Q3 2024 Revolution Medicines Inc Earnings Call
Good day and thank you for standing by. Welcome to the Revolution Medicines Q3 2024 earnings conference call. At this time, all participants are an illicit 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, please press star 1-1 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Ryan Asay, Senior Vice President of Corporate Affairs. Please go ahead.
Ryan Asay: Thank you and welcome everyone to the third quarter 2020 Thorough News call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicine Chairman and Chief Executive Officer.
Ryan Asay: Dr. Steve Kelsey, our president of R&D, and Jack Anders, our Chief Financial Officer. Dr. Wayland, our Chief Medical Officer, who joined us for the Q&A portion of today's call.
Ryan Asay: of Electconformia, the certain statements we make during this call will be forward-looking, because such statements still with future events and are subject to many risks and uncertainties. After a result may differ materially from those in the forward-looking statements.
Ryan Asay: For a full discussion of these risk and answer these, please review our annual report on 10K in our Quarterly Report.
Ryan Asay: and FountainQ that are followed to US Security and Exchange Commission.
Ryan Asay: This afternoon we released the natural adults for the quarter end at September 30, 2024, and recent quarter updates.
Ryan Asay: The Press releases available on the Investor section of our website at rantmed.com. With that, I'll turn the call over to Dr. Mark Goldsmith, Reveal the Shamedic and Chairman and Chief Executive Officer. Mark?
Speaker Change: Thanks Ryan, it's good to be with you this afternoon.
Speaker Change: At Revolution Medicines, we are committed to revolutionizing treatment for patients with racydic cancer through the discovery, development, and delivery of innovative targeted medicines.
Ryan Asay: We believe that we have increasingly been able to demonstrate that our portfolio of RASO on inhibitors has the potential to provide meaningful impact for patients living with some of the most difficult to treat cancers.
Ryan Asay: At the start of the year we provided a roadmap of strategic development priorities for 2024. Focus on our three.
Ryan Asay: Pioneering grass on inhibitors in clinical development, RMC6236, RMC6291 and RMC985.
Ryan Asay: The highest priority has been to advance RMC 6236, our first in-class RAS on multi-selective inhibitor into its first pivotal trials. One in pancreatic ductal adenocarsanoma, which we refer to as P-DAC, and one in non-small cell lung cancer.
Ryan Asay: Our second priority aimed to begin defining the path to expanding the reach of RMC636 into earlier lines of therapy, particularly in PDAQ.
Ryan Asay: Our third priority, aimed to qualify our mutant selected inhibitors, Rmc6291, a RAS on G12C selected inhibitor, and Rmc985, a RAS on G12D selected inhibitor, for late stage development.
Ryan Asay: We've made substantial progress against these priorities.
Ryan Asay: We demonstrated compelling durability data, specifically progression-free survival and overall survival, in a cohort of patients with previously treated Metastatic P-DAC, treated with RMS-6236.
Ryan Asay: Based on these results, we initiated our first global randomized phase 3 study in second-line treatment of patients with metastatic, PDAQ, and are now actively dosing patients in this study.
Ryan Asay: Last month we shared encouraging safety, tolerability and anti-tumor activity with RMC-9805, in patients with K-RAS G12DPDAC.
Ryan Asay: We continue to advance the extender pipeline, including RMC9805 and RMC6291.
Ryan Asay: by exploring new combinations to inform the design of future pivotal studies in earlier lines of therapy and across multiple tumor types, including PDAQ and non-small cell lung cancer.
Ryan Asay: and there's more to come. We have a number of disclosure milestones ahead this quarter when we look forward to sharing updates across our RAS on a new bit of portfolio, including several approaches we're taking in non-small cell lung cancer, including both monotherapy and combinations.
Speaker Change: I'd now like to hand the call over to Dr. Steve Kelsey, our president of R&D. Who will summarize the PDAQ results we recently shared from the RMC 6236 and RMC 9805 Monotherapy Studies.
Speaker Change: At the EORTC NCI ACR Symposium, commonly referred to as the triple meeting.
Ryan Asay: to also provide a brief overview of our plans in non-small cell lung cancer.
Ryan Asay: or CFO will then provide a summary of the third quarter financial results before I share a few closer than remarks and open the call to Q&A. Be it?
Speaker Change: Thanks Mark.
Speaker Change: At the recent triple meeting in October, we had the opportunity to present data on two of our Raston inhibitors in P-DAC.
Ryan Asay: including updated progression free survival and overall survival from our RMC-6236 Monotherapy Study and initial safety and anti-tumor activity from our RMC-9805 Monotherapy Study.
Ryan Asay: Before I review these results, I would like to provide some perspective into revmads, our and dear approach relating to this devastating disease.
Ryan Asay: More than 60,000 pancreatic cancer patients have diagnosed every year in the United States alone, with more than half of all cases being diagnosed at the metastatic stage.
Ryan Asay: Over 90% of cases are driven by rations with the majority being G12x.
Ryan Asay: G12D is the single most common rasmetation, found in approximately 40% of P-dak.
Ryan Asay: Keenotherapy is the current standard of care for pancreatic cancer.
Ryan Asay: Based on published clinical trials, median progression free survival or PFS is 2-3.5 months for second-line patients who have progressed on first-line therapy.
Ryan Asay: and Media and Overall Survival in these patients is 6-7 months.
Ryan Asay: We believe these treatment results indicate a need for improved outcomes for patients.
Ryan Asay: While patients treated with first-line combination chemotherapy at initial diagnosis of metastatic P-dact, do better. The reported median PFS of approximately 7 months, and median OS of approximately 11 months.
Ryan Asay: Delieve Room for Improvement.
Speaker Change: I will now provide a brief summary of the results recently presented for our oral RASO multi-selective inhibitor RMC6236 and our oral RASO MG12D-selective inhibitor RMC-9805.
Ryan Asay: The details can be found on the events and presentations page of our corporate website at revmed.com.
Ryan Asay: Beginning with RNC 6236
Ryan Asay: As the data have matured and as of the data cut off of the 23rd July 2024
Ryan Asay: We can now report that patients who have received one prior chemotherapy regimen for metastatic P-DAC with G12 excmetations.
Ryan Asay: and who received RMC6236 monotherapy across the dose levels of 160-300mg daily.
Ryan Asay: Achieve the median PFS of 8.5 months with a median OS of 14.5 months.
Ryan Asay: For all second line patients with Ras Mutton Pdack at these dose levels, the median PFS was 7.6 months, and median OS was 14.5 months.
Ryan Asay: At these doses, including the highest dose of 300 mg daily, the safety and tolerability profile was manageable, and the average dose intensity of RMC 6236 was 92%.
Ryan Asay: The overall response rate for patients with G12 X-Tumers in the second line setting at these doses was 29%.
Ryan Asay: Also reflecting increasing maturation of the data.
Ryan Asay: This clinical profile is clearly encouraging and the robustness of these data continues to justify our optimism about RASALU to 302.
Ryan Asay: Our Phase 3 Registrational Study, in patients who have received one prior line of therapy for metastatic pancreatic cancer.
Ryan Asay: The study is actively recruiting patients as highlighted in last month's press release, announcing the first patient dose in the study.
Ryan Asay: Moving to RMC 9805, our RASON G12D Selective inhibitor.
Ryan Asay: At the Triple Meeting last month, we presented the initial clinical data from the Phase I Monotherapy Study of RMC-9805 with a main focus on patients with PIDAC.
Ryan Asay: As of September, the second 2020 4-day-to-cut update, RMC-9805, demonstrated encouraging preliminary clinical anti-tumoractivity.
Ryan Asay: We reported a 30% objective response rate and an 80% disease control rate for patients treated with 1200 mg daily.
Ryan Asay: which is a candidate recommended face to those.
Ryan Asay: Ryan C9805 was well tolerated at this dose level with manageable and predominantly low-grade treatment related adverse events.
Ryan Asay: One grade three adverse event was reported amongst 179 patients.
Ryan Asay: While the data are early, the safety and tolerability profile as well as the initial read on anti-tuberant activity are clearly encouraging.
Ryan Asay: Based on our experience as RMC-626.
Ryan Asay: It will take more time for the RMC-9805 data to mature sufficiently to characterize the true overall response rate.
Ryan Asay: and the durability of the RNC-9805IVTumor Activity, as represented by the more relevant outcome measures of progression free survival and overall survival.
Ryan Asay: The initial profile of 9805 is also consistent with potential using combinations which continues to be an important strategic priority for us.
Ryan Asay: The encouraging data from both RMC-6236 and RMC-985.
Ryan Asay: Provides with several options for development in RASG12DPDAC, including the RASOM-Dublic combination of RMC-6236-WIS RMC-9A-S5, which is currently undergoing clinical evaluation.
Ryan Asay: Ultimately, we hope that these agents will provide important optionality for pancreatic and anti-accipations with whom is harboring K-Rest G12D, the largest genetically defined subset of P-DAC patients.
Ryan Asay: Switching gears, I'd like to share a brief overview of our work in non-small cell lung cancer.
Ryan Asay: We anticipate a number of upcoming disclosures for both RMC6236 and RMC6291, our Rasson G12C-selected inhibitor.
Ryan Asay: We remain fully committed and look forward to sharing the remaining 2024 data disclosures in the remaining part of the fourth quarter.
Ryan Asay: when we plan to share updated RMC6236 monotherapy activity data in non-small-cell lung cancer, as well as initial data from our exploratory combination studies, including RMC6236 plus pembrolizumab,
Ryan Asay: and the Racon inhibitor doublet of RMC6236 plus RMC6291.
Speaker Change: Now I'd like to turn the call over to our CFO, Jack Anders, to provide a financial update. Jack.
Jack Anders: Thanks, Steve.
Jack Anders: We ended the third quarter of 2024 with $1.55 billion in cash and investments.
Jack Anders: which we project can fund planned operations into 2027 based on our current operating plan.
Jack Anders: Earnings to expenses.
Jack Anders: R&D expenses for the third quarter of 2024 were $151.8 million compared to $107.7 million for the third quarter of 2023.
Jack Anders: The increase in R&D expenses was primarily due to increases in clinical trial-related expenses for our first wave of Rathon inhibitors.
Jack Anders: personnel related expenses associated with additional headcount and stock based compensation expense.
Jack Anders: G&A expenses for the third quarter of 2024 were $24.0 million compared to $15.5 million for the third quarter of 2023.
Jack Anders: The increase in G&A expenses was primarily due to increases in personnel related expenses associated with additional headcount.
Jack Anders: commercial preparation activities, and stock-based compensation expense.
Jack Anders: Net loss for the third quarter of 2024 was $156.3 million compared to $108.4 million for the third quarter of 2023.
Jack Anders: The increase in net loss was due to higher operating expenses.
Jack Anders: We are reiterating our 2024 financial guidance and continue to expect projected full year 2024 gap net loss to be between $560 million and $600 million.
Jack Anders: which includes estimated non-cash stock-based compensation expense of between $70 million and $80 million.
Jack Anders: That concludes the financial update. I'll now turn the call back over to Mark.
Mark Goldsmith: Thank you, Jack.
Mark Goldsmith: Revolution Medicines continues to make substantial progress across our portfolio. The recent triple meeting presentations for RMC 6236 and RMC 9805 underscore the compelling opportunities we have to meaningfully impact outcomes
Jack Anders: among patients with PDAC.
Jack Anders: Based on the profiles demonstrated so far, we are advancing both programs with intensity and speed.
Jack Anders: As Steve shared, the PFS and OS results for RMC6236 in previously treated PDAC patients support our optimism that if reproduced in the ongoing global randomized controlled phase 3 study, RMC6236 could become a potential new standard of care in this setting.
Jack Anders: These data also position us well to move into evaluation in the frontline PDAC setting.
Jack Anders: The initial RMC9805 monotherapy data in PDAC are also very encouraging.
Jack Anders: We recognize it will take time for the data to mature sufficiently to provide clarity about the optimal development approach and portfolio strategy, including understanding the potential for combinations.
Jack Anders: Nonetheless, based on their differentiated clinical profiles,
Jack Anders: We believe there should be a place for both compounds in the potentially emerging targeted therapy paradigm for patients with PDAC.
Speaker Change: We're very pleased that RMC9805 is the third RAS-on inhibitor from our portfolio to achieve proof-of-concept with an acceptable safety profile, representing important validation of our innovation engine and a significant milestone for Revolution Medicines as an organization.
Jack Anders: Thank you very much.
Jack Anders: Our tri-complex platform has delivered three distinct oral inhibitors with compelling clinical profiles.
Jack Anders: This work has charted new territory in oncology by targeting the oncogenic Rasson protein state, an extraordinary achievement.
Jack Anders: These three investigational drugs include two covalent Rasson inhibitors and one non-covalent Rasson inhibitor.
Jack Anders: One RAS-on inhibitor designed for BRETs and two designed for mutation selectivity.
Jack Anders: and one RAS-on inhibitor that covalently, irreversibly, and selectively engages aberrant aspartic acid at amino acid position 12 in RAS.
Jack Anders: To our knowledge, a chemistry first in a clinical stage investigational drug.
Jack Anders: Importantly, the strength of the clinical data we've obtained with the first wave of rafts on inhibitor programs.
Jack Anders: highlights the clinical translatability of our discovery and preclinical efforts and encourages us to continue driving progress in this space.
Jack Anders: In conclusion, we are successfully executing and making significant progress on our key 2024 priorities and laying the foundation for long-term, sustainable progress supporting our goal of revolutionizing treatment for patients with RAS-addicted cancers.
Jack Anders: Initiating our first phase 3 clinical study in second-line pancreatic cancer is a significant milestone in this company's evolution and an important step in our mission to improve outcomes for patients with RAS-indicted cancers.
Jack Anders: We anticipate it will be the first of many registrational studies in patients with RAS-addicted cancers.
Jack Anders: Our non-small cell lung cancer monotherapy and combination studies are ongoing, and we look forward to sharing an update with you this quarter.
Jack Anders: And we remain well capitalized, enabling us to continue to advance our pipeline in these high unmet need cancers.
Jack Anders: I'd like to take a moment to recognize and thank the patients and caregivers, clinical investigators, scientific and business collaborators, advisors, and shareholders.
Jack Anders: and the tireless efforts of RedMed employees on behalf of patients.
Jack Anders: Without their commitment and support, the progress we've made wouldn't be possible.
Jack Anders: This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session.
Speaker Change: Thank you. At this time, we will 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.
Speaker Change: To withdraw your question, please press star 1 1 again. Please stand by while we compile the Q&A roster
Jack Anders: Our first question comes from Peter Lawson with Barclays. Your line is now open.
Peter Lawson: Great, thanks so much. Thanks for taking the questions. I guess the first one would just be around what we should be looking for in the combination data sets that we get over the next...
Jack Anders: A few months, six months, in terms of
Jack Anders: The combination with PEMBRO and then the combinations between the Multi and the G12C and how we should be thinking about those in terms of side effect profiles versus any efficacy signals.
Speaker Change: Thank you, Peter. I appreciate the question. Well, I think there is a difference between the PEMBER studies and the GRASS, Pollen Inhibitor Double-Up Study. The PEMBER study is primarily a safety study.
Jack Anders: and there the most important signal that we are, you know, zeroed in on is the hepatotoxicity signal that was seen with the first generation
Jack Anders: RASP off G12C inhibitors.
Jack Anders: We want to clear that issue, as we've mentioned a number of times in the past, we did have data reported actually about 12 months ago.
Jack Anders: that referred to patients who had recently come off of pembrolizumab and started RMC6236, and those patients who were considered to be at high risk for hepatoflexicity if there was a combination problem.
Jack Anders: did not really show any evidence of significant hepatotoxicity, so that gives us some level of preview, but what we have underway now is concurrent administration of the two compounds, and that's primarily what we're looking for.
Jack Anders: with the RMC 6236 plus 6201 combination.
Jack Anders: We're less focused on tolerability because we don't really have a particular issue that we
Jack Anders: anticipate needing to clear. But there we're looking for some sort of qualitative evidence that the activity that we saw, the characteristics, the profile that we saw in preclinical models
Jack Anders: In which the combination outstripped and really distinguished itself even qualitatively from the Monotherapy agents that we see something that translates that into people
Jack Anders: and that's about the best that I can tell you you know today about those two studies obviously we're getting closer to disclosing those and
Jack Anders: and from here to that point, I think we'll just have to leave it open.
Speaker Change: Great, thanks so much.
Speaker Change: Thank you. Bye.
Jack Anders: Thank you.
Speaker Change: Our next question comes from Michael Schmidt with Guggenheim Securities. Your line is now open.
Michael Schmidt: Hey guys, thanks for taking my questions. Just to follow up on the RAS on inhibitor-double-ed combination, could you just remind us of the patient background, the patient population in that study? Is that exclusively lung cancer patients, or are there other histologies included as well, and what about prior treatment?
Speaker Change: with the Covalent G12C inhibitor. And then a question on the planned phase three study in lung cancer. I know you sort of slightly pushed that timing out. Can you just comment on what some of the items are that you have to align with the FDA?
Speaker Change: Sort of faded out a little bit at the end there, but I think you were asking about the timing, what drove the timing of the phase three lung cancer trial. Is that the second part of your question?
Speaker Change: on the EFG on that.
Speaker Change: Yeah.
Speaker Change: So on the first question,
Speaker Change: We can't provide a lot of detail about that, about the eligibility. Obviously it's patients with TRS-G12C bearing tumors. It's a mixture of solid tumor types, it's a mixture of prior treatment backgrounds, and it'll be best understood when you see the data.
Speaker Change: And with regard to the
Speaker Change: I want to make it really clear that we remain committed to launching a Phase III Registrational Trial in lung cancer in the near future, and we fully expect, as Steve pointed out, to complete our analysis and our internal deliberations on an updated Phase I dataset.
Speaker Change: and to share these this quarter.
Speaker Change: but practically speaking with the December holiday.
Speaker Change: just around the corner.
Speaker Change: It's just become too much of a stretch to assume that on top of these activities, all of which are critical paths to the program, that we can also obtain regulatory alignment on the study details and initiate the trial before the end of the year, and simply having recognized this reality, we wanted to be transparent about it.
Speaker Change: I do want to point out that we were able to accelerate the launch of the Phase 3 pancreatic cancer trial. We call that the Resolute 302 study.
Speaker Change: But apparently we were a bit too optimistic on the timing for the lung cancer study initiation. We will certainly continue pushing hard to achieve lift off on this second pivotal trial as soon as practical
Speaker Change: Again, let me just emphasize, we do expect to be able to move forward, but can't provide any more detail today. Just ask everybody to stay tuned for the promised data disclosure this quarter.
Speaker Change: Great. Thanks for clarifying, Mark.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Jay Olson with Oppenheimer. Your line is now open.
Jay Olson: Oh, hey, congrats on all the progress, and thanks for...
Jay Olson: taking the questions. Since you have a clinical collaboration with Tango Therapeutics evaluating the combination of 6236 and 9805 with their
Jay Olson: PRMT5 inhibitor.
Jay Olson: Can you provide some color on the clinical development strategy there and indications that you're focusing on? Thank you.
Speaker Change: Thanks, Jay.
Speaker Change: Unfortunately, no. We can't really provide any more information than what TANGO reported. We're obviously happy to be participating, but we're providing clinical drug supply to TANGO. We'll sponsor the studies. Can't really give you more information.
Jay Olson: Other than that, we have done some preclinical work with that combination.
Speaker Change: each of these two agents addresses a different signaling component that may be contributing to oncogenesis in those patients who have both a RAS mutation and MTAP deletion and so it certainly makes sense.
Speaker Change: to try to suppress both of those signaling contributors and the pre-clinical results were encouraging in that regard. So we're excited to be able to help support the combination study.
Speaker Change: Great, thank you.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Mark Fromm with TD Cohen. Your line is now open.
Mark Fromm: Thanks for taking my questions. Just following up on Michael's earlier question,
Speaker Change: You know, about a year ago, you put out the kind of initial statement that you intended to start phase threes for pancreatic and lung, you know, so that kind of decision seems like it was made kind of in parallel. Can you just kind of explain why, how?
Speaker Change: the questions you still needed to answer to actually, you know, move forward from that decision you made a year ago to starting the trial differed and kind of what, how the timelines have seemed to have diverged for the two.
Speaker Change: I don't really think there's much color we can get to that. I mean the steps that we have to go through for those are essentially the same.
Speaker Change: enrollment paces can differ.
Speaker Change: It's just a practical reality. It's very hard to predict a year ago exactly what they will be able to start a study. I don't think there's really much more to be able to provide than that.
Speaker Change: Okay, and then maybe...
Speaker Change: Not so much about the Tango collaboration itself, but just talk through kind of your strategy moving forward with kind of novel novel combinations. How are you approaching that with 6236?
Speaker Change: Should we see a lot more of these deals, or these types of collaborations, or is this more of a one-off?
Speaker Change: I doubt it's going to be a one-off. We have a long list.
Speaker Change: of requests for collaboration for combination with RMC 6236.
Speaker Change: It almost overwhelms us just in terms of reviewing the list, but so I do expect there will be other other agents, other targets, other things for which we'll do collaborative studies, of course.
Speaker Change: We've prioritized the studies that we feel we need to do as priority studies and you know what those are. We're combining RMC 6236
Speaker Change: with other RAS-LOM inhibitors. We're combining RMC6236 with Temporalizumab.
Speaker Change: We're combining RMC6236 with chemotherapy and various combinations, you know, multiplex combinations of those. So those are our near-term priorities, but I do expect there will be other combination studies that will emerge over time.
Speaker Change: Okay, thank you.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Alec Stranahan with Bank of America. Your line is now open.
Alec Stranahan: Hey guys, thanks for taking our questions.
Speaker Change: Just looking ahead to the preclinical AML data, we should expect that at ASH.
Speaker Change: Curious to hear your thoughts around the application of the RAS on platform to liquid tumors and maybe what you'd want to see to proceed to clinical studies here and any color around combinations in the setting seems like Glitter it in a and venetoclax or maybe some options being considered based on that Abstract. Thank you
Speaker Change: To be true, Alex, the hematology component of our program has almost been completely outsourced to academic collaborators up to now and they're going to be the ones that will be presenting data at ASH and other meetings going forwards.
Speaker Change: We have been so focused on pancreatic cancer, non-strong cell lung cancer, and colorectal cancer.
Speaker Change: that we have not really had an opportunity to plan any clinical development in
Speaker Change: Some of the more infrequent tumors that carry graft mutations like AML. We do appreciate the
Speaker Change: We do appreciate the mechanistic basis there and the unmet medical need and that is increasing of course as it becomes clear that one of the major mechanisms by which AML escapes from
Speaker Change: targeted therapies like FIT3 inhibitors is through acquisition of RAS mutation, but right now
Speaker Change: For a relatively medium-sized biotech company on the west coast of the United States, it's not a top priority for us. We do very much appreciate the work that's being done by the academic collaborators that might set us up for success.
Speaker Change: at Tranquil Development at some point in the not-too-distant future.
Speaker Change: It makes sense. Thank you.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Jonathan Chang with Lerink Partners. Your line is now open.
Jonathan Chang: Hi, guys. Thanks for taking the question. Just one from me. On CASH runway guidance, can you provide some color on what's baked into the runway guidance? Specifically, what's baked in in terms of the different ways you could proceed in pancreatic cancer and lung cancer across your pipeline? Thank you.
Speaker Change: Thanks, Jonathan. I think Jack can comment on that.
Speaker Change: Yeah, with regards to the cash guide, what's baked in there is the two phase three second line studies that we've disclosed that we are moving ahead with. Beyond that, we use a probability-adjusted model with regards to costs.
Speaker Change: and each, there's a multitude of potential opportunities and programs that we push forward in additional pivotal trials, but we use
Speaker Change: and the probability adjusted model. So we can't really describe specifically what additional programs are in it.
Speaker Change: The Cash Primary Forecast, but what's fully baked in there are those two Phase 3 second-month trials.
Speaker Change: Understood. Thank you.
Speaker Change: Thank you.
Speaker Change: As a reminder, to ask a question, please press star 11 on your phone. Our next question comes from Eric Joseph with JP Morgan. Your line is now open.
Eric Joseph: Thank you. Thanks for taking the questions. Just on the combination work of 6236 with PEMBRO, I'm curious to know if you're also looking at combinations of a triplet, 6236, PEMBRO, and chemotherapy.
Speaker Change: I guess, how do you think about the strategic futility of that triplet regimen potentially as we look to expand in frontline opportunities in non-spousal lung cancer?
Speaker Change: Thank you.
Speaker Change: where you want to have another, yeah.
Speaker Change: Within the study, what you refer to as a triplet really is a quadruplet of R6236 plus 10 to a plus.
Speaker Change: Platinum Doublet Chemotherapy, that's actually built into the protocol itself, so we're actually doing it sequentially after clearly identifying the appropriate dose for the doublet of 636-plot-10-probe, then we'll initiate the combination with the chemotherapy at it all.
Speaker Change: So, hopefully, we'll be able to meet you guys again.
Speaker Change: Okay, got it. And just with the, just on...
Speaker Change: The OPEC side, you know, pretty, pretty significant jump this past quarter, but you're keeping full year spend guidance intact. I'm just wondering whether there's any.
Speaker Change: one-time items that are non-recurring items you should keep in mind and, you know, I guess how should we be thinking about sort of the sequential ramp year into the early part of 2025.
Speaker Change: Thank you very much.
Speaker Change: So with regards to one-time items or potential one-time items within the historical results
Speaker Change: With what we've reported to date in 2025, nothing that stands out as one-time items.
Speaker Change: If you kind of take a look at the midpoint of our guidance.
Speaker Change: for 2024 and look at where we are here to date. So we probably are about 405 million net loss here to date. You know, the mid-2014 guidance is 580 million, so that assumes a little bit of a ramp going into Q4 from a net loss perspective.
Speaker Change: And with regards to 2025, we haven't guided to any specific guidance and we will likely do that in the future. However, I think that it's fair to assume that our expenses are going to go up.
Speaker Change: Obviously we were, we plan on starting two phase two. We started one phase three trial and we plan on starting another. We are also kind of building out the organization at least from a, you know, preparing from a commercial launch perspective. And we have a lot of opportunities outside of those two physical trials that we've said that we.
Speaker Change: So, there is specific guidance for 2025. I will tell you, you can expect expenses to increase.
Speaker Change: Okay, got it. Thanks for taking the questions.
Speaker Change: Thank you.
Speaker Change: Thank you very much, Eric.
Speaker Change: Thank you. Our next question comes from Laura Prendergast with Raymond James. Your line is now open.
Laura Prendergast: Hey guys, a quick question regarding the Nature paper that was published last week out of MSK.
Speaker Change: This shows proof of concept at 6236.
Speaker Change: actually increases RAS-G12x GTPase activity. Is this a mechanism that you guys have also been looking at internally? And just generally any comments on how you're thinking about this, especially in regards to potential combinations or just in general. Thank you.
Speaker Change: Yeah, thanks Laura
Speaker Change: Yeah, of course, we're very aware of this additional mechanism.
Speaker Change: And in fact, we discovered it some time ago, and we first exposed it ourselves at an NCI RAS scientific conference a few years ago. So yes, we're quite familiar with it. We think it's quite interesting. It may, in fact, contribute to the therapeutic index of RMC6236.
Speaker Change: by affecting RAS signaling more in cancer cells with uprated endografts on signaling than in normal cells that have a lower level.
Speaker Change: of RASOM signaling. So we were happy to see it. We were familiar with the work, for sure, and helped lay the foundation for it, and we think it is likely to be a contributor to RMC666.
Speaker Change: Great, thank you.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Ellie Murrell with UBS. Your line is now open.
Speaker Change: Hey guys, it's Sam on for Ellie. I guess just as you're thinking about a potential phase 3 study in first-line PDAC,
Speaker Change: I guess, what are the different potential strategies that you could be kind of looking for here?
Speaker Change: And related to this, and moving into the first line, just like mechanistically, is Roth like more or less of a driver? And like, I guess, how might we expect efficacy to translate into this earlier setting?
Speaker Change: Okay, thank you for the questions. I think there were three questions in there.
Speaker Change: And I think I remember two of them. So the one I remember most is, are we waiting for results from the phase three second-line study before launching a first-line study? That one's the easiest one. No.
Speaker Change: We'll move into that first-line study as soon as we have the regimen sorted out, the optimized regimen and overall trial design.
Speaker Change: I think sets up what's going to be in that study and how are we going to get there. Maybe Wei can talk to us a little bit about the various things that we have going on helping us determine what we might include in that.
Wei: Happy to answer that.
Wei: Right now, I think we believe the SetLine data, with the PFS OS exceeding the FirstLine Benchmark, already established the proof of concept in our mind of this agent as a monotherapy being active in the FirstLine setting.
Speaker Change: So, I think, so we are moving forward with planning for a retro phase three with a single agent monotherapy as one of the potential therapy arms.
Speaker Change: We're also actively developing a combination with Standard Care that includes a Fibre-Based Regimen as well as a Gem-Saturin-Based Regimen, and those potentially can be enabled as additional treatment arms, experimental and investigational arms.
Speaker Change: in that phase three trial. So that's kind of the way we're thinking about the first line study. I think, expanding on, I think your question, I'm gonna rephrase it, please let me know if I.
Speaker Change: address it correctly. I think what you're trying to ask is
Speaker Change: We believe that RAS is a driver across different lines of therapy whether that changes or not and whether the efficacy could potentially change or not. I think, number one, I think we do believe that RAS is a fundamental driver regardless of line of therapy.
Speaker Change: Providing selective pressure with a RAS inhibitor in any line of therapy, then the sensitivity
Speaker Change: remain the same across lines.
Speaker Change: because there has not been a sort of pressure for resistance at all. Therefore, we do believe the second line of the concept should be translated to the first line. We have also shown data.
Speaker Change: For third line which really demonstrate that it's also actually the third line plus patients and so validating that scientific concept.
Speaker Change: And in that comparison between second-line and third-line data, we've shown that we're more than double the PFS.
Speaker Change: in either line.
Speaker Change: I think among target therapy, there's this concept of treatment effect built in in terms of measure by hash ratio, right? So proportionately, we actually have a greater than 50% risk reduction in progression in second and third line. So we hope that if that...
Speaker Change: basic concept hold, then we can expect similar treatment effect applying to first lines while meeting a reduction of risk for progression in first line of 50% or greater. So those are the kind of our current thinking.
Speaker Change: Thank you so much.
Speaker Change: Thank you.
Speaker Change: Our final question comes from Kelly Shea with Jeffreys. Your line is now open.
Speaker Change: Hi, this is Claire Allen for Kelly. Thanks for taking our questions. So, we just have a quick follow-up question on Tango's clinical collaboration. Wondering if you can add any color on the reason for the choice of collaboration partner among other clinical PRMT-5 programs. Thank you.
Speaker Change: It looks like an interesting compound. There certainly are other compounds in the field.
Speaker Change: We've done some preclinical work with the Tango compound, as I mentioned earlier, and they've done some preclinical work with our compounds. So, you know, we have some visibility into what that combination looks like in preclinical model systems.
Speaker Change: But that doesn't mean that we wouldn't do a collaboration study with another PRMT5 inhibitor.
Speaker Change: You know, we are actively trying to find the best combination partner store on C6236.
Speaker Change: And it's far too early for us to make any declarations about that, but we're happy to be in the collaboration and it's one of, as I mentioned earlier, probably many different combination studies we'll do with agents across many different disease targets.
Speaker Change: Appreciate the color.
Speaker Change: I'm showing no further questions at this time. I would now like to turn it back to Mark Goldsmith, Chairman and Chief Executive Officer, for closing remarks.
Mark Goldsmith: Thank you, Operator, and thank you to everyone for participating today and for your continued support of Revolution Medicines.
Speaker Change: Thank you. Bye.
Speaker Change: Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.
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Speaker Change: Good day, and thank you for standing by. Welcome to the Revolution Medicine's Q3 2024 Earnings Conference Call. At this time, all participants are in a listen-only mode.
Speaker Change: 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 11 on your telephone. You will then hear an automated message advising that your hand is raised.
Speaker Change: To withdraw your question, please press star 1 1 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Ryan Asay, Senior Vice President of Corporate Affairs. Please go ahead.
Ryan Asay: Thank you and welcome everyone to the third quarter 2024 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines Chairman and Chief Executive Officer.
Speaker Change: Dr. Steve Kelsey, our President of R&D, and Jack Anders, our Chief Financial Officer. Dr. Wei Lin, our Chief Medical Officer, will join us for the Q&A portion of today's call.
Speaker Change: I'd like to inform you that certain statements we make during this call will be forward-looking because such statements deal with future events and are subject to many risks and uncertainties. Actual results may differ materially from those in the forward-looking statements.
Speaker Change: For a full discussion of these risks and uncertainties, please review our annual report on Form 10-K and our quarterly report.
Speaker Change: on Form 10-Q that are filed with the U.S. Securities and Exchange Commission.
Speaker Change: This afternoon, we released financial results for the quarter ended September 30th, 2024, and recent corporate updates.
Speaker Change: The press release is available on the investor section of our website at RevMed.com. With that, I'll turn the call over to Dr. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer. Mark.
Mark Goldsmith: Thanks, Ryan. It's good to be with you this afternoon.
Speaker Change: At Revolution Medicines, we are committed to revolutionizing treatment for patients with rat-addicted cancers through the discovery, development, and delivery of innovative targeted medicines.
Speaker Change: We believe that we have increasingly been able to demonstrate that our portfolio of Rason inhibitors has the potential to provide meaningful impact for patients living with some of the most difficult-to-treat cancers.
Speaker Change: At the start of the year, we provided a roadmap of strategic development priorities for 2024, focused on our three
Speaker Change: pioneering Rasson inhibitors in clinical development, RMC6236, RMC6291, and RMC9805.
Mark Goldsmith: The highest priority has been to advance RMC6236, our first-in-class Rasson multi-selective inhibitor, into its first pivotal trials, one in pancreatic ductal adenocarcinoma, which we refer to as PDAC, and one in non-small cell lung cancer.
Mark Goldsmith: Our second priority aims to begin defining the path to expanding the reach of RMC6236 into earlier lines of therapy, particularly in PDAC.
Mark Goldsmith: Our third priority aims to qualify our mutant-selective inhibitors, RMC6291, a RAS-on G12C-selective inhibitor, and RMC9805, a RAS-on G12D-selective inhibitor, for late-stage development.
Mark Goldsmith: We've made substantial progress against these priorities.
Mark Goldsmith: We demonstrated compelling durability data, specifically progression-free survival and overall survival, in a cohort of patients with previously treated metastatic PDAC treated with RMC6236.
Mark Goldsmith: Based on these results, we initiated our first global randomized phase 3 study in second-line treatment of patients with metastatic PDAC and are now actively dosing patients in this study.
Mark Goldsmith: Last month we shared encouraging safety, tolerability, and anti-tumor activity with RMC 9805 in patients with KRAS G12d PDAC.
Mark Goldsmith: by exploring new combinations to inform the design of future pivotal studies in earlier lines of therapy and across multiple tumor types, including PDAC and non-small cell lung cancer.
Mark Goldsmith: And there's more to come. We have a number of disclosure milestones ahead this quarter when we look forward to sharing updates across our RAS-on inhibitor portfolio, including several approaches we're taking in non-small cell lung cancer, including both monotherapy and combinations.
Speaker Change: I'd now like to hand the call over to Dr. Steve Kelsey, our president of R&D, who will summarize the PDAC results we recently shared from the RMC6236 and RMC9805 monotherapy studies
Speaker Change: at the EORTC-NCI AACR Symposium, commonly referred to as the Triple Meeting.
Speaker Change: They'll also provide a brief overview of our plans in non-small cell lung cancer.
Speaker Change: Jack Anders, our CFO, will then provide a summary of the third quarter financial results before I share a few closing remarks and open the call to Q&A. Steve?
Steve Kelsey: Thanks, Mark.
Speaker Change: At the recent TRIPLE meeting in October, we had the opportunity to present data on two of our Rason inhibitors in PEDAC.
Speaker Change: including updated progression-free survival and overall survival from our RMC6236 monotherapy study and initial safety and anti-tumor activity from our RMC9805 monotherapy study.
Speaker Change: Before I review these results, I would like to provide some perspective into RevMed's R&D approach relating to this devastating disease.
Speaker Change: More than 60,000 pancreatic cancer patients are diagnosed every year in the United States alone, with more than half of all cases being diagnosed at the metastatic stage.
Speaker Change: Over 90% of cases are driven by RAS mutations, with the majority being G12X.
Speaker Change: G12D is the single most common RAS mutation, found in approximately 40% of PDAC.
Speaker Change: Chemotherapy is the current standard of care for pancreatic cancer.
Speaker Change: Based on published clinical trials, median progression-free survival or PFS is 2 to 3.5 months for second-line patients who have progressed on first-line therapy.
Speaker Change: and median overall survival in these patients is six to seven months.
Speaker Change: We believe these treatment results indicate a need for improved outcomes for patients.
Speaker Change: still leave room for improvement.
Speaker Change: I will now provide a brief summary of the results recently presented for our Oral-Racon Multi-Selective Inhibitor RMC6236 and our Oral-Racon G12D Selective Inhibitor RMC9805.
Speaker Change: beginning with RNC 6236.
Speaker Change: As the data have matured, and as of the data cut-off of the 23rd of July 2024,
Speaker Change: We can now report that patients who have received one prior chemotherapy regimen for metastatic PDAC with G12X mutations
Speaker Change: and who received RMC6236 monotherapy across the dose levels of 160 to 300 milligrams daily.
Speaker Change: achieved a median PFS of 8.5 months with a median OS of 14.5 months.
Speaker Change: For all second-line patients with RAS mutant PDAC at these dose levels, the median PFS was 7.6 months and median OS was 14.5 months.
Speaker Change: At these doses, including the highest dose of 300 mg daily, the safety and tolerability profile was manageable, and the average dose intensity of RMC6236 was 92%.
Speaker Change: The overall response rate for patients with G12x tumors in the second-line setting of these doses was 29%.
Speaker Change: also reflecting increasing maturation of the data.
Speaker Change: This clinical profile is clearly encouraging, and the robustness of these data continue to justify our optimism about RAS-ELUT302.
Speaker Change: our Phase III Registrational Study in patients who have received one prior line of therapy for metastatic pancreatic cancer.
Speaker Change: This study is actively recruiting patients, as highlighted in last month's press release announcing the first patient dosed in the study.
Speaker Change: Moving to RMC9805, our Rasson G12D selective inhibitor.
Speaker Change: At the triple meeting last month, we presented the initial clinical data from the Phase 1 Monotherapy Study of RMC9805, with a main focus on patients with PDAC.
Speaker Change: As of the September 2, 2024 data cutoff date, RMC9805 demonstrated encouraging preliminary clinical anti-tumor activity.
Speaker Change: We reported a 30% objective response rate and an 80% disease control rate for patients treated with 1,200 milligrams daily.
Speaker Change: which is the candidate recommended phase 2 dose.
Speaker Change: One grade 3 adverse event was reported amongst 179 patients.
Speaker Change: While the data are early, the safety and tolerability profile, as well as the initial read on anti-tumor activity, are clearly encouraging.
Speaker Change: based on our experience with RMC6236.
Speaker Change: It will take more time for the RMC9805 data to mature sufficiently to characterize the true overall response rate and the durability of the RMC9805 anti-tumor activity as represented by the more relevant outcome measures of progression-free survival and overall survival.
Speaker Change: The initial profile of 9805 is also consistent with potential use in combinations, which continues to be an important strategic priority for us.
Speaker Change: the encouraging data from both RMC6236 and RMC9805.
Speaker Change: provide us with several options for development in RAS G12d PDAC, including the RAS-on-Doublet combination of RMC6236 with RMC9805, which is currently undergoing clinical evaluation.
Speaker Change: Ultimately, we hope that these agents will provide important optionality for pancreatic cancer patients with tumors harboring KRAS G12D, the largest genetically defined subset of PDAC patients.
Speaker Change: Switching gears, I'd like to share a brief overview of our work in non-small cell lung cancer.
Speaker Change: We anticipate a number of upcoming disclosures for both RMC6236 and RMC6291, our Rasson G12C selected inhibitor.
Speaker Change: We remain fully committed and look forward to sharing the remaining 2024 data disclosures in the remaining part of the fourth quarter.
Speaker Change: when we plan to share updated RMC6236 monotherapy activity data in non-small-cell lung cancer, as well as initial data from our exploratory combination studies, including RMC6236 plus pembrolizumab,
Speaker Change: and the Rassom inhibitor doublet of RMC6236 plus RMC6291.
Speaker Change: We expect to reach regulatory alignment and initiate a phase 3 registrational study evaluating RMC6236 as monotherapy in patients with previously treated advanced RAS mutant non-small cell lung cancer in the first quarter of 2025.
Speaker Change: Now I'd like to turn the call over to our CFO, Jack Anders, to provide a financial update. Jack.
Jack Anders: Thanks, Steve.
Speaker Change: We ended the third quarter of 2024 with $1.55 billion in cash investments.
Speaker Change: which we project can fund planned operations into 2027 based on our current operating plan.
Speaker Change: Turning to expenses.
Speaker Change: R&D expenses for the third quarter of 2024 were $151.8 million compared to $107.7 million for the third quarter of 2023.
Speaker Change: The increase in R&D expenses was primarily due to increases in clinical trial-related expenses for our first wave of Rathon inhibitors.
Speaker Change: personnel related expenses associated with additional headcount and stock based compensation expense.
Speaker Change: G&A expenses for the third quarter of 2024 were $24.0 million compared to $15.5 million for the third quarter of 2023.
Speaker Change: The increase in G&A expenses was primarily due to increases in personnel related expenses associated with additional headcount.
Speaker Change: Commercial Preparation Activities
Speaker Change: and stock-based compensation expense.
Speaker Change: Net loss for the third quarter of 2024 was $156.3 million compared to $108.4 million for the third quarter of 2023.
Speaker Change: The increase in net loss was due to higher operating expenses.
Speaker Change: We are reiterating our 2024 financial guidance and continue to expect projected full year 2024 gap net loss to be between $560 million and $600 million.
Speaker Change: which includes estimated non-cash stock-based compensation expense of between $70 million and $80 million.
Speaker Change: That concludes the financial update. I'll now turn the call back over to Mark.
Mark: Thank you, Jack.
Mark: Revolution Medicines continues to make substantial progress across our portfolio. The recent triple meeting presentations for RMC6236 and RMC9805 underscore the compelling opportunities we have to meaningfully impact outcomes
Mark: among patients with PDAC.
Speaker Change: As Steve shared, the PFS and OOS results for RMC6236 in previously treated PDAC patients
Speaker Change: support our optimism that if reproduced in the ongoing global randomized controlled phase 3 study RMC 6236 could become a potential new standard of care in this setting.
Speaker Change: These data also position us well to move into evaluation in the frontline PDAC setting.
Speaker Change: The initial RMC9805 monotherapy data in PDAC are also very encouraging.
Speaker Change: We recognize it will take time for the data to mature sufficiently to provide clarity about the optimal development approach and portfolio strategy, including understanding the potential for combinations.
Speaker Change: Nonetheless, based on their differentiated clinical profiles,
Speaker Change: We believe there should be a place for both compounds in the potential emerging targeted therapy paradigm for patients with PDAC.
Speaker Change: We're very pleased that RMC9805 is the third RASon inhibitor from our portfolio to achieve proof of concept with an acceptable safety profile.
Speaker Change: represent the important validation of our innovation engine and a significant milestone for Revolution Medicines as an organization.
Speaker Change: Our tri-complex platform has delivered three distinct oral inhibitors with compelling clinical profiles.
Speaker Change: This work has charted new territory in oncology by targeting the oncogenic Rasson protein state, an extraordinary achievement.
Speaker Change: These three investigational drugs include two covalent Rasson inhibitors and one non-covalent Rasson inhibitor.
Speaker Change: One RAS-on inhibitor designed for breadth and two designed for mutation selectivity.
Speaker Change: and one RAS-on inhibitor that covalently, irreversibly, and selectively engages aberrant aspartic acid at amino acid position 12 in RAS.
Speaker Change: To our knowledge, a chemistry first in a clinical stage investigational drug.
Speaker Change: Importantly, the strength of the clinical data we've obtained with the first wave of RAS non-inhibitor programs
Speaker Change: highlights the clinical translatability of our discovery and preclinical efforts and encourages us to continue driving progress in this space.
Speaker Change: In conclusion, we are successfully executing and making significant progress on our key 2024 priorities and laying the foundation for long-term sustainable progress supporting our goal of revolutionizing treatment for patients with RAS-addicted cancers.
Speaker Change: Initiating our first phase 3 clinical study and second line pancreatic cancer is a significant milestone in this company's evolution and an important step in our mission to improve outcomes for patients with RAS-addicted cancers.
Speaker Change: We anticipate it will be the first of many registrational studies in patients with RAS-addicted cancers.
Speaker Change: Our non-small cell lung cancer monotherapy and combination studies are ongoing and we look forward to sharing an update with you this quarter.
Speaker Change: and we remain well capitalized enabling us to continue to advance our pipeline in these high unmet need cancers.
Speaker Change: I'd like to take a moment to recognize and thank the patients and caregivers, clinical investigators, scientific and business collaborators, advisors, and shareholders.
Speaker Change: and the tireless efforts of RedMed employees on behalf of patients.
Speaker Change: Without their commitment and support, the progress we've made wouldn't be possible.
Speaker Change: This concludes our prepared remarks for today, and I'll now turn the call over to the operator for the Q&A session.
Speaker Change: Thank you. At this time we will conduct the question and answer session. As a reminder, to ask a question you will need to press star 1 1 on your telephone and wait for your name to be announced.
Speaker Change: To withdraw your question, please press star 1 1 again. Please stand by while we compile the Q&A roster.
Speaker Change: Our first question comes from Peter Lawson with Barclays. Your line is now open.
Peter Lawson: Great, thanks so much. Thanks for taking the questions. I guess the first one would just be around what we should be looking for in the combination data sets that we get over the next...
Peter Lawson: few months to six months in terms of
Speaker Change: The combination with PEMBRO and then the combinations between the Multi and the G12C and how we should be thinking about those in terms of side effect profiles versus any efficacy signals.
Speaker Change: Thank you, Peter. I appreciate the question. Well, I think there is a difference between the PEMBRA studies and the GRASP on inhibitor double-up study. The PEMBRA study is primarily a safety study, and there the most important signal that we are, you know, zeroed in on is the hepatotoxicity signal that was seen with the first generation.
Speaker Change: RASP off G12C inhibitors.
Speaker Change: We want to clear that issue, as we've mentioned a number of times in the past, we did have data reported actually about 12 months ago.
Speaker Change: that referred to patients who had recently come off of
Speaker Change: of Embrolizumab, it started RMC6236, and those patients who were considered to be at high risk for hepatotoxicity if there was a combination problem.
Speaker Change: did not really show any evidence of significant beta-toxicity, so that gives us some level of preview, but what we have underway now is concurrent administration of the two compounds, and that's primarily what we're looking for.
Speaker Change: with the RMC 6236 plus 62001 combination.
Speaker Change: We're less focused on tolerability because we don't really have a particular issue that we
Speaker Change: I can't say anything. I think whether it's known or not know little
Speaker Change: In which the combination outstripped and really distinguished itself even qualitatively from the Monotherapy agents that we see something that translates that into people
Speaker Change: and that's about the best that I can tell you you know today about those two studies obviously we're getting closer to disclosing those and and from here to that point I think we'll just have to leave it leave it open.
Speaker Change: Great. Thank you so much.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Michael Schmidt with Guggenheim Securities. Your line is now open.
Michael Schmidt: And then a question on the planned phase 3 study in lung cancer. I know you sort of slightly pushed that timing out. Can you just comment on what some of the items are that you have to align with the FDA?
Speaker Change: Sort of faded out a little bit at the end there, but I think you were asking about the timing, what drove the timing of the phase three lung cancer trial? Is that the second part of your question?
Michael Schmidt: CFA.
Michael Schmidt: So on the first question,
Michael Schmidt: We can't provide a lot of detail about that, about the eligibility. Obviously it's patients with TRS-G12C bearing tumors. It's a mixture of solid tumor types, it's a mixture of prior treatment backgrounds, and it'll be best understood when you see the data.
Michael Schmidt: And with regard to the
Michael Schmidt: I want to make it really clear that we remain committed to launching a Phase III registrational trial in lung cancer in the near future, and we fully expect, as Steve pointed out, to complete our analysis and our internal deliberations on an updated Phase I dataset.
Michael Schmidt: and to share these this quarter.
Michael Schmidt: but practically speaking with the December holiday.
Speaker Change: just around the corner, it's just become too much of a stretch to assume that on top of these activities, all of which are critical path to the program, that we could also obtain regulatory alignment on the study details and initiate the trial before the end of the year. And simply having recognized this reality, we wanted to be transparent about it.
Speaker Change: I do want to point out that we were able to accelerate the launch of the Phase 3 pancreatic cancer trial. We call that the Resolute 302 study.
Speaker Change: But apparently we were a bit too optimistic on the timing for the lung cancer study initiation. We will certainly continue pushing hard to achieve lift-off on this second pivotal trial as soon as practical.
Speaker Change: Again, let me just emphasize that we do expect to be able to move forward, but can't provide any more detail today. Just ask everybody to stay tuned for the promised data disclosure this quarter.
Speaker Change: Great. Thanks for clarifying, Mark.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Jay Olson with Oppenheimer. Your line is now open.
Jay Olson: Oh hey, congrats on all the progress and thanks for taking the questions. Since you have a clinical collaboration with Tango Therapeutics evaluating the combination of 6236 and 9805 with their
Speaker Change: PRMT5 inhibitor. Can you provide some color on the clinical development strategy there and indications that you're focusing on? Thank you.
Speaker Change: Thanks, Jay.
Speaker Change: Unfortunately, no. We can't really provide any more information than what TANGO reported. We're obviously happy to be participating, but we're providing clinical drug supply to TANGO. We'll sponsor the studies. Can't really give you more information.
Speaker Change: Other than that, we have done some preclinical work with that combination.
Speaker Change: Each of these two agents addresses a different signaling component that may be contributing to oncogenesis in those patients who have both a RAS mutation and MTAP deletion, and so it certainly makes sense.
Speaker Change: to try to suppress both of those signaling contributors and the preclinical results were encouraging in that regard. So we're excited to be able to help support the combination study.
Speaker Change: Great, thank you.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Mark Fromm with TD Cohen. Your line is now open.
Mark Fromm: Thank you.
Mark Fromm: Hi, thanks for taking my questions. I'm just following up on Michael's earlier question.
Speaker Change: You know, about a year ago, you put out the kind of initial statement that you intended to start phase threes for pancreatic and lung. You know, so that kind of decision seems like it was made kind of in parallel. Can you just kind of explain why, you know, how the questions you still needed to answer to actually, you know, move forward from that decision you made a year ago to starting the trial differed and kind of what, how the timelines seem to have diverged for the two?
Speaker Change: I don't really think there's much color we can get to that. I mean the steps that we have to go through for those are essentially the same.
Speaker Change: You know, enrollment paces can differ.
Speaker Change: It's just a practical reality. It's very hard to predict a year ago exactly what they will be able to start a study. I don't think there's really much more to be able to provide than that.
Speaker Change: Okay, and then maybe...
Speaker Change: Not so much about the Tango collaboration itself, but just talk through kind of your strategy moving forward with kind of novel novel combinations. How are you approaching that with 6236?
Speaker Change: Should we see a lot more of these deals or these types of collaborations, or is this more of a one-off?
Speaker Change: I doubt it's going to be a one-off. We have a long list.
Speaker Change: of requests for collaboration for combination with RMC 6236.
Speaker Change: It almost overwhelms us just in terms of reviewing the list, but so I do expect there will be other other agents, other targets, other things for which we'll do collaborative studies. Of course,
Speaker Change: we prioritized the studies that we feel we need to do as priority studies and you know what those are. We're combining RMC 6236
Speaker Change: with other RAS-LOM inhibitors. We're combining RMC6236 with Temporalizumab.
Speaker Change: We're combining RMC6236 with chemotherapy and various combinations, multiplex combinations of those. So those are our near-term priorities, but I do expect there will be other combination studies that will emerge over time.
Speaker Change: Okay, thank you.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Alec Stranahan with Bank of America. Your line is now open.
Alec Stranahan: Hey guys, thanks for taking our questions. Just looking ahead to the preclinical AML data, we should expect that at ASH.
Speaker Change: Curious to hear your thoughts around the application of the RAS on platform to
Speaker Change: To be true, Alex, the hematology component of our program has almost been completely outsourced to academic collaborators up to now, and they're going to be the ones that will be presenting data at ASH and other meetings going forwards.
Speaker Change: We have been so focused on pancreatic cancer, non-strong cell lung cancer, and colorectal cancer.
Speaker Change: that we have not really had an opportunity to plan any clinical development in some of the more infrequent tumors that carry graft mutations like AML. We do appreciate the
Speaker Change: We do appreciate the mechanistic basis there and the unmet medical need and that is increasing of course as it becomes clear that one of the major mechanisms by which AML escapes from
Speaker Change: Targeted therapies like FIT3 inhibitors is through acquisition of RAS mutation, but right now
Speaker Change: For a relatively medium-sized biotech company on the West Coast of the United States, it's not a top priority for us. We do very much appreciate the work that's being done by the academic collaborators that might set us up for success.
Speaker Change: at Chemical Development at some point in the not-too-distant future.
Speaker Change: It makes sense. Thank you.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Jonathan Chang with Leibring Partners. Your line is now open.
Jonathan Chang: Hi guys, thanks for taking the question. Just one for me. On CASH runway guidance, can you provide some color on what's baked into the runway guidance? Specifically, what's baked in in terms of the different ways you could proceed in pancreatic cancer and lung cancer across your pipeline? Thank you.
Speaker Change: Thanks, Jonathan. I think Jack can comment on that.
Speaker Change: With regards to the cash guide, what's baked in there is the two Phase III second-line studies that we've disclosed that we are moving ahead with. Beyond that, we use a probability-adjusted model with regards to costs.
Speaker Change: There are a multitude of potential opportunities and programs that we can push forward and additional pivotal trials, but we use...
Speaker Change: We use the probability adjusted model, so we can't really describe specifically what additional programs are in.
Speaker Change: The Cash Primary Forecast, but what's fully baked in there are those two Phase 3 Second Mock Trials.
Speaker Change: Understood. Thank you.
Speaker Change: Thank you.
Speaker Change: As a reminder, to ask a question, please press star 11 on your phone. Our next question comes from Eric Joseph with JP Morgan. Your line is now open.
Eric Joseph: Thank you. Thanks for taking the questions. Just on the combination work of 6236 with Pembro was in there. I'm curious to know if you're also looking at combinations of a triplet 6236 Pembro and chemotherapy.
Eric Joseph: I guess, how do you think about the strategic utility of that triplet regimen potentially as we look to expand in frontline opportunities in non-fossil lung cancer?
Speaker Change: where you want to pop another, yeah.
Speaker Change: Within the study, what you refer to as a triplet, really, it's a quadruplet of R6236 plus 10 to a plus.
Speaker Change: Platinum Doublet Chemotherapy, that's actually built into the protocol itself. So, we're actually doing it sequentially after clearly identifying the appropriate dose for the doublet of 6-3-3-6-12-10-probe, then we'll initiate the combination with the chemotherapy method up.
Speaker Change: Thank you very much.
Speaker Change: Okay, got it. And just with the, just on.
Speaker Change: The OPEC side, you know, pretty, pretty significant jump this past quarter, but you're keeping full year spend guidance intact. I'm just wondering whether there's any.
Speaker Change: one-time items that are non-recurring items you should keep in mind and, you know, I guess how should we be thinking about sort of the sequential ramp from here into the early part of 2025.
Speaker Change: Thanks a lot.
Speaker Change: So with regards to one-time items or potential one-time items within the historical results
Speaker Change: and what we've reported to date in 2025, nothing that stands out as one-time items. If you kind of take a look at the midpoint of our guidance,
Speaker Change: Ryan Asay, Erin Graves, Jack Anders, Erin Graves, Jack Anders, Ryan Asay, Erin Graves,
Speaker Change: A little bit of a ramp going into Q4 from a net loss perspective.
Speaker Change: And with regards to 2025, we haven't guided to any specific guidance, and we will likely do that in the future. However, I think that it's fair to assume that our expenses are going to go up.
Speaker Change: we are
Speaker Change: Go to Beadaholique.com for all of your beading supply needs!
Speaker Change: We're going to be launching. So, no specific guidance for 2025. Outside, you do expect expenses to increase.
Speaker Change: Thank you for tuning in and have a great day.
Speaker Change: Okay, got it. Thanks for taking the questions.
Speaker Change: Thank you.
Speaker Change: Thank you. Thank you.
Speaker Change: Thank you. Our next question comes from Laura Prendergast with Raymond James. Your line is now open.
Laura Prendergast: Hey guys, quick question regarding the Nature paper that was published last week out of MSK.
Speaker Change: This shows proof of concept at 6236.
Laura Prendergast: actually increases RAS G12x GTPase activity. Is this a mechanism that you guys have also been looking at internally? And just generally any comments on how you're thinking about this, especially in regards to potential combinations or just in general? Thank you.
Speaker Change: Thanks, Laura.
Speaker Change: Yeah, of course, we're very aware of this Additional mechanism and in fact we discovered it some time ago, and we first disclosed it ourselves at an NCI RAS scientific conference a few years ago So yes, we're quite familiar with it. We think it's quite interesting It may in fact contribute to the therapeutic index of RMC 6236
Speaker Change: by affecting RAS signaling more in cancer cells with upregulated RAS on signaling than in normal cells that have a lower level.
Speaker Change: We were happy to see it. We were familiar with the work, for sure, and helped lay the foundation for it, and we think it is likely to be a contributor to RMC-666.
Speaker Change: Great, thank you.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Ellie Merle with UBS. Your line is now open.
Speaker Change: Hey guys, it's Sam on for Ellie. I guess just as you're thinking about a potential phase 3 study in first-line PDAC,
Laura Prendergast: And related to this, moving into the first line, just like mechanistically, is Roth like more or less of a driver? And like, I guess, how might we expect efficacy to translate into this earlier setting?
Speaker Change: Okay, thank you for the questions. I think there were three questions in there.
Speaker Change: And I think I remember two of them. So the one I remember most is, are we waiting for results from the phase 3 second-line study before launching a first-line study? That one's the easiest one. No.
Speaker Change: I think sets up what's going to be in that study and how are we going to get there. Maybe Wei can talk to us a little bit about the various things that we have going on, helping us determine what we might include in that.
Wei Lin: Okay, yeah, happy to answer that.
Wei Lin: Right now, I think we believe the SetLine data, with the PFS OS exceeding the FirstLine Benchmark, already established the proof of concept in our mind of this agent as a monotherapy being active in the FirstLine setting.
Wei Lin: So, I think, so we are moving forward with planning for a retrogen A3 with a single agent monotherapy as one of the potential therapy arms.
Wei Lin: We're also actively developing a combination with Standard Care that includes a fiber-based regimen as well as a gem-siderine-based regimen, and those potentially can be enabled as additional treatment arms, experimental and investigational arms.
Wei Lin: in that phase three trial. So that's kind of the way we're thinking about the first one study. I think, expanding on, I think your question, I'm gonna rephrase it, please let me know if I.
Wei Lin: address it correctly. I think what you're trying to ask is
Wei Lin: We believe that RAS is a driver across different lines of therapy whether that changes or not and whether the efficacy could potentially change or not. I think, number one, I think we do believe that RAS is a fundamental driver regardless of line of therapy. And without... ... ... ... ...
Wei Lin: Providing selective pressure with a RAS inhibitor in any line of therapy, then the sensitivity
Wei Lin: remain the same across lines.
Wei Lin: Because there has not been such pressure for resisting to talk. Therefore, we do believe the second line of the concept should be translate to the first line. We have also shown data
Wei Lin: For third line, which really demonstrates that it's also actually the third line plus patients and so validating that scientific concept.
Wei Lin: And in that comparison between second-line and third-line data, we've shown that we're more than double the PFS.
Wei Lin: in either line.
Wei Lin: I think among target therapy, there's this concept of treatment effect building in terms of measure by hash ratio, right? So proportionately, we actually have a greater than 50% risk reduction in progression in second and third line. So we hope that if that...
Wei Lin: basic concept holds, then we can expect similar treatment effect applying to first lines while meeting a reduction of risk for progression in the first line of 50% or greater. So those are kind of our current thinking.
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Speaker Change: Thank you so much.
Speaker Change: Thank you.
Speaker Change: Our final question comes from Kelly Shea with Jeffreys. Your line is now open.
Speaker Change: Hi, this is Clara. I'm for Kelly. Thanks for taking our question. So, we just have a quick follow-up question on Tango's clinical collaboration. Wondering if you can add any color on the reason for the choice of collaboration partner among other clinical PRM-T5 programs. Thank you.
Speaker Change: Oh yes, so you're asking about our choice, not Tango's choice of us, but our choice of Tango's compound. Sure.
Speaker Change: It looks like an interesting compound. There certainly are other compounds in the field.
Wei Lin: We've done some preclinical work with the Tango compound as I mentioned earlier and they've done some preclinical work with our compounds so you know we have some visibility into what that combination looks like in preclinical model systems.
Wei Lin: But that doesn't mean that we wouldn't do a collaboration study with another PRMT5 inhibitor.
Wei Lin: You know, we are actively trying to find the best combination partners for RMC6236, and it's far too early for us to make any declarations about that. But we're happy to be in the collaboration, and it's one of, as I mentioned earlier, probably many different combination studies we'll do with agents across many different disease targets.
Speaker Change: Appreciate the color.
Speaker Change: I'm showing no further questions at this time. I would now like to turn it back to Mark Goldsmith, Chairman and Chief Executive Officer for closing remarks.
Mark Goldsmith: Thank you, Operator, and thank you to everyone for participating today and for your continued support of Revolution Medicines.
Mark Goldsmith: Thank you. Bye.