Revolution Medicines - Q1 2023
May 8, 2023
Transcript
Operator (participant)
Good day, welcome to Revolution Medicines' 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 one one on your telephone. You will hear an automated message advising that your hand is raised. To withdraw your question, simply press star one one again. 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, 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, Erin Graves, Senior Director of Corporate Communications and Investor Relations. Erin, please go ahead..
Erin Graves (Senior Director of Corporate Communications and Investor Relations)
Thank you. Welcome, everyone, to the first quarter 2023 earnings call. Joining me on today's call are Dr. Mark Goldsmith, Revolution Medicines' 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. Except as required by law, the company undertakes no obligation to revise or update any forward-looking statement.
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 Medicines' Chairman and Chief Executive Officer. Mark?
Mark Goldsmith (Chairman and CEO)
Thanks, Erin. It's good to be with you this afternoon and to provide an update on our 1st 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 Anders 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 1st quarter. First, we communicated early findings from the phase I, Ib study of RMC-6236, our first-in-class RAS multi-ON inhibitor, which showed encouraging antitumor 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 RMC-6236, 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 RMC-6236 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?
Steve Kelsey (President of R&D)
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 RMC-6236, our RAS multi-(ON) inhibitor in the RMC-6236-001 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 5, day one on RMC-6236 at 80 milligrams daily. The partial response was subsequently confirmed by RECIST with an 82% reduction in tumor measurements on cycle 7, day one. The CT scans are shown on slide 14 of the corporate deck. This patient continues on treatment.
Second, we have escalated the dose level through 160 mg daily and are now evaluating 220 mg daily while also continuing to backfill the 120 and 160 mg dose levels. We are encouraged that we continue to accumulate clinical evidence of antitumor activity for RMC-6236 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 RMC-6291, our mutant-selective KRAS G12C RAS(ON) inhibitor.
Eric Joseph (Senior Equity Research Analyst, Biotechnology)
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. RMC-6291 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 RMC-6291-001 study and are now focused on a twice-daily dosing schedule to maximize continuous drug exposures. RMC-6291 continues to be well-tolerated, and we have not yet reached the maximum tolerated dose or selected a recommended phase II dose. We remain on track to provide an update in the second half of this year.
Steve Kelsey (President of R&D)
RMC-9805, our mutant-selective oral and covalent KRAS G12D RAS(ON) inhibitor, remains on track in support of the goal of beginning clinical evaluation of this groundbreaking compound in mid-2023. We'll shortly have our entire first wave of three RAS(ON) inhibitors under clinical evaluation. Many RAS mutant epithelial tumors have a propensity to metastasize to the brain, it is important to define the potential activity of these RAS(ON) inhibitors against tumors that have metastasized into the central nervous system. This may become particularly important if improvements in treatment of systemic or visceral disease allow more cases involving the central nervous system to emerge. Today, we highlight preclinical studies demonstrating antitumor 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. For validation, adjacent to it is a group of animals treated with adagrasib at 100 milligrams per kilogram twice daily that showed a roughly 10x lower signal representing significant tumor reduction. This model and results match those published by Mirati, an important point since adagrasib was reported last year to display antitumor activity against brain metastases 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 RMC-6236 at 25 milligrams per kilogram daily, showing encouraging antitumor impact that is essentially indistinguishable from that of adagrasib. The next group in blue is mice treated with RMC-6291 at 100 milligrams per kilogram twice daily, a dose selected to be identical to the adagrasib treatment regimen, where a greater antitumor effect was observed. Finally, on the right is an analogous study of RMC-9805 versus control in an intracranial model of pancreatic cancer carrying KRAS G12D, showing a profoundly reduced signal, indicating a significant antitumor 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 anticancer 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 SHP2 inhibitor, RMC-4630. The global Phase II RMC-4630-03 trial evaluating RMC-4630 in combination with sotorasib for patients with KRAS G12C non-small cell lung cancer is fully enrolled. We remain on track to read our top-line results in the second half of this year.
Second, our mTORC1-selective inhibitor, RMC-5552, 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 6 to 8 mg 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 mg per week.
We plan to provide a clinical update on RMC-5552 at a scientific meeting in the second half of this year. Back to you, Mark.
Mark Goldsmith (Chairman and CEO)
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 RMC-6236. 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, Nektar and Erasca, 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 lifecycle management, commercial strategy and launch planning. 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?
Jack Anders (CFO)
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 31st, 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 $0.72 per share. We are updating our financial guidance for 2023 and now expect full year 2023 GAAP net loss to be between $360 million and $400 million, which includes estimated non-cash stock-based compensation expense of $40 million-$50 million. The increase in expected GAAP net loss is a result of increased investments to support and strengthen clinical advancement of our first wave of RAS(ON) inhibitors, including expanded clinical supply and additional senior leaders across late-stage development, manufacturing and commercial planning for RMC-6236. With that, I'll now turn the call back over to Mark.
Mark Goldsmith (Chairman and CEO)
Thank you, Jack. 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 RevMed employees in pursuit of our mission to outsmart RAS-addicted cancers. This concludes our prepared remarks for today. I'll now turn the call over to the operator for the Q&A session.
Operator (participant)
Thank you. At this time, we'll conduct a question-and-answer session. As a reminder, to ask a question, you'll need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, simply press star one one 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 Marc Frahm with TD Cowen. Marc, your line is open. Please go right ahead. Marc Frahm?
Marc Frahm (Managing Director and Senior Equity Research Analyst – Biotechnology)
Yes. Sorry, thanks for taking my questions and congrats on the progress and the little bit of data update, Steve, that you dropped in there. Just looking forward to the additional RMC-6236 updates. Maybe just start off just can you give some context for the kind of patient numbers? Right now, you know, most of the data has been in G12D patients, you know, 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 and histologies? Or, you know, is this really staying given the epidemiology, just very focused on G12D? I'll probably have a follow-up there.
Mark Goldsmith (Chairman and CEO)
Thanks, Mark. To anticipate your question, I don't think we can really give you a lot more color around 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. 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 G12D is the most common mutation, and that's what we're seeing in the study. 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.
There are some others as well. It's hard to say from where we are today. We'll know better, as we get closer to that, to that disclosure point.
Marc Frahm (Managing Director and Senior Equity Research Analyst – Biotechnology)
Okay. That's helpful. 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 the monotherapy expansion for the multi-RAS and maybe the G12C? Is that just really the combo work getting underway and, you know, kind of what's the priorities there?
Mark Goldsmith (Chairman and CEO)
Yeah. I don't think today we're necessarily announcing 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. We do feel that there, it is justified to increase our commitment to supply, which we'll 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. 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 in, 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.
Marc Frahm (Managing Director and Senior Equity Research Analyst – Biotechnology)
Okay. Thank you.
Mark Goldsmith (Chairman and CEO)
You're welcome.
Operator (participant)
Please stand by for our next caller. Our next question comes from the line of Eric Joseph with JPMorgan. Eric, your line is open. Go ahead.
Eric Joseph (Senior Equity Research Analyst, Biotechnology)
Thanks for taking the question. Just on the dose escalation update, now at 220, can you talk a little bit what you're, what you saw in terms of tolerability at 160 that you're comfortable with widening the dose interval? I guess, do you think currently where you are right now that there's perhaps headroom to further dose escalate?
Mark Goldsmith (Chairman and CEO)
I think Steve will comment on that.
Steve Kelsey (President of R&D)
Sure. The tolerability profile of RMC-6236 continues to be what we consider favorable. There have been no qualitative changes in the tolerability profile of RMC-6236 since our last update. We feel comfortable in continuing to dose escalate. 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 gonna become dose-limiting. We had previously articulated, I believe, that we would expect on the basis mechanistic studies and non-clinical toxicity studies, that maybe GI toxicity would ultimately become dose-limiting. As of now, that's not happening, we're continuing to dose escalate. It's very difficult to, Eric, to predict where we're gonna stop with this. I honestly cannot give you color on that.
I may do even if I. Other than that, you know, the program continues extremely well.
Eric Joseph (Senior Equity Research Analyst, Biotechnology)
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 from the.
A meaningful difference in the scope of data reading at, sort of mid-year from what you might present at a medical meeting with this program.
Mark Goldsmith (Chairman and CEO)
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, that, you know, series that starts in Q3. I think those are all part of the same series that'll begin in Q3.
Eric Joseph (Senior Equity Research Analyst, Biotechnology)
Got it. Okay, thanks for clarifying. Appreciate you taking the questions.
Mark Goldsmith (Chairman and CEO)
Yeah, thank you.
Operator (participant)
Stand by for our next caller. We have Michael Schmidt from Guggenheim. Michael, your line is open. Please go ahead.
Michael Schmidt (Senior Biotech Analyst and Senior Managing Director, Equity Research)
Hey, guys. Thanks for taking the questions. Question on RMC-6291, now that we've seen a few more clinical data sets from other G12C inhibitors at AACR, you know, I guess, what are you looking for in the clinic for your program? I guess what degree of, you know, differentiation, you know, be it either on efficacy or safety are you looking for at a minimum, you know, relative to the others which feel rather comparable? Then a follow-up question on the switch to the BID dosing. Just help us understand a bit more, you know, what drove that decision to move into twice-daily from the originally planned once-daily dosing schedule. Thank you.
Mark Goldsmith (Chairman and CEO)
Yeah. Hi, Michael. Thanks for your questions. I might just take both of those, Steve can add to it if there's anything to add. 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 pre-clinically. Pre-clinically, we saw and have reported that the half-life of RMC-6291, 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 pre-clinically. In fact, almost all of the pre-clinical data we reported were from daily dosing. The pre-clinical differentiation that we reported was supported by that daily dosing.
Nonetheless, in humans, we want to have every opportunity to be successful here, and there's really not a good argument for 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. That's really all there is. There's nothing else from the clinic that drove that decision. Your... The first question was?
Michael Schmidt (Senior Biotech Analyst and Senior Managing Director, Equity Research)
I was just asking about the.
Mark Goldsmith (Chairman and CEO)
Yeah.
Michael Schmidt (Senior Biotech Analyst and Senior Managing Director, Equity Research)
Of differentiation you're sort of looking for in the clinic relative to the other G12C inhibitors out there that you look fairly comparable so far.
Mark Goldsmith (Chairman and CEO)
Yes. Well, I think that's the sort of the key point is that the entire RAS(OFF) inhibitor, pool of drug candidates, they look relatively similar. 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 gonna be chasing, trying to get a leg up, but without much biological ability to do so. Ultimately, we'd like regimens that incorporate RMC-6291 to give us greater clinical benefit. 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 of response, and/or, greater tolerability.
Those are all features that we've, you know, that we've seen pre-clinically, 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 RMC-6291 is to move it into combination studies as quickly as we can and to focus the long-term plan on combinations. I think the puck has already moved past monotherapy, and so we're trying to play where the puck is gonna be in the future on behalf of patients. The answer to that is we're not really prepared to define for you an answer to that.
We're gonna move into combination studies as quickly as we can. We need to get sort of the basic profile in monotherapy. We need to compare that to the benchmarks. How much superiority or differentiation we see relative to those benchmarks, we don't know. We're not too concerned about it because we know mechanistically it's going to be, it is going to be differentiated, qualitatively differentiated, so we're not too hyped up about exactly what we see in a relatively small number of patients. 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. You know, it, we don't really anticipate that from a phase 1 dose-escalation study.
Michael Schmidt (Senior Biotech Analyst and Senior Managing Director, Equity Research)
Great. Thank you, Mark.
Mark Goldsmith (Chairman and CEO)
Yep.
Operator (participant)
Stand by for our next question. Chris Shibutani joins us from Goldman Sachs. Chris, your line is open. Go ahead.
Speaker 13
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 RasON platform at this point. 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 tri-complex mechanism of action that might influence the translatability of that intracranial activity that you're seeing in mouse models so far?
Steve Kelsey (President of R&D)
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. Ultimately, as we get into earlier lines of therapy, as we have the opportunity to control the visceral disease more effectively, then I think that brain metastases are gonna be an increasingly large part of the unmet medical need. That's when you will see the impact of the translatability, so to speak, of compounds getting into CNS metastases. With regards to the tri-complex technology per se, particularly the mutant-selective compounds which caused these regressions in these implanted tumors, you know, they're highly selective for mutant RAS, so 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.
Speaker 13
Great. That's helpful. Thank you so much. Then maybe just a quick one on RMC-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 RMC-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?
Mark Goldsmith (Chairman and CEO)
I mean, I think at this point, everything is open. Obviously, with the RAS multi-inhibitor that is, 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. For example, a SHP2 inhibitor and a RMC-6236, 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. An example of that might be PD-1. RMC-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. 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.
Speaker 13
Yeah, I really appreciate it. Thank you so much.
Mark Goldsmith (Chairman and CEO)
You bet.
Operator (participant)
Stand by for our next caller. Alec Stranahan joins us from Bank of America. Alex, your line is open. Go ahead.
Speaker 12
Hey, guys. This is John. I'm on for Alex. Just a quick one on RMC-9805. Obviously, we saw some preclinical data at AACR. In terms of getting into the clinic as you dose the first patient in your monotherapy dose escalation study, what's the kind of like patient baseline characteristics we can expect? You know, what tumor types are you gonna go for in the study? If you could shed some light on that. Thanks.
Steve Kelsey (President of R&D)
Well, right now the plan for RMC-9805 is to identify a recommended phase 2 dose as expediently as possible and obviously convince ourselves that that's the right dose and persuade other constituencies out there that we have the right dose. Apart from an obvious restriction for patients with tumors harboring a KRAS G12D mutation, I don't think you're gonna see a lot of difference from the RMC-6236 dose escalation, frankly. You know, we know the histotypes in which KRAS G12D mutations predominate. You know, we have enough experience now with 6236 to get a handle on the types of patients that we're gonna get in the phase 1 study. They're gonna be predominantly patients with lung cancer, pancreatic cancer, and colorectal cancer.
I think that's pretty much all we can say right now. There is nothing unusual about the phase I plan for this compound.
Speaker 12
Got it. Can I ask a quick follow-up?
Mark Goldsmith (Chairman and CEO)
It might be worth adding that, I don't know if slightly underlying it was a question about access to patients, which we sometimes get asked about. You know, We estimate 55,000 new U.S. cases of KRAS G12D cancers each year. 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 gonna be any impact of either competition from others to the extent that there is any versus competition from RMC-6236. We'll have plenty of access to patients with KRAS G12D tumors.
Speaker 12
Okay. Thank you. A quick follow-up to that. You mentioned that, CRC is likely going to be, one of the, type of patients, recruited. 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?
Mark Goldsmith (Chairman and CEO)
I think just to build on Steve's comments, you know, the first thing to do with the compound is a phase I 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 and have a good sense of where you might prioritize. I think Steve mentioned there will be relatively few restrictions other than sort of conventional exclusion criteria, and then the inclusion is a KRAS G12D mutation. I don't think we'll be putting any other genetic, you know, significantly other genetic, restrictions.
Speaker 12
Okay. Thank you. Thanks for the color.
Mark Goldsmith (Chairman and CEO)
Yeah. Thank you.
Operator (participant)
Stand by. Our next question comes from Ben Burnett with Stifel. Ben, please go ahead.
Ben Burnett (Managing Director, Equity Research Analyst – Biotechnology)
Hey, thank you very much. Just wanna build off a an earlier question just about the regulatory path for the RAS multi RMC-6236. I realize it's early days, but do you have a sense for how many different sort of genetic variants of KRAS you need to show data on to get a broad sort of mutation agnostic label?
Mark Goldsmith (Chairman and CEO)
Hi. Hi, Ben. No, we don't know. It'll just depend on how much activity there is when we have a more mature dataset, and then that will ultimately depend on conversation with the people who make that decision.
Ben Burnett (Managing Director, Equity Research Analyst – Biotechnology)
Okay. All right. Got it. Thank you.
Mark Goldsmith (Chairman and CEO)
Mm-hmm.
Operator (participant)
All right. Please stand by for our next question. Jay Olson joins us from Oppenheimer. Jay, your line is open. Please go ahead.
Jay Olson (Managing Director and Senior Analyst – Biotechnology)
Hey, thanks for taking the question, and congrats on all the progress. Can you talk about any feedback you received from physicians following AACR? Also, is the brain penetrant property of your three molecules by design, or is there a particular reason for the high CNS activity? Thank you.
Mark Goldsmith (Chairman and CEO)
Remind, I was sort of thinking about your second question, but remind me what the first question was. Could you say it again?
Jay Olson (Managing Director and Senior Analyst – Biotechnology)
Any feedback-
Mark Goldsmith (Chairman and CEO)
Oh, feedback.
Jay Olson (Managing Director and Senior Analyst – Biotechnology)
-you got from physicians following AACR? Thank you.
Mark Goldsmith (Chairman and CEO)
Okay, are you asking about feedback on our programs, or are you asking about feedback on other things at AACR? Could you just clarify?
Jay Olson (Managing Director and Senior Analyst – Biotechnology)
Feedback on the data you presented.
Mark Goldsmith (Chairman and CEO)
I think generally, the feedback continues to be very positive. Our investigators are quite enthusiastic. We've, 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. 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 RMC-6236. Now I've forgotten the second question.
Jay Olson (Managing Director and Senior Analyst – Biotechnology)
Was it by design?
Mark Goldsmith (Chairman and CEO)
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. 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 inhibitors based on, you know, macrocyclic, large, chemical backbones. They now have been endowed with these properties through pretty directed efforts.
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 maybe more of a philosophical question than anything else. That mean I don't have to answer philosophical questions, I guess.
Jay Olson (Managing Director and Senior Analyst – Biotechnology)
Okay, great. Thank you. If I could maybe one follow-up on RMC-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?
Mark Goldsmith (Chairman and CEO)
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, you know, the course of the treatment for those patients who have already been on drug and who remain on. We're going to get a sense from backfill patients, a deeper sense of tolerability and a deeper sense of antitumor activity from those backfill patients. Might not have as much durability data from those if they're enrolled later in the game.
Of course, we have escalation data that shows us, you know, 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 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. 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.
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. 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 I, Ib 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.
Jay Olson (Managing Director and Senior Analyst – Biotechnology)
Great. It's super helpful. Thank you so much for taking the questions and congrats again on all the progress.
Mark Goldsmith (Chairman and CEO)
Yeah, thanks, Jay.
Operator (participant)
I'm bringing on our next caller. Please stand by. Ami Fadia joins us from Needham. Ami, your line is open.
Ami Fadia (Managing Director, Senior Biotech Equity Research Analyst)
Great. Thanks for taking my question. With regards to RMC-6236, can you discuss where the 220 milligram dose is relative to the dose that you tested in the preclinical models? 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? Maybe let me pause here, and I'll ask the next question after that.
Mark Goldsmith (Chairman and CEO)
Okay. Thank you, Ami. I appreciate the questions. You know, just to remind you how dose 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. If we've cleared the DLT window, they proceed to a dose escalation, and they determine, of course, with input from Revolution Medicines, how much to increase. They determine the 220 milligram increase versus the 160. 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. We don't know. We can't know a priori. We have projections around that, but projections are projections. Can't answer that question today. Your second or third?
Speaker 14
how important is it to be, keep going up?
Mark Goldsmith (Chairman and CEO)
Yeah. I mean, I think we 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 know, most antitumor drugs. We'd like to get up as high as we can within the bounds of safety and tolerability. You're sort of asking a question that Project Optimus is also asking, and it's an equally difficult question to answer for Project Optimus, 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, we're not, you know, we're not in that zone where we even have to be worrying about it. 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. We're pretty pleased with the exposures we've had at the other dose levels up through 160. It's, 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. We're well above that. We've, you know, we've been above it for a bit. Exactly where we are, 220 is hard to say.
Ami Fadia (Managing Director, Senior Biotech Equity Research Analyst)
Thank you. I guess my follow-up question is, at what point do you think the clinical data will support the sort of superiority to other KRAS, you know, off drugs, that RAF off drugs that you saw in the preclinical data set? 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 time frame in at least that patient subset? Thank you.
Mark Goldsmith (Chairman and CEO)
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.
Ami Fadia (Managing Director, Senior Biotech Equity Research Analyst)
Sure.
Mark Goldsmith (Chairman and CEO)
Is that right?
Ami Fadia (Managing Director, Senior Biotech Equity Research Analyst)
Yeah. Yes.
Mark Goldsmith (Chairman and CEO)
Yeah. Well, we, 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 you know, as we dose escalate and when we report it out, with the data set, we'll have a firmer answer as opposed to a preliminary answer at that point.
Ami Fadia (Managing Director, Senior Biotech Equity Research Analyst)
Thank you.
Mark Goldsmith (Chairman and CEO)
On versus off. Yeah. You know, RMC-6236 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. It sort of defines a class of its own, and it has to stand on its own. It'll be compared more to standard of care in each of the, you know, histologies. I think RMC-6291 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.
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 RMC-6291 program. In the combinations, 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 G12C inhibitor in large part because of its RAS(ON) mechanism. That will be additive to whatever combination play is put together when it's tested in a phase 2 kind of context.
Ami Fadia (Managing Director, Senior Biotech Equity Research Analyst)
Understood. Thank you.
Mark Goldsmith (Chairman and CEO)
You're welcome.
Operator (participant)
Okay, stand by for our last question. It comes from the line of Jonathan Chang with SVB Securities. Jonathan, you're on the air.
Jonathan Chang (Senior Research Analyst, Emerging Oncology)
Hi, guys. Thanks for taking my question. Just one from me. What do you see as the competition for RMC-6236? Thank you.
Mark Goldsmith (Chairman and CEO)
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 G12V, obviously there are some other compounds that have entered the clinic, in principle, those are competitive for that population, the genotype, the KRAS G12V genotype. That's not a statement of my judgment about which compound is superior. You just wanna know what's on the list? You know, those compounds that are in the clinic or about to be in the clinic, those would have to be considered competition.
Jonathan Chang (Senior Research Analyst, Emerging Oncology)
Got it. Thanks for taking my question.
Mark Goldsmith (Chairman and CEO)
You're welcome.
Operator (participant)
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.
Mark Goldsmith (Chairman and CEO)
Well, thank you, operator, and thank you to everyone for participating today and for your continued support of Revolution Medicines.
Operator (participant)
Thank you for your participation. This does conclude the program. You may now disconnect.