Revolution Medicines, Inc. Q4 FY2021 Earnings Call

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. Please be advised that today's conference call is being recorded. 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 Medicines 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. These cancers are often also supported and maintained by other cellular proteins, which 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 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 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, 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 U.S. each year with tumors bearing one of various mutations at amino acid 12 in KRAS, the dominant hotspot for KRAS cancer mutations. We refer to these collectively as KRAS 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 other KRAS G12 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 planned to enter the clinic. This one focuses specifically on KRAS G12C. 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 RMC-6236, as shown in 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 antitumor 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 RMC-6236 and RMC-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. It 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 agents, it is also orally 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 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 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 (ON) 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 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 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 drugs that suppress 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 node 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 sotorasib in second-line and beyond treatment of various KRAS G12C tumors in the CodeBreaK 101 trial, which is predominantly U.S.-based. 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 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. In their studies, Sanofi has 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 signals 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 understand frequently limit the single-agent 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 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 two other complementary strategies that may be pursued in parallel to SHP2 inhibitor combinations 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; secondly, inhibition of additional escape RAS mutations beyond the primary RAS-mutant driver; and in addition, inhibition of cooperating wild-type RAS proteins in cancer cells. In other contexts, 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 cooperating KRAS mutations that sustain these cancers. Ultimately, we anticipate that each of these three combination treatment strategies will need to be evaluated in parallel, and 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 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 mTOR 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 benefits to patients with tumors that have mutations in the mTOR pathway. As RAS mutations and co-mutations in the mTOR 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 in that they showed 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 assessments suggest 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 were evaluable for efficacy as of January 7, 2022, all with tumors carrying mutations associated with hyperactive mTORC1 signaling. Three of these patients have experienced a best response of stable disease, and one 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 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 mTOR 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 suggest 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 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 non-cash, non-recurring revenue adjustment in the third quarter of 2021, resulting from a change in accounting estimate 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 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 Revolution Medicines 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 everyone in 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. Our first question comes from Jonathan Chang with SVB Leerink. Your line is open.

Hi, guys. Thanks for taking my questions. First question: Approximately how many addressable second-line non-small cell lung cancer KRAS G12C patients are there in the U.S.? Amgen is saying it's around 7,000. Is that consistent with your views? Got it. On the second question on RMC-5552: How does targeting just mTORC1 compared to targeting both mTORC1 and mTORC2? And how does RMC-5552 overcome potential resistance mechanisms encountered by existing mTOR inhibitors? Thank you.

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's probably the better place to do it at this time. Steve, would you like to take the second question?

Sure. I think the first part of your question 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 mTORC1 substrate 4EBP1, which is critical for cap-dependent translation of certain oncogenes such as MYC, for instance, among others. The challenge with dual mTORC1/mTORC2 inhibitors is that inhibition of mTORC2 confers toxicity, and the problem with mTORC2-mediated toxicity is that you can't dose high enough to inhibit the 4EBP1 substrate; you can only inhibit the S6 kinase substrate. That's been shown very clearly by AstraZeneca in a series of PD-driven clinical evaluations that they did. So I think that's essentially the uniqueness of RMC-5552's selectivity: by selectively inhibiting mTORC1 and avoiding mTORC2-mediated toxicity, you can inhibit both substrates of mTORC1, which are S6 kinase and 4EBP1. We think inhibiting 4EBP1 is really critical in order to get a therapeutic effect. That also addresses the second part of your question: rapalogs, such as conventional rapamycin or derivatives like everolimus, do not inhibit 4EBP1. There are mechanistic reasons for that, but essentially RMC-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 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 to use in certain histologies or tumor types or at a certain specific setting?

This is Mark — thanks for your question. Just to clarify, are you asking for a comparison of the pharmacokinetics of RAS (ON) inhibitors in our portfolio versus RAS (OFF) inhibitors (KRAS G12C off inhibitors), or are you asking about differences even within our own portfolio?

Sorry. This is for your RAS (ON) inhibitors within your portfolio.

Among our compounds you're asking? Okay. Steve, do you want to take that?

Yes. The connection to the pharmacokinetics of our RAS (ON) inhibitors is quite complex because it's a multi-compartmental model. Basically, you've got the plasma, you've got entry into tissue, potential interaction of the molecule with intracellular cyclophilin A, which is abundant, and that affects the actual tissue pharmacokinetics which vary from tissue to tissue and from drug to drug. Then you've got binding to the target, which is driven not just by affinity for cyclophilin A and affinity for KRAS, but also by whether the compound has a covalent warhead or is non-covalent. So fundamentally there are really two sets of differences across our range of inhibitors. The first is affinity for cyclophilin A, which has a significant impact on intracellular retention time and intracellular potency. The second is whether the warhead is covalent or non-covalent. Of the four compounds Mark described, three of them have a covalent warhead — the ones for G12C, G13C and G12D have a covalent warhead, which means once they bind they are effectively irreversible. RMC-6236 does not have a covalent warhead; its inhibition is non-covalent, but it is very tightly bound to cyclophilin A. So it stays within tumor cells considerably longer than it does in normal tissue. We've shown data for that in several scientific meetings. At the end of the day, it's very hard for us to predict which will be best in which context; we're going to evaluate this across clinical programs. But it's safe to say we have a range of optionality here and can exploit it for the best combinations and settings.

Got it. That's super interesting. Thank you.

Our next question comes from Eric Joseph with JPMorgan. Your line is open.

Hi, this is Sean in for Eric. Thanks for taking our questions. Looking ahead to the preliminary data readout from the RMC-4630-03 study, wondering if you could frame expectations there in terms of final number of patients and the follow-up, and are you targeting any particular medical or scientific conferences for a presentation? Thanks.

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

Yes, sure. We've said previously and you can read it on ClinicalTrials.gov. The RMC-4630-03 study, which is the one we're sponsoring, is the only one we can talk about in detail. The two other studies are sponsored by Amgen and Sanofi respectively, so questions about those studies should be directed to those companies. For RMC-4630-03, we're planning to treat up to 46 patients. They will be retrospectively stratified by whether or not they have co-mutations in either STK11 or KEAP1. Based on how the data is falling out right now we expect about a 2:1 split, so we expect somewhere in the region of 30 patients will not have co-mutations in STK11 or KEAP1 and about 15 will. The primary outcome measure for efficacy will be overall response rate by RECIST. We're basically comparing against a historical overall response rate in that patient population derived from the sotorasib approval, which gave a response rate of 36%. If you take out the STK11 and KEAP1 mutant patients, it goes up a little bit, maybe into the low 40s percent, perhaps around 40–41%, and that will be the reference rate.

Yes. That's helpful. Thank you.

And just to address the second part of your question regarding forum and timing: 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. It's not likely that there will be a scientific forum exactly aligned with that timing. So we may have to make some disclosure outside of a conference context, and then follow it up with a more detailed disclosure at a subsequent scientific meeting. We're still working through that and until we have better visibility on enrollment pace and the timing of those data we really can't be more specific.

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

Thanks, Marc. It's going to come down to how dynamically we deploy those expansions. Steve, do you want to 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 database for safety and tolerability so that we can make 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, we will refine the types of patients we enroll as we start to pick up signals of efficacy. For instance, for RMC-6291 it's obvious the dynamic goes in two dimensions: whether patients have or haven't received a KRAS inhibitor previously and whether they have lung cancer or colon cancer. For RMC-6236 it's a bit more complex. We will refine enrollment as the dose increases and we get more information. This approach contributes significantly to selecting the recommended Phase 2 dose.

Thanks. That's helpful. And then thinking through combinations: what do you need to see from the monotherapy trials before you would start the combination studies? And related to that, do you need to see additive efficacy in the sotorasib combination for RMC-4630 to pursue RMC-4630 combinations with your own RAS inhibitors, or are there subtleties across different mutations that make them independent decisions?

I don't want to draw a hard line in the sand, but we do expect to see activity in combination with sotorasib and that's a useful dataset for us to build on. If RMC-4630 is combinatorially active with sotorasib then there would be no real reason to believe it shouldn't be combinatorially active with our KRAS G12C inhibitor, so starting with G12C makes sense. If it isn't active, we'd want to understand why, and that could influence decisions about combining it with RMC-6291. The biology does differ across genotypes; some are more likely to be sensitive to SHP2-mediated effects than others. So it's not necessarily the case that every genotype should be treated in the same way. Largely, though, we're looking for clear evidence of combinatorial activity in the Amgen and our own studies with sotorasib and RMC-4630.

It's also worth mentioning that histology matters as well as genotype. The mechanisms of escape emerging in colon cancer with sotorasib are very different from those in lung cancer. We have optionality and other companion agents beyond RMC-4630. We have confidence in RMC-4630 based on a lot of mechanistic data, but we have to figure out which combination is best for individual patients.

Okay. Thank you.

Our next question comes from Chris Shibutani with Goldman Sachs. Your line is open.

Hi, all. This is CJ on for Chris. Thanks for taking the question. One topic that has come up a lot lately in the KRAS space is discussion about the potential for accelerated pathways for new novel molecules, particularly in the G12C space. As you potentially advance a registrational plan for RMC-4630, what timing might that be — next year potentially — and is there potential for RMC-4630 to follow an accelerated pathway or would this need to be a more traditional pathway given that the unmet need may be filled? And for your pipeline KRAS inhibitors, the potential for accelerated approval may be available for those as well. Could you comment? Thank you.

Those are great questions. You have to separate KRAS G12C from the other mutants. For the non-G12C mutants there are no approved therapies, so options for accelerated pathways remain more open. For G12C it's more complex because sotorasib is already approved and a second G12C inhibitor will likely be approved later this year, so strategic considerations are different in that space. We'll consider multiple options and decide strategically which to pursue.

I would add two points. First, don't confuse accelerated approval with rapid approval; there are ways to get to market relatively quickly without necessarily invoking the FDA's accelerated approval pathway. Second, the options available to us and the speed at which we might move depend on the strength of the Phase 2 data we see in the trials we're running. In principle, if the data is compelling, the FDA has historically been willing to consider accelerated approval, and confirmatory trials would be required. The precedent set by sotorasib is relevant and could remain informative for 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 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?

Thanks for your interest. We published data in the corporate deck that shows very good pharmacodynamic effects in vivo over an extended period of time with RMC-9805. It shows suppression of the pathway well beyond 24 hours with just a single dose in mouse transplant models. Those experiments used 100 mg/kg in mice as a conventional dose. That gives a sense that a single dose can provide rapid, deep and sustained effects in preclinical models. What that translates into in people will depend on human pharmacokinetics. Although we have modeling based on multiple preclinical species, those are projections. Until we're in the clinic and establish the actual PK and PK variability in humans, we can't definitively answer dosing frequency. In an ideal world we'd dose once a day and be in the ballpark or less than current doses used for KRAS G12C inhibitors, but that's 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.