventional exclusion criteria. And then the inclusion is a KRAS G12D mutation, but I don't think we'll be putting any other genetic, you know, significantly other genetic restrictions. Okay.
spk06: Thank you. Thanks for the call. Yeah. Thank you. And standby. Our next question comes from Ben Burnett with Stifel. Ben, please go ahead.
spk03: Hey, thank you very much. I just want to build off an earlier question just about the regulatory path for the RAS Multi RMC-636. I realize it's early days, but do you have a sense for how many different genetic variants of KRAS you need to show data on to get a broad mutation agnostic label?
spk05: Hi, Ben. No, we don't know. It'll just depend on how much activity there is when we have a more mature data set. And then that will ultimately depend on conversation with the people who make that decision.
spk03: Okay. All right. Got it. Thank you.
spk06: All right. Please stand by for our next question. And Jay Olson joins us from Oppenheimer. Jay, your line is open. Please go ahead.
spk04: Hey, thanks for taking the question, and congrats on all the progress. Can you talk about any feedback you received from physicians following AACR? And also, is the brain penetrant property of your three molecules by design, or is there a particular reason for the high CNS activity?
spk05: Thank you. So the first – I was sort of thinking about your second question, but reminding me what the first question was. Could you say it again?
spk04: Any feedback you got from physicians following AACR? Thank you.
spk05: And are you asking about, Kay, are you asking about feedback on our programs or are you asking about feedback on other things at ACR? Could you just clarify? Feedback on the data you presented. I think generally the feedback continues to be very positive. Our investigators are quite enthusiastic. We've said that previously. We are not able to make available as many investigational study slots as we'd like to be able to make available. You know, they're constrained just by the escalation sort of paradigm. And there's high demand and patients waiting and investigators waiting. And we continue to receive feedback that so far the compound appears to be well tolerated and active. And so there's quite a lot of excitement about RMC6236. And then now I've forgotten the second question. Oh, was it by design? Depends on who you ask. Yeah. You know, I think in a certain sense, there are physical chemical properties that the chemists at RevMed have determined and also, most importantly, have figured out how to incorporate those properties into these compounds. And those create more drug-like molecules. So it is notable, I think, that all three of these, you know, have this property and all three are orally bioavailable, which, you know, as somebody who's lived through the history of this, that was not universally accepted as a set of assumptions going into the discovery and development of these RAS on inhibitors based on, you know, macrocyclic large chemical backbones. But they now have been endowed with these properties through pretty directed efforts. So I think we should acknowledge that the medicinal chemistry team, with support by many others, was able to do that. Whether or not they designed them specifically aiming to get them into the CNS probably may be more of a philosophical question than anything else. So I don't have to answer philosophical questions, I guess.
spk04: Okay, great. Thank you. And if I could, maybe one follow-up on 6236. Can you just talk about the next data update and what sort of data you'll have and what investors should expect to learn from that?
spk05: Well, sure. As we've noted, we're following any patient who stays on drugs. We continue following them, so we'll get a much better sense of durability and the course of the treatment for those patients who have already been on drugs and who remain on. We're going to get a sense from backfill patients, a deeper sense of tolerability and a deeper sense of anti-tumor activity from those backfill patients. We might not have as much durability data from those if they're enrolled later in the game. And then, of course, we have escalation data that shows us where we are on the tolerability scale and get a better sense of how, when, and at what level we'll reach a recommended Phase II dose or candidates for a recommended Phase II dose. The tumor types are going to be, as we talked about earlier, they are what they are, and the mutations are what the epidemiology dictates them to be. Depending on how large the total set is, that will determine what's the absolute number of each of those histotypes and each of those genotypes. Just too hard to say today. So I think investors should be looking for a larger data set than what we've shown before with more information that's kind of deeper and broader. And we'll see whether the trends that we described earlier, to what degree they continue, to what degree, if there are differences, to what degree there are differences. And we'll couple that with, we hope, clarity about what comes next. We've already given you in our body language that we are definitely looking beyond the phase 1, 1B dose escalation. We're definitely thinking about where this compound needs to go and are sort of scaling up our activities to support all of that, but more detail when we have the data to support it. Great.
spk04: Well, thank you so much for taking the questions, and congrats again on all the progress.
spk05: Yeah, thanks, Jay.
spk06: And I'm bringing on our next caller. Please stand by. Ami Fadia joins us from Needham. Ami, your line is open.
spk08: Great. Thanks for taking my question. With regards to RNC 6236, Can you discuss where the 220 milligram dose is relative to the dose that you tested in the preclinical models? And how important is it, you know, to achieve a comparable dose in order to really reach the ORRs that you were able to see in the preclinical studies? And maybe let me pause here and I'll ask the next question after that.
spk05: Okay, thank you. I appreciate the questions. You know, just to remind you how the selection is made, there's a dose selection committee, which is made up of all the investigators. They review all the activity data and tolerability and safety data in a big package that they receive before a meeting is called. They look at that. They look at the PK. And if we've cleared the DLT window, then they proceed to a dose escalation, and they determine Of course, with input from RevMed, how much to increase. And they determined the 220 milligram increase versus 160. So, just to make sure everybody understands how we arrive at those numbers. With regard to what dose, what exposure level we'll be at at 220 milligrams, we'll know after we dose the patients and obtain their blood samples and determine PK. Okay. So we don't know. We can't know a priori. We have projections around that, but projections are projections. So can't answer that question today. And then your second or third.
spk10: How important is it to keep going up?
spk05: Yeah. I mean, I think we've said in various ways, you know, more is always better. That seems to be the case for most of these compounds, not just ours, but for most, you anti-tumor drugs. So we'd like to get up as high as we can within the bounds of safety and tolerability. And you're sort of asking a question that Project Optimist is also asking, and it's an equally difficult question to answer for Project Optimist, which is how much is enough? You know, we're not in that realm right now because, as Steve pointed out, we're continuing to see good tolerability. So we're not, you know, we're not in that zone where we even have to be worrying about it. But at some point, there will be side effects. It's just hard to conceive of that there won't be side effects and even more significant side effects than we've seen so far. But we're pretty pleased with the exposures we've had at the other dose levels up through 160. And we're above what we believe is the equivalent in mouse exposure of 10 milligrams per kilogram, which was very much an active dose level in the mice or exposure level in the mice. And so we're well above that. We've been above it for a bit. But exactly where we are at 220 is hard to say.
spk08: Thank you. I guess my follow-up question is maybe just at what point do you think the clinical data will support the sort of superiority to other KRAS, you know, off drugs, RAS off drugs that you saw in the preclinical data set. And then perhaps if you could, in terms of time to respond, you know, relative to the data set that you shared at the last earnings call, do you expect responses to improve beyond that timeframe in at least that patient subset? Thank you.
spk05: Okay. I think your second follow-up question there was, do we expect response rate to improve over time as patients stay on drug? I think that's how I heard that question. Is that right? Sure.
spk08: Yes. Yes.
spk05: Yeah. Well, you know, we made that statement back at the end of February. We did assert that. And, you know, we stand by that assertion. We're continuing to accumulate evidence of anti-tumor clinical activity. But we stand by the assertion we made previously. And we'll see over time whether that holds as we dose escalate. And when we record it out with the data set, we'll have a firmer answer as opposed to a preliminary answer at that point. Thank you. So on versus off. Yeah. You know, RMC6236 is probably not the best place to test the on versus off because it is unique in its profile as far as we know for any compound that's in the clinic or about to be in the clinic in that it's active against so many different genotypes. And so it sort of stands, it sort of defines a class of its own and it has to stand on its own. And so it'll be compared more to standard of care in each of the histologies. I think RMC6291 is one where Ultimately, the treatment regimen must show differentiation from standard of care, and standard of care, at least in second line, now includes a targeted KRAS G12C off-inhibitor. But that is likely to come from us in the form, ultimately, of combination strategies. That's what we've conveyed as our vision for the RNC6191 program. In the combination, we'd like to have the very best RAS inhibitor that there is, and we think RMC-6291 is a candidate to be the best, you know, KRAS-GTLC inhibitor in large part because of its on mechanism. But that will be additive to whatever combination play is put together when it's tested in a phase two kind of context.
spk08: Understood. Thank you.
spk06: You're welcome. Okay, and stand by for our last question. And it comes from the line of Jonathan Chang with SVP Securities.
spk07: Jonathan, you're on the air. Hi, guys. Thanks for taking my question. Just one from me. What do you see as the competition for RMC 6236? Thank you.
spk05: Thanks, Jonathan. That's a good question. For most of the indications, the competition is standard of care. You know, that's what we're going up against. For example, for G12V or any of the other G12X mutations, aside from C, there aren't other compounds, you know, in the clinic today. For G12D, obviously, there are some other compounds that have entered the clinic. And so, in principle, those are competitive for that population, the genotype, the KRAS-G-12D genotype. That's not a statement of my judgment about which compound is superior. You just want to know what's on the list. And, you know, those compounds that are in the clinic or about to be in the clinic, those would have to be considered competition.
spk07: Got it. Thanks for taking my question.
spk06: You're welcome. And that concludes our Q&A. I would like to turn it now back to Dr. Mark Goldsmith, Chairman and Chief Executive Officer, for closing remarks.
spk05: Well, thank you, Operator, and thank you to everyone for participating today and for your continued support of Revolution Medicines.
spk06: Thank you for your participation. This does conclude the program. You may now disconnect.
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