Revolution Medicines, Inc. (RVMD) Q4 2021 Earnings Report, Transcript and Summary

Good day, ladies and gentlemen, and welcome to the Revolution Medicines Fourth Quarter and Full Year 2021 Financial Results Conference Call and Webcast. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a Q&A session. [Operator Instructions]. Please be advised that today's conference call 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 and other matters. During this presentation, we will be referring to a few slides from our corporate presentation. The entire presentation was posted on our website immediately prior to this call. With that, I will turn the call over to Dr. Mark Goldsmith, 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 Medicine's continued building momentum with our targeted therapeutics pipeline, advancing our mission to improve treatments on behalf of patients with a wide range of RAS-addicted cancers, representing some 30% of all cancer patients. As depicted on slide five, RAS-addicted cancers are induced primarily by mutations that cause RAS (ON) proteins to behave as cancer drivers. That often these cancers are also supported and maintained by other cellular proteins recall 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 compounding inhibitors, to suppress the cooperating proteins. In many instances, we expect drugs of these two types may be combined to deliver the greatest clinical benefit. I'll spend the next few minutes briefly recapping four 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 critical stage RAS companion inhibitors, RMC-4630 SHP2 and RMC-5552 mTORC1. Our first RAS (ON) inhibitor, RMC-6236 is an innovative and exciting drug candidates, our first-in-class RAS multi (ON) inhibitor with potentially very broad utility across many RAS cancer variants. As shown on slide 12, initially, we are particularly interested in more than 130,000 new pancreatic, colorectal and/or lung cancer patients in the US 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 G12 new 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 meeting mutant selective inhibitor plans to enter the clinic. This one focus specifically on the KRAS G12C. RMC-6291 is differentiated from first generation KRAS G12 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 US patients per year, primarily with lung or colorectal cancers. As with the 6263 compound, as shown in slide 16, we expect to submit an IND for our RMC-6291 in the first half of this year, followed by beginning single agent dose escalation in patients with various tumors carrying a 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 progress in 6236, and 6291 through IND submission as expected in the first half of this year, we recently announced two 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 is highly potent and benefits from what we believe to be the first ever highly selective covalent engagement of the oxygenic aspartic acid in this clinically important RAS variant. Indeed, it appears to be the first drug candidate ever to deploy this selective target binding mechanism directed against an aspartic containing disease target. Like our other development stage acids, it is also all bioavailable, promoting effective target coverage in cancer cells. We recently showed that RMC-9805 drives deep and durable anti-tumor responses as a single agent in pre-clinical 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 on slide 20, an exciting mutant-selective inhibitor of the KRAS G13C cancer variant. That forms a selective bond with the oncogenic cysteine in this KRAS target that has not been previously drugged. Like our other development stage, RAS arm inhibitors RMC-8839 exhibits attractive potency, selectivity and oral bioavailability and was shown recently to drive significant anti-tumor responses as a single agent in pre-clinical 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 four groundbreaking development stage RAS(ON) inhibitors, I mentioned earlier that our strategy also includes developing specific KRAS companion inhibitors, as illustrated on slide 24. Targeted drug has suppressed cooperating targets and pathways known to work in coordination with KRAS cancer drivers to sustain KRAS addicted cancers, and in some instances, confer drug resistance. We believe that combining best-in-class KRAS 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 two 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 known that contributes to RAS addicted cancers and is believed to mediate some types of resistance to KRAS 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 cancers. We are now primarily focused on evaluating RMC-4630 as a companion inhibitor in combination with KRAS 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 sulfur acid in second line and beyond treatment of various KRAS G12C tumors in the CodeBreaK 101 trial, which is predominantly US 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 2 study of RMC-4630 plus sotorasib, specifically in KRAS G12C lung cancer patients who have not previously received the 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 center acid for both our US and ex-US 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 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 a 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 type-2 first generation KRAS G12C off inhibitors. 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 maybe similarly useful for countering RAS pathway resistance mechanisms that were emerged with RAS mutant selective inhibitors directed to other RAS variants, such as with RMC-9805 in KRAS G12D mutant cancers. Slide 27 also outlines two 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 contexts, patients may gain maximal clinical benefit from the broad activity of our RAS multi inhibitor, RMC-6236, which in preclinical experiments, has shown three 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 contexts, a mutant-selective RAS (ON) inhibitors such as RMC-9805, may be optimized by using RMC-636 is a companion inhibitor, an approach that combines highly selective suppression of the particular cancer driver with direct inhibition of KRAS mutations that cooperate to sustain these councils. Ultimately, we anticipate that each of these three 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 but 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 RAS logs, 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 benefits to patients with tumors there are mutations in the mTORC pathway, as RAS mutations and comutations 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 1 single agent clinical trial, and the initial results are summarized in Slide 29. They are encouraging and that they showed clear evidence of anti tumor 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 assessments suggests that mucositis is the dose limiting toxicity at higher doses, which we believe is an on target biological effect Four patients have been treated at 6 milligrams IV weekly, and we're a valuable for efficacy as of the 7th of January 2022. All with tumors carrying mutations associated with hyperactive mTORC1 signal. Three of these patients have experienced a best response to stable disease and one patient with a head neck cancer and P10 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 2 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 co-activation 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 six development stage assets, which are supported by exciting, robust and growing datasets 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 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 with $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 non-cash, non-recurring revenue adjustment in the third quarter of 2021, resulting from a change in accounting estimate under the agreement 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 increase 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 both 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 financial guidance for 2022, we expect, full year 2022 GAAP net loss to be between $260 million and $290 million, which includes, estimated non-cash 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, with a compelling strategy, a growing set of exciting product assets and a strong balance sheet. We're proud of the tireless commitment of 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 companion 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?

Thank you. [Operator Instructions] Our first question comes from Jonathan Chang with SVB Leerink. Your line is open.

Hi, guys. Thanks for taking my questions. First question. Approximate how many addressable second line non-small cell lung cancer KRAS G12C patients are there in the US? So Amgen is saying it's around 7,000? Is that consistent with your views?

Hey, 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 compared to targeting both mTORC1 and mTORC2? And how does 5552 overcome potential resistance mechanisms encountered by existing mTORC1 inhibitors? Thank you.

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

Sure. There 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 4EBP1, which is critical for cap and in translation of certain oncogenes such as MYC, for instance, but a bunch of others as well. But the challenge with the mTORC1, mTORC2 in 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 4EBP1 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 its selectivity of inhibit -- 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 4EBP1. And we think the 4EBP1 is really critical to inhibit in order to get a therapeutic effect. I think that sort of addresses part two of your question as well, because rapalogs don't inhibit 4EBP1, either conventional rapamycin or rapamycin derivatives like everolimus. They just don't inhibit 4EBP1. And 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 4EBP1.

Got it. Thanks for taking the questions.

Our next question comes from Michael Smith with Guggenheim securities. Your line is open.

Hey, good afternoon. This is Ede [ph] on for Michael. Thanks for taking our questions. 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 or certain histology or tumor types or at a certain specific setting? A – Mark Goldsmith: 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? Q – Unidentified Analyst: Sorry. This is for your (ON) inhibitors and inhibitor A – Mark Goldsmith: Among our compounds you're asking? Q – Unidentified Analyst: That's right. A – Mark Goldsmith: Okay. Steve, do you want to fix me with that?

Yes, I think the first thing to say is that the connect to the pharmacokinetics of our RAS (ON) inhibitors is quite complex because it's a multicart 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, is an access and that does that 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 of suction A and the affinity for KRAS but it's also driven quite significantly by whether the 12D all have a covalent warhead is a covalent binding warhead or not, non covalent binding warheads. So fundamentally I think you can -- I can simplify this by saying there are really two sets of differences between -- across our range of inhibitors. The first is affinity for cyclophilin A, that that does have a significant impact on the intracellular retention time and the effect of intracellular potency. And the second thing is whether or not the warhead is covalent, or not covalent. There are of the three compounds that Mark described, sorry, all the four compounds that Mark described, three of them have a covalent warhead, the two for the 12C, 13C and 12D all have a covalent warhead, which means one essentially -- once that bind that they're effectively reversing the band, RMC-6236 does not have a covalent warhead, it's inhibition is non-covalent. But that is very tightly bound to cyclophilin that compounds very tightly bound for the cyclophilin A. So it stays within tumor cells considerably longer than it does in 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 -- we're going to evaluate this during all clinical programs, but I think it's safe to say that you know, we have a range of optionality here and we can exploit it for in the interest of the best combinations Q – Unidentified Analyst: Got it. That's super interesting. Thank you.

Our next question comes from Eric Joseph with JPMorgan. Your line is open. Q – Unidentified Analyst: Hi, this is Sean [ph] in for Eric, thanks for taking our questions. So looking ahead into the preliminary data readout from the 4630. They're all three study, wondering if you could frame expectations there in terms of final number of patients and then the follow-up, or -- and are you targeting any particular medical scientific conferences for a presentation? Thanks.

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. 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 two other studies, one is being sponsored by Amgen was sponsored by Sanofi. So, really the -- those questions will 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 expect it to be about a 2:1 split, so we expect maybe somewhere in the region of 30 patients will not have co-mutation in STK11 or KEAP1 and 515, 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 that the label which gave them a response program 36%. If you take out the STK11 and KEAP1 mutant patients, it goes up a little bit. Maybe it bumps up to maybe sort of low 40%, 41%. And that will be the reference at [indiscernible]. Q – Unidentified Analyst: Yes. That's a helpful. Thank you.

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. Your line is open.

Thanks for taking my questions. Maybe 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?

Hi, 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. The below MTD expansions 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 2 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 roll. For instance, for 6291, it's pretty obvious that the dynamic goes in two dimensions. One is whether or not they have or haven't received a KRAS inhibitor previously. And the second is whether or not you've got lung cancer or colon cancer. But for RMC-6236, 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 ship two back in 2018. But now, of course, it’s taken on a whole new dimension with this FDA project Optimas-type thing where, they want us to spend more time and energy really drilling down on the best Phase 2 dose expansion. I think it contributes significantly to the best selection of the recommended Phase 2 dose to take forward. So that's essentially while doing that.

Okay. Thanks. That's helpful. And then just thinking through -- obviously those agents have some -- you have potential as monotherapies, but also big part of your overall strategy is combination approach. So, what do you need to see from the monotherapy trials before you would start the combination of purchase? And I guess related to that is, what do you need -- do you need to see additive efficacy in the sotorasib combo for 4630 to pursue for 4630 combos with your own RAS inhibitors or there are 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, Steve emphasized gathering safety data and dose selection, and primarily using the expansions below MTD to help build that dataset. I think we should also acknowledge though, in the context of 6236, where we're evaluating multiple genotypes, as well cystotypes, 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 below MTD expansions. And then with regard to your second question, do we need to see activity of common arterial activity in the either all three study or CodeBreaK 101c study before we would combine 4630, with I think, you mean specifically with our G12C inhibitor or with any of our - ?

Both actually.

Yeah. 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 projected that we should see activity in combination with sotorasib and that that's a very nice dataset for us to build on, and if RMC-4630 is common tutorial is additive with sotorasib then there would be no real reason to believe it shouldn't be additive with our – our KRAS G12C inhibitor, 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 will still combine it with RMC-6291 or not. I think that relationship largely probably holds for the other RAS mutant inhibitors as well, that the biology does differ across different genotypes. Some are more likely to be sensitive to the modulating effects of signaling through SHP2 to 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 common authorial activity in the combination of the Amgen and RVMD studies with sotorasib RMC-4630.

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

Okay. Thank you.

[Operator Instructions] Our next question comes from Chris Shibutani with Goldman Sachs. Your line is open.

Hi, all. This is CJ on for Chris tonight. Thanks for taking the question. 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 wringing about the potential for accelerated pathways for new novel molecules, particularly in the G12C space, curious as you potentially advanced 4630 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 definition of unmet need has potentially be filled and then presumably, for your pipeline KRAS inhibitors and put the multi and other mutations, the potential for accelerated approval may be available for those as well. Could you comment? Thank you.

Yeah. Thanks very much, CJ. 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 KRASG12C 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're unserved by targeted therapies. And so all options I think, would be still open there will have Steve comments on that. I think that one's an easier one with KRASG12C, 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 are options to pursue rather than just do they exist? Steve, do you want to give any more color to that.

Well, I think the only two bits of color I would add to that is firstly, CJ 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. 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 confirmatory 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 US and also a rapid approval globally. And obviously, at the end of the day, the options available to us which to some extent and the speed at which we get there will depend on the strength of the Phase 2 data that we see in the three trials that were running. So certainly for 4630. I don't think the situation has changed for the RAS inhibitors, particularly outside 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 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 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 mutations as well.

Great. Thank you.

And our final question comes from Ben Burnett with Stifel. Your line is open.

Good afternoon. This is Neil on for Ben. Your KRASG12D inhibitor will be administered orally. Can you talk to the bio availability and target covered you've seen pre-clinically and any early thoughts you may have around dose levels or dosing frequency?

Yes, thanks for your interest in 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 MC-9805. I think it shows suppression of the pathway out to you know, well beyond 24 hours with just a single dose. And we and it also shows the pharmacokinetics associated with that of course this is in a mouse, as you know, transplant a context. So -- and that was those that 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, you know, 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 important parameters. 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.

Great. Thank you.

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

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.