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

Good day, ladies and gentlemen, and welcome to the Revolution Medicines Fourth Quarter and Full Year 2021 Financial Results Conference Call and Webcast. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to hand the conference over to Peg Horn, Revolution's Chief Operating Officer, for opening remarks. Peg, you may begin.

Good afternoon, everyone, and thank you all for joining us today. Joining me on today's call are Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer; Dr. Steve Kelsey, the company's President of R&D; and Jack Anders, our Senior Vice President of Finance and Principal Accounting Officer. As we begin, I'd like to caution you that our presentation today will contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act regarding the current beliefs of the company with respect to our business. These statements are subject to a number of assumptions, risks and uncertainties. Actual results may differ materially from these statements. And except as required by law, the company undertakes no obligation to revise or update any forward-looking statements. I encourage you to review the legal disclaimer slide we are presenting today as well as all of the company's filings with the SEC concerning these other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted to our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, Revolution's Chairman and Chief Executive Officer. Mark?

Good afternoon, and thank you for joining us. We're very pleased to report that during the fourth quarter of 2021, Revolution Medicines continued building momentum with our targeted therapeutics pipeline, advancing our mission to improve treatment on behalf of patients with a wide range of RAS-addicted cancers, representing some 30% of all cancer patients. As depicted on Slide 5, RAS-addicted cancers are induced primarily by mutations that cause RAS(ON) proteins to behave as cancer drivers. But often, these cancers are also supported and maintained by other cellular proteins we call RAS cooperating targets and pathways. We believe it is important scientifically to match our treatment strategies to this biological cooperativity by developing RAS(ON) inhibitors to suppress the primary RAS drivers as well as RAS companion inhibitors to suppress the cooperating proteins. In many instances, we expect drugs of these 2 types may be combined to deliver the greatest clinical benefit. I'll spend the next few minutes briefly recapping 4 drug candidates that constitute our development-stage RAS(ON) inhibitor portfolio directed against RAS variants that are the primary drivers of RAS-addicted cancers. Dr. Steve Kelsey, our President of R&D, will then highlight recent updates on our clinical-stage RAS companion inhibitors, RMC-4630, SHP2 and RMC-5552, mTORC1. Our first RAS(ON) inhibitor, RMC-6236 is an innovative and exciting drug candidate, a first-in-class RASMULTI(ON) inhibitor with potentially very broad utility across many RAS cancer variants. As shown on Slide 12, initially, we are particularly interested in the more than 130,000 new pancreatic, colorectal and/or lung cancer patients in the U.S. each year, with tumors bearing one of various mutations at amino acid 12 and KRAS, the dominant hotspot for KRAS cancer mutations. We refer to these collectively as G12X-mutations. RMC-6236 has demonstrated strong single-agent activity across numerous cancer models with such G12X driver mutations derived from non-small cell lung, pancreatic and colorectal cancer patients. We believe this compound has the potential to be the first RAS-targeted therapy for many patients still reliant upon chemotherapy, including those with tumors bearing KRAS G12D or KRAS G12V mutations. This compound is in the late stages of IND preparation, and we are on track to submit an IND in the coming months. And then to begin single-agent dose escalation with an initial focus on patients with various tumors carrying KRAS G12X mutations. During dose escalation, we plan to deploy a dynamic below MTD expansion strategy to help us both find the right dose and schedule and discover the most sensitive tumor types as efficiently as possible. The next compound, RMC-6291, is our first mutant selective inhibitor plans to enter the clinic. This one focuses specifically on the KRAS G12C target. RMC-6291 is differentiated from first-generation KRAS G12C(OFF) inhibitors, which sequester the KRAS G12C(OFF) form by its mechanism of directly inhibiting the KRAS G12C(ON), or active protein form. We believe direct inhibition of the (ON) form of RAS cancer variants offers important biological advantages that could translate into meaningful increases in patient benefit relative to KRAS G12C(OFF) inhibitors. Based on extensive preclinical characterization, showing compelling response rates, depth and durability, we believe RMC-6291 has best-in-class potential for treating KRAS G12C cancers, addressing approximately 29,000 new U.S. patients per year, primarily with lung or colorectal cancers. As with the 6236 compound, as shown on Slide 16, we expect to submit an IND for RMC-6291 in the first half of this year, followed by beginning single-agent dose escalation in patients with various tumors carrying KRAS G12C mutations. Likewise, we plan to deploy a dynamic below MTD expansion strategy to help us both find the right dose and obtain anti-tumor activity data in select populations as efficiently as possible. Our overall ambition is to demonstrate clinical superiority to the first-generation KRAS G12C(OFF) inhibitors. In addition to progressing 6236 and 6291 through IND submission as expected in the first half of this year, we recently announced 2 new RAS(ON) inhibitors from our RAS innovation platform that have advanced into IND-enabling development. The first is RMC-9805 summarized on Slide 17, a remarkable mutant-selective inhibitor of the KRAS G12D cancer driver. It's highly potent and benefits from what we believe to be the first ever highly selective covalent engagement of the oncogenic aspartic acid in this clinically important RAS variant. Indeed, it appears to be the first drug candidate ever to deploy this sort of selective target-binding mechanism directed against an aspartate-containing disease target. Like our other development-stage assets, it is also orally bioavailable, promoting effective target coverage in cancer cells. We recently showed that RMC-9805 drives deep and durable antitumor responses as a single agent in preclinical KRAS G12D pancreatic and colorectal cancer models in vivo. We aim to file an IND for this highly innovative compound in the first half of 2023. Our second new development candidate is RMC-8839 summarized in Slide 20, an exciting mutant-selective inhibitor of the KRAS G13C cancer variant that forms a selective bond with the oncogenic cystine in this RAS target that has not been previously drugged. Like our other development-stage RAS(ON) inhibitors, RMC-8839 exhibits attractive potency, selectivity and oral bioavailability and was shown recently to drive significant antitumor responses as a single agent in preclinical KRAS G13C lung cancer models in vivo. We aim to file an IND for this novel compound in the second half of 2023. Beyond these 4 groundbreaking development stage RAS(ON) inhibitors, I mentioned earlier that our strategy also includes developing specific RAS companion inhibitors as illustrated on Slide 24. Targeted drugs that suppressed cooperating targets and pathways known to work in coordination with RAS cancer drivers to sustain RAS-addicted cancers and in some instances, confer drug resistance. We believe that combining best-in-class RAS inhibitors with best-in-class companion inhibitors offers the greatest chance to deliver the best clinical outcomes. In that context, Dr. Kelsey will review briefly 2 clinical-stage assets that are designed to support combination treatment approaches. Steve?

Thanks, Mark. RMC-4630 is our potent, selective and oral inhibitor of SHP2, a convergent signaling node that contributes to RAS-addicted cancers and is believed to mediate some types of resistance to RAS inhibition. We developed an innovative intermittent dosing regimen that is designed to maximize dose intensity without compromising safety and tolerability. And in doing so, have demonstrated that RMC-4630 is clinically active as a single agent in RAS-addicted cancers. We are now primarily focused on evaluating RMC-4630 as a companion inhibitor in combination with RAS inhibitors. Currently, only KRAS G12C inhibitors are in clinical development and available as partners for RMC-4630. The ongoing and planned RMC-4630 clinical program is summarized in Slide 25. Amgen continues its initial evaluation of dosing of RMC-4630 in combination with sotorasib in second line and beyond treatment of various KRAS G12C tumors in the CodeBreaK 101 trial, which is predominantly U.S.-based. And recently, Amgen announced its intention to disclose initial dose escalation data from the C arm of this study, which includes RMC-4630, in the second half of this year. We have recently initiated a new global Phase II study of RMC-4630 plus sotorasib specifically in KRAS G12C lung cancer patients who have not previously received a KRAS G12C inhibitor and are actively recruiting patients. We announced in January that the first patient has been treated, and enrollment is ongoing. Amgen is supporting this trial with clinical supply of sotorasib for both our U.S. and ex U.S. study sites. Our goal is to complete enrollment in this study and communicate our preliminary evaluation of the available data in 2022. Sanofi, our global partner for development and commercialization of RMC-4630, is the sponsor of another study with Mirati of adagrasib plus RMC-4630 in lung cancer patients that is currently in preparation to begin. And in their study, Sanofi have demonstrated that RMC-4630 can be combined with pembrolizumab without unacceptable toxicity. And they are now studying that combination as a first-line treatment for patients with PD-L1 positive lung cancer. Moving to Slide 26. And regarding our near-term clinical priorities for RMC-4630. Our aim is to complete the evaluation of RMC-4630 as a RAS companion inhibitor in KRAS G12C non-small cell lung cancer. In addition, we intend to pursue a registration study, if this is appropriate and supported by the data, and expand the combination strategy to additional KRAS G12C tumor types and perhaps even additional KRAS G12C inhibitors. Looking at Slide 27. Clinical data recently published suggests that the majority of RAS-mutant non-small cell lung cancer escaping on or after treatment with a KRAS G12C inhibitor have no identifiable genomic resistance mechanism. Many studies have shown that adaptive resistance may occur due to hyperactive receptor tyrosine kinase signaling that signal through SHP2. Combining RMC-4630 with the KRAS G12C inhibitor is, therefore, an example of a strategy to inhibit the primary RAS cancer driver while also suppressing RAS pathway resistance mechanisms that we now know or understand frequently limit the single-agent activity of the first-generation KRAS G12C(OFF) inhibitors. Now there's no reason to believe that these emergent resistance mechanisms will be specific to KRAS G12C mutations. As suggested on Slide 27, RMC-4630 may be similarly useful for countering RAS pathway resistance mechanisms that emerge with RAS mutant selective inhibitors directed to other RAS variants such as with RMC-9805 in KRAS G12D mutant cancers. Slide 27 also outlines 2 other complementary strategies that may be pursued in parallel to SHP2 inhibitor combinations and to address other mechanisms of RAS inhibitor resistance such as increased flux through wild-type RAS or acquisition of other RAS mutations beyond G12C. In some clinical context, patients may gain maximum clinical benefit from the broad activity of our RASMULTI inhibitor, RMC-6236, which in preclinical experiments, has shown 3 separate effects in a single drug candidate. Firstly, deep and durable suppression of the primary RAS-mutant cancer driver; inhibition of additional escape RAS mutations beyond the primary RAS-mutant cancer driver; and in addition of cooperating wild type RAS proteins in cancer cells. In other context, a mutant selective RAS(ON) inhibitor such as RMC-9805 may be optimized by using RMC-6236 as a companion inhibitor, an approach that combines highly selective suppression of the particular cancer driver with direct inhibition of RAS K mutations that cooperate to sustain these cancers. Ultimately, we anticipate that each of these 3 combination treatment strategies will need to be evaluated in parallel, but will ultimately prove to be optimal in biomarker-defined specific patient subsets. I'd also like to highlight here RMC-5552, our innovative, potent and selective inhibitor of mTORC1 that may also prove to be useful as a RAS companion inhibitor in certain situations. As shown in Slide 28, RMC-5552 has a unique pharmacologic profile. It is distinct from mTORC active site inhibitors as it is selective for mTORC1 over mTORC2, thereby avoiding mTORC2 mediated toxicities. Also, unlike rapalogs, it is able to inhibit phosphorylation of both substrates of mTORC1. We believe based on extensive preclinical studies that RMC-5552 has the potential to deliver clinical benefit to patients with tumors bearing mutations in the mTORC pathway. As RAS mutations and co-mutations in the mTORC pathway are relatively common in epithelial tumors, RMC-5552 could become an important companion inhibitor for our RAS(ON) inhibitor portfolio. In 2021, we began treating patients in the dose escalation portion of the initial Phase I single agent clinical trial. And the initial results are summarized in Slide 29. They are encouraging in that they show clear evidence of antitumor activity at a dose that has acceptable safety and tolerability. So far, the compound has been well tolerated at doses up through 6 milligrams weekly. Preliminary assessment suggests that mucositis is the dose-limiting toxicity at higher doses, which we believe is an on-target biological effect. 4 patients have been treated at 6 milligrams IV weekly and were a variable for efficacy as of the 7th of January 2022, all with tumors carrying mutations associated with hyperactive mTORC1 signaling. 3 of these patients have experienced a best response of stable disease, and 1 patient with a head and neck cancer and PTEN loss of function mutation has exhibited a confirmed partial response based on a 63% reduction of tumor volume from baseline. This patient had a single dose of 12 milligrams followed by 6 milligrams weekly and continues on treatment. We hope to complete the single-agent dose escalation for RMC-5552 this year in order to be able to select a recommended Phase II dose and start to study RMC-5552 in selected expansion cohorts and ultimately, aim to initiate testing of combinations with our RAS(ON) inhibitors in patients that have coactivation of the RAS and mTORC pathways. And now I'll turn it back to Mark.

Thank you, Steve. With these prepared comments, we have briefly summarized the status of 6 development-stage assets, which are supported by exciting, robust and growing data sets that suggests large clinical opportunities we may be able to serve for patients with a wide range of RAS-addicted cancers. Further, we expect that our pipeline will continue to grow, with highly distinctive new assets deriving from our RAS cancer innovation engine, which should expand our science-driven strategies to outsmart RAS-addicted cancers. Please take the opportunity to review the full corporate slide deck that you can download from our Investor Relations website. I'll now turn it to Jack Anders, our Senior Vice President for Finance, to report on our financial condition. Jack?

Thank you, Mark. As shown on Slide 33, we ended the year with $577 million in cash and investments. Revenue from our collaboration agreement with Sanofi was $9.5 million for the fourth quarter of 2021 and $29.4 million for the full year. The decrease in revenue for the full year of 2021 compared to 2020 was primarily driven by a noncash nonrecurring revenue adjustment in the third quarter of 2021, resulting from a change in accounting estimate under the -- under our agreement with Sanofi and to a lesser extent, lower reimbursed manufacturing costs. Total operating expenses for the fourth quarter of 2021 increased to $62 million, largely driven by R&D expenses, which totaled $54 million. Total operating expenses for the full year of 2021 increased to $217 million, with R&D expenses increasing to $187 million. The increase in total operating expenses in 2021 was due to the expansion of the company's preclinical research portfolio, an increase in headcount and an increase in stock-based compensation. Net loss for the fourth quarter of 2021 was $53 million or $0.71 per share. For the full year of 2021, net loss was $187 million or $2.57 per share. With regards to the financial guidance for 2022, we expect full year 2022 GAAP net loss to be between $260 million and $290 million, which includes estimated noncash stock-based compensation expense of $35 million to $40 million. The increase in expected net loss for 2022 is a result of increased expenses as we expand and advance our research and development programs. And with that, I'll now turn the call back over to Mark.

Thank you, Jack. We believe that Rev Med is in an excellent position to continue aggressively pursuing our mission on behalf of cancer patients. We have a compelling strategy, a growing set of exciting product assets and a strong balance sheet. We're proud of the tireless commitment to patients by our organization and are grateful to our patients and their families and the many partners who work with us for providing Revolution Medicines with the opportunity to advance our unique pipeline of RAS(ON) inhibitors and RAS-dependent inhibitors, which we believe may transform the treatment of RAS-addicted cancers. This concludes our prepared remarks for today. And I'll now turn the call over to the operator for the Q&A session. Operator?

[Operator Instructions] Our first question comes from Jonathan Chang with SVB Leerink.

First question. Approximate how many addressable second-line non-small cell lung cancer KRAS G12C patients are there in the U.S.? So Amgen is saying it's around 7,000. Is that consistent with your view?

Thanks, Jonathan. This is Mark Goldsmith, appreciate the question. It's actually a fairly complex question. And we're aware of the subtleties and the discussion going on around that right now with regard to Amgen's comments on that. I'd suggest that's something we could discuss with you offline and that that's probably the better place to do it at this time.

Got it. On the second question on RMC-5552. How does targeting just mTORC1 compare to targeting both mTORC1 and 2? And how does 5552 overcome potential resistance mechanisms encountered by existing mTORC1 inhibitors?

Thanks very much. Steve, would you like to take this question?

Sure. Yes, the first question -- the first part of your question, I think, is best addressed in the clinical data that's available for the dual mTORC1, mTORC2 inhibitors. When we set out to develop RMC-5552, we were specifically going after the substrate of mTORC1, which is 4E-BP1, which is critical for cap-dependent translation of certain oncogenes, such as MEK for instance, but a bunch of others as well. The challenge with the mTORC1/2 inhibitors, the dual inhibitors, is specifically that the inhibition of TORC2 confers toxicity. And the problem with the TORC2-mediated toxicity is that you can't dose high enough to inhibit the 4E-BP1 substrate, you can only inhibit the S6 kinase substrate. And that's been shown very clearly by AstraZeneca in a series of sort of, PD-driven clinical evaluations that they did. So I think that's essentially the uniqueness of selectivity of -- the inhibition of mTORC1 selectively is that you don't have the mTORC2-mediated toxicity and you can inhibit both substrates of TORC1, which is both the S6 kinase and the 4E-BP1. And we think the 4E-BP1 is really critical to inhibit in order to get a therapeutic effect. I think that, that sort of addresses part 2 of your question as well because rapalogs don't inhibit 4E-BP1 either. Conventional rapamycin and rapamycin derivatives like everolimus, they just don't inhibit 4E-BP1. There are some complex sort of mechanistic reasons why that's the case. But essentially, I think 5552 is unique in its ability to inhibit phosphorylation for 4E-BP1.

Our next question comes from Michael Schmidt with Guggenheim Securities.

This is Yige on for Michael. You now have a suite of KRAS inhibitors. Just curious, besides the KRAS selectivity, how different are these compounds in their pharmacokinetics? And would the potential difference in PK make one of them better be used for certain histology or tumor types or at a certain specific setting?

This is Mark. Thanks for your question. Just to clarify, are you asking for comparing the kinetics of RAS(ON) inhibitors in our collection with RAS(OFF) inhibitors, KRAS G12C RAS(OFF) inhibitors? Or are you asking about differences even within our own portfolio?

Sorry, this is for your own inhibitors, among your inhibitors.

Among our compounds, you're asking?

That's right.

Okay. Steve, do you want to take a swing at that?

Yes. I think the first thing to say is that the pharmacokinetics of our RAS(ON) inhibitors is quite complex because it's a multi-compartmental model. You've got -- basically, you've got the plasma, you've got the entry into the tissue, the potential interaction of the molecule with intracellular cyclophilin A, which is in abundance, it's in access. And that does sort of things to the actual tissue pharmacokinetics, which vary from tissue to tissue and from drug to drug. And then obviously, you've got the binding to the target, which is not just driven by the affinity for cyclophilin A and the affinity for KRAS, but it's also driven quite significantly by whether the warhead is a covalent binding warhead or not covalent binding warhead. So fundamentally, I think you can -- I can simplify this by saying there are really 2 sets of differences across our range of inhibitors. The first is affinity for cyclophilin A, that does have a significant impact on the intracellular retention time and the effective intracellular potency. And the second thing is whether or not the warhead is covalent or not covalent. Now of the 3 compounds that Mark described -- sorry, of the 4 compounds that Mark described, 3 of them have a covalent warhead. The 2 for the 12C, 13C and 12D all have a covalent warhead, which means essentially once they bind, they're effectively reversing the bind. RMC-6236 does not have a covalent warhead. Its inhibition is non covalent. But that is very tightly bound -- at that compound is very tightly bound with cyclophilin A. So it stays within tumor cells considerably longer than it does with a normal tissue, and we've shown data for that in several scientific meetings. So at the end of the day, it's very hard for us to predict what's going to be best. We're going to evaluate this during our clinical programs. But I think it's safe to say that we have a range of optionality here, and we can exploit it for -- in the interest of the best combinations.

Our next question comes from Eric Joseph with JPMorgan.

This is Chuan in for Eric. So looking ahead into the preliminary data readout from the 4630-03 study, wondering if you could frame expectations there in terms of number of patients and signs of follow-up. And are you targeting any particular medical scientific conferences for presentation?

Steve, do you want to address the question of numbers and outcome measures?

Yes, sure. I think it's -- we -- we've said previously, and I think you could probably read it on clinicaltrials.gov, that the RMC-4630-03 study, which is the one that we're sponsoring, is the only one actually that we're able to really talk to in detail. The 2 other studies, one is being sponsored by Amgen, one's been sponsored by Sanofi. So really, those questions would have to be addressed to those companies. But for RMC-4630, we're planning to treat up to 46 patients. We do -- they will be retrospectively stratified by whether or not they have a co-mutation in either STK11 or KEAP1. And the way that the data is falling out right now, we suggest -- we're expecting around about a 2:1 split. So we expect maybe somewhere in the region of 30 patients will not have a care mutation in STK11 or KEAP1, and about 15 will do. And of course, the primary outcome measure for efficacy will be overall response rate by RAS. So we're basically comparing against a historical overall response rate in that patient population that's derived from the sotorasib approval of the label, which gave them a response rate of around 36%. If you take out the STK11/KEAP1 mutant patients, it goes up a little bit, maybe it bumps up to maybe sort of low -- maybe 40%, 41%. And that will be the reference, that will be the reference efficacy number.

Yes. And just to address the second part of your question, this is Mark again, as to what forum we might present results in. We're not expecting to have these observations put together in a form that we can talk about until towards the end of the year. And so it's not likely that there's going to be a scientific forum that's perfectly available to us at exactly the right time. So we may have to make some sort of disclosure outside of that context and then follow it up with a more detailed disclosure at a subsequent scientific meeting. But that's something we're still sort of working through. And until we have much better visibility on enrollment pace and the timing of those data, we really can't get more specific than that.

Our next question comes from Marc Frahm with Cowen & Company.

Maybe just to start with the design of the 6236 and 6291 trials that you're getting close to opening up. When you talk about having below MTD expansion cohorts and starting those kind of early, will those be really just very broad enrollment expansion cohorts across all sorts of mutations and tumor types to really just kind of backfill the overall experience? Or are you already going to be kind of subdividing patients into either by their mutation or by tumor type?

Marc, thanks for joining us. Thanks for your question. Yes, I think it's going to come down a little bit to the word dynamic and how that gets deployed. Maybe Steve can comment on our below MTD dynamic expansion plans.

Yes, Marc, the below MTD expansions are -- have a number of utilities, but the primary utility is to increase the sort of database for safety, tolerability, such so that we can make much more informed decisions about the optimal dose to take into any Phase II expansion. In that context, the specific tumor types or mutations are not so relevant because they don't really drive the tolerability profile. Having said that, at the end of the day, Firstly, we do refine the types of patients that we like, we would want to enroll as we start -- if we start picking up an efficacy signal, we'll start refining the types of patients that we want to involve. For instance, for 6291, it's pretty obvious that the dynamic goes in 2 dimensions. One is whether or not they have or haven't received a KRAS inhibitor previously, and the second is whether or not they've got lung cancer or colon cancer. For RMC-6236, it's a little bit more complex than that. But we do refine it as the dose increases and as we get more and more information. But really, this is in part, although we started doing this for SHP2 back in 2018. But now, of course, it's taken on a whole new dimension with this FDA project optimist type thing where they want us to spend more time and energy really drilling down on the best Phase II dose expansion. I think it contributes significantly to the best selection of the recommended Phase II dose to take forward, and that's essentially why we're doing that.

Okay. That's helpful. And then just thinking through -- obviously, those agents have some -- have potential as monotherapies, but also a big part of your overall strategy is a combination approach. So what do you need to see from, I guess, the monotherapy trials before you would start the combination approaches? And I guess, related to that is what do you -- do you need to see additive efficacy in the sotorasib combo for 4630 to pursue 4630 combos with your own RAS inhibitors? Or are there subtleties to the different mutations that kind of make them an independent decision?

Yes. Marc, if I could just add one more point to the discussion on the first question that you asked, which is, as Steve emphasized, gathering safety data and dose selection and primarily using the expansions below MTD to help build that data set. Now I think we should also acknowledge though in the context of 6236 where we're evaluating multiple genotypes as well as histotypes, we may begin to see some evidence about which tumor types or which genotypes are responding during that dose escalation. And that could be another opportunity for us to expand some of that early information to help us really clarify whether we're seeing a particular signal in a particular context. So that would be a secondary objective of the below MTD expansions. And then with regard to your second question, do we need to see activity of -- combinatorial activity in the either our 03 study or the CodeBreaK 101C study before we would combine 4630 with, I think you mean specifically with our G12C inhibitor or with any of our RAS inhibitor?

Both, actually.

Yes. I don't want to draw a sort of a hard line in the sand, but we do expect that we're going to see -- we project that we should see activity in combination with sotorasib, and if that's a very nice data set for us to build on. And if RMC-4630 is combinatorial, is additive with sotorasib, then there would be no real reason to believe it shouldn't be additive with our KRAS G12C inhibitors, so just starting with G12C. And if it isn't, I think we'd really want to understand why it isn't. And that could influence the decision about whether we would still combine it with RMC-6291 or not. I think that relationship largely probably holds for the other RAS mutant inhibitors as well, but the biology does differ across different genotypes. Some are more likely to be sensitive to the modulating effects of signaling through SHP2 through RTKs and some may be less likely to be sensitive. And so it's not necessarily the case that every genotype should be treated in the same way. But still largely, I think we're looking for clear evidence of combinatorial activity in the combination of the Amgen and RevMed studies with sotorasib in RMC-4630.

So it's probably also worth mentioning, Marc, that it's not just the genotypes that differ, but also the histotypes differ very considerably as well. I mean the mechanisms of escape that are emerging from -- in colon cancer with sotorasib, adagrasib are very different from the mechanism of escape emerging with -- in lung cancer. So I think we have optionality. We have to pay attention to the histotype, the genotype. And also, we also have other companion inhibitors beyond RMC-4630. I think we have a lot of confidence in RMC-4630 because of the sheer weight of mechanistic data that's available for it. But we -- at the end of the day, we have others to go with as well. And we have to -- somehow, we have to figure out which is the best one for an individual patient.

[Operator Instructions] Our next question comes from Chris Shibutani with Goldman Sachs.

This is C.J. on for Chris today. I think we've talked about a lot of different topics so far. One of interest that has come up a lot lately in the KRAS space is hand ringing about the potential for accelerated pathways for new novel molecules particularly in the G12C space. Curious as you potentially advance 4630 to a registrational trial, first timing of that, would that be next year potentially? And is there potential for 4630 to follow an accelerated pathway? Or would this need to be more of a traditional pathway if that definition of unmet need has potentially be filled? And then presumably for your pipeline RAS inhibitors both the multi and other mutations, potential for accelerated approval may be available for those as well? Could you comment there?

Yes. Thanks very much, C.J. Those are great questions, and they're sort of hot topics that are actively discussed within RevMed and with regard to 4630, of course, with our partner, Sanofi. So we don't have definitive answers, but it's probably the case that you have to separate KRAS G12C sotorasib combination from the others, given that that's a space in which there's already one approved treatment and there will be a second undoubtedly later this year. Whereas all the other mutants, there are no and there won't be any approved therapies anytime in the near future. So I think those are a lot easier to think about because they're unprecedented at that point. They are unserved by targeted therapies. And so all options, I think, would be still open there. We'll have Steve comment on that. I think that one is an easier one. With KRAS G12C, it's a little bit more complex, and it might be that there are several different options and that the question to be decided is strategically which option or options to pursue rather than just do they exist. Steve, do you want to give any more color to that?

Yes, I think the only 2 bits of color I would add to that is, firstly,, C.J., don't confuse accelerated approval with rapid approval. There are plenty of ways of getting to market relatively quickly without necessarily having to invoke the subpart H of CFR 21, which is the accelerated approval option. There are -- as you pointed out, there were already pre-existing issues with accelerated approval even before the recent sort of controversies around how long it takes to get the complementary trials done and whether or not the Alzheimer's drug should have got it in the first place, all that sort of stuff. But we are currently looking at a whole load of options, both for accelerated approval within the U.S. and also a rapid approval globally. And obviously, at the end of the day, the options available to us to some extent and the speed at which we get there will depend on the strength of the Phase II data that we see in the 3 trials that we're running. So certainly for 4630, I don't think the situation has changed for the RAS inhibitors, particularly outside of G12C. I don't think the situation has changed. I think that if you -- if the data is compelling, then it's very hard for the Food and Drug Administration to deny patients access to it under the accelerated approval banner. I think they will obviously require confirmatory trials to be done. And of course, we're very happy to do them. But that -- all that remains to us remains an option. I think in principle, the RAS mutant space remains -- the precedent that was set by sotorasib will remain true for the other RAS mutant mutations as well.

And our final question comes from Ben Burnett with Stifel.

This is Neil on for Ben. Your KRAS G12D inhibitor will be administered orally. Can you talk to the bioavailability and target coverage you've seen preclinically? And any early thoughts you may have around dose levels or dosing frequency?

Yes. Thanks for your interest and for your question. We actually put out, I think, in this corporate deck and in the investor deck in January data that shows very good pharmacodynamic effects in vivo over an extended period of time with RMC-9805, I think it shows a suppression of the pathway out to well beyond 24 hours with just a single dose. And it also shows the pharmacokinetics associated with that. Of course, this is in a mouse xenotransplant context. And that was dosed at 100 mg per kilogram sort of a convenient kind of conventional dose for that purpose. I don't think we showed a dose response per se in that particular experiment. So that gives you a sense that at least in that context, a single dose can provide not only very rapid and deep effects, but quite sustained effects. And what that will translate into people will depend a lot on what pharmacokinetics we see in people. And although we have modeling around that based on multiple preclinical species, that simply is going to be projection. And I think until we're in the clinic and establish the actual PK and PK variability which is always an important parameter as well, I don't think we can answer the question. In an ideal world, we'll be dosing once a day and we'll be dosing in the ballpark of or less than the current doses that are used for KRAS G12C inhibitors. But that's very, very hard to say today.

As there are no more questions in the queue, I will turn the call back over to Dr. Goldsmith for closing remarks.

Thank you, operator, and thank you to everyone, including our analysts who asked questions for participating today and for your continued support of Revolution Medicines.

This concludes the program. You may now disconnect. Everyone, have a great day.