Revolution Medicines Q1 2023 Earnings Call Transcript

Quartr
Provided by Quartr
May 8, 2023

There are 12 speakers on the call.

Operator

Good day, and welcome to Revolution Medicine's First Quarter 2023 Earnings Conference Call. At this time, all participants are in a listen only mode. After the speakers' presentation, there will be a question and answer to ask a question during the session, you will need to press star 11 on your telephone. You will then hear an automated message advising that your hand is raised. To withdraw your questions simply press star 11 again.

Operator

Now we ask that each participant limit their questions to one initial question and one follow-up question. After that, we just simply ask that you rejoin the queue and we will address additional questions as time permits. As a reminder, today's conference is being recorded. I would now like to turn the conference over to your host, Erin Graves, Senior Director of Corporate Communications and Investor Relations. Erin, please go ahead.

Speaker 1

Thank you, and welcome, everyone, to the Q1 2023 earnings call. Joining me on today's call are Doctor. Mark Goldsmith, Revolution Medicine's Chairman and Chief Executive Officer Doctor. Steve Kelsey, our President of R and D And Jack Anders, our Chief Financial Officer Peg Horn, our Chief Operating Officer, will also join us for the Q and A portion of today's call. As we begin, I would like to note that our presentation will include statements regarding the current beliefs of the company with respect to our business that constitute forward looking statements within the meaning of the Private Securities Litigation Reform Act.

Speaker 1

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 of our corporate presentation or the earnings press release as well as all of the company's filings with the SEC concerning these and other matters. During this call, we will be referring to a few slides from our corporate presentation, which was posted to our website prior to this call. With that, I will turn the call over to Doctor.

Speaker 1

Mark Goldsmith, are Revolution Medicine's Chairman and Chief Executive Officer. Mark?

Speaker 2

Thanks, Aaron. It's good to be with you this afternoon and to provide an update on our Q1 in the call will provide a brief update on our company progress. Doctor. Kelsey will cover will be available on our R and D progress and Jack Andrews will provide highlights of our financial results before we open the line for questions. We're off to a strong start this year with 2 important steps that we shared in the Q1.

Speaker 2

First, we communicated are in early findings from the Phase 1, 1b study of RMC6236, our 1st in class RAS multi ON inhibitor, which showed encouraging antitumor activity, safety and tolerability for patients with advanced solid tumors harboring a range of distinct KRAS G12X mutations, particularly KRAS G12D and KRAS G12V. While covering a relatively small sample size, this was an important update as it provided initial validation of the novel mechanism of action and potential clinical utility of RMC6236 and also carried positive implications across our pioneering and deep portfolio of RASL inhibitors. A second important step was a successful public equity offering in March, which raised $345,000,000 of gross proceeds and further reinforced our strong financial position. The additional capital is allowing us to consider additional near term and long term investments to strengthen clinical development of our first wave of RASON inhibitors and to prepare our organization for the advancement of RMC6236 through the hiring of additional senior leaders and staff. We'll now turn to Doctor.

Speaker 2

Steve Kelsey to review several clinical and preclinical highlights from the quarter. Steve? Thank you, Mark.

Speaker 3

Let me provide a few additional comments on our first wave of development stage RASL on drug candidates beginning with updates on dose escalation of RMC-six thousand two hundred and thirty six, our RAS multi on inhibitor in the RMC-six thousand two hundred and thirty six thousand and one trial. First, I am pleased to report an date on a case we highlighted in February of a patient with previously treated metastatic pancreatic cancer harboring a KRAS G12D mutation. We reported that this patient had an unconfirmed partial response at cycle 5 day 1 on RMC-six in tumor measurements on cycle 7 day 1. The CT scans are shown on Slide 14 of the corporate deck, and this patient continues on treatment. 2nd, we have escalated the dose level through 160 milligrams daily And are now evaluating 220 milligrams daily, while also continuing to backfill the 120 for RNC6236 at doses that appear to be well tolerated.

Speaker 3

We currently plan to provide additional updates on the program will be able to conduct a new clinical update this year. These will be a combination of corporate disclosures and presentations at scientific meetings are beginning in Q3. We expect to be able to provide a more detailed schedule of these updates in connection with our Q2 earnings release. We'll next discuss RMC-six thousand nine hundred and

Operator

one,

Speaker 3

our mutant selective KRAS G12C ON inhibitor. At the recent AACR Annual Meeting, we presented new preclinical data have provided the first disclosure of the chemical structure of this drug candidate. This is the first structure disclosure of a drug candidate from our pioneering RASON inhibitor collection. RMC-six thousand two hundred and ninety one exemplifies how we are able to bring favorable drug like properties, including potency, selectivity and oral bioavailability to these beyond rule of 5 macrocyclic compounds. We are continuing to dose escalate in the RMC 6291 in the 1 study and are now focused on a twice daily dosing schedule to maximize continuous drug exposures.

Speaker 3

RMC-six thousand two hundred and ninety one continues to be well tolerated, and we have not yet reached the maximum tolerated dose all selected a recommended Phase II dose. We remain on track to provide an update in the second half of this year. RMC-nine thousand eight hundred and five, our mutant selective oral and covalent in KRAS G12D ON inhibitor remains on track in support of the goal of beginning clinical evaluation of this groundbreaking compound in mid As many RAS mutant epithelial tumors have a propensity to metastasize to the brain, It is important to define the potential activity of these RASon inhibitors against tumors that have metastasized into the central nervous system. This may become particularly important if improvements in treatment of systemic or visceral disease allow more cases involving the central nervous system to emerge. Today, we highlight preclinical studies demonstrating antitumor activity in intracranial tumors by each of the 3 first wave Rason inhibitors.

Speaker 3

As shown on Slide 21 of the corporate deck, we used a well validated intracranial xenograft model of human non small cell lung cancer carry the KRAS G12C mutation, the LU99 model, in which an embedded in the press release, the graph on the far left of the slide shows the bioluminescent signal intensity of tumors in untreated animals. And for validation, adjacent to it is a group of animals treated with adacrasib at 100 milligrams per kilogram twice daily that showed a roughly 10 times lower signal representing significant tumor reduction. This model and results match those published by Mirati. An important point since adagracin was reported last year to display antitumor activity against brain metastases in patients with KRAS G12C Lung Cancer consistent with the preclinical results. The next group in orange shows the signal for implanted brain tumors treated with RMC6 are in the range of 2 36 at 25 milligrams per kilogram daily, showing encouraging antitumor impact that is are essentially indistinguishable from that adaggressive.

Speaker 3

And the next group in blue is mice treated with RMC-six thousand nine hundred and one at 1

Operator

are in the range of 100 milligrams per kilogram twice

Speaker 3

daily, a dose selected to be identical to the adagracin treatment regimen where a greater antitumor effect is observed. And finally, on the right is an analogous study of RMC-nine thousand eight hundred and five versus control in an intracranial model of pancreatic cancer carrying KRAS G12D, showing a profoundly reduced signal indicating a significant antitumor effect by this compound as well. Despite the limitations of these orthotopic models, collectively, these favorable preclinical results define a shared property of all 3 RASON inhibitors to potentially penetrate inter central nervous system metastases, a property not shared by all anticancer agents. This will be evaluated in subsequent clinical trials. Finally, I'd like to provide a brief status update on our 2 clinical stage RAS companion inhibitors.

Speaker 3

First, our SHIP-two inhibitor, RMC-four thousand six hundred and thirty. The global Phase II RMC-four in the 3,003 trial evaluating RNC4630 in combination with sotiracil for patients with KRAS G12C in non small cell lung cancer is fully enrolled, and we remain on track to readout top line results in the second half of this year. 2nd, our mTORC1 selective inhibitor, RMC-five thousand five hundred and fifty two, continues its evaluation as monotherapy in patients with tumors carrying mutations associated with hyperactivation of mTORC1 signaling, with the goal of advancing into combination are in the range of 8 milligrams a week range after observing dose limiting nucleositis in patients treated at higher doses, a side effect that is common with mTOR inhibitors. Since then, we have successfully piloted a revised prophylaxis strategy It appears to diminish both the frequency and severity of mucositis and has allowed dose escalation above 8 milligrams per week. We plan to provide a clinical update on RMC-five thousand five hundred and fifty two at a scientific meeting in the second half of this year.

Speaker 2

Back to you, Mark. Thank you, Steve. In conjunction with the clinical momentum described above, We've also continued building our organization with a particular emphasis on enhancing our late stage capabilities to support further progression of assets such as RMC6236. I'm especially pleased to announce today Several new executives who have joined the leadership group at RevMed and bring substantial experience and track records to our efforts. Doctor.

Speaker 2

Wei Lin, an oncologist with academic and industry experience, has joined us as Chief Medical Officer, are a significant leadership addition to Doctor. Kelsey's R and D organization. After completing medical training at Harvard Medical School and the MD Anderson Cancer Center, Way led early stage and late stage cancer drug development programs during a career at Genentech, Nektar and Erasca, Andy now oversees clinical strategy and medical affairs at Revolution Medicines. Alicia Gardner has joined as Senior Vice President for Commercial. In her career at Genentech, Alicia held a variety of leadership roles across its oncology and hematology franchises, including Lifecycle Management, Commercial Strategy and Launch Planning.

Speaker 2

And we have also welcomed Nisha Brown as Vice President of Commercial Development Zane Rogers as Vice President of Regulatory Affairs And Sriram Naganathan as Vice President of Chemistry, Manufacturing and Controls. With these highlights of our recent R and D and organizational will progress. I'll now turn to Jack Andrews, our CFO, to provide a financial update. Jack?

Speaker 4

Thank you, Mark. During the Q1, we strengthened our balance sheet with the upsized public offering of common stock, are raising gross proceeds of $345,000,000 Net proceeds were approximately $324,000,000 after deducting underwriting discounts, commissions and estimated offering expenses. Including the financing, are ending cash and investments balance as of March 31, 2023 was $909,800,000 which is now expected to fund planned operations into 2025. Revenue from our collaboration agreement with Sanofi was are in the Q1 of 2023. Total operating expenses for the Q1 of 2023 were $82,200,000 and increased by 25% over the prior year period.

Speaker 4

The increase in operating expenses was largely due to are in the range of R and D expenses related to the advancement of RMC6236 and RMC6291 into clinical trials as well as an increase in personnel related expenses related to additional headcount. Net loss for the Q1 of 2023 was $68,100,000 or $0.72 per share. We are updating our financial guidance for 2023 now expect full year 2023 GAAP net loss to be between $360,000,000 $400,000,000 which includes estimated non cash stock based compensation expense of $40,000,000 to 50,000,000 The increase in expected GAAP net loss is a result of increased investments to support and strengthen clinical advancement of our first wave of RASON inhibitors, including expanded clinical supply and additional senior leaders across late stage development, Manufacturing and commercial planning for RMC6236. And with that, I'll now turn the call back over to Mark.

Speaker 2

Thank you, Jack. We are highly energized by the exciting pipeline and organizational progress so far this year with ambitious plans to continue amplifying this momentum. We look forward to sharing further clinical updates on our first wave of RAS ON inhibitors and RAS companion inhibitors in will be in the second half of the year. We deeply appreciate the support of our patients, clinical investigators, scientific and business collaborators, advisors and shareholders and the tireless efforts of our RevNet employees in pursuit of our mission to outsmart RAS addicted cancers. This concludes our prepared remarks for today.

Speaker 2

And I'll now turn the call over to the operator for the Q and A session.

Operator

We ask that each participant limit their questions to one initial question and one follow-up question. And after that, we'll ask participants rejoin the queue and we'll address additional questions as time permits. Please stand by while we compile the Q and A roster. Our first question comes from Mark Fromm with TD Cowen. Mark, your line is open.

Operator

Please go right ahead. Your line is open. Mark Fromm?

Speaker 5

Yes. Sorry. Thanks for taking my questions and congrats on the progress and a little bit of data update Steve that will be dropped in there. Just looking forward to the additional 6,236 updates. Maybe to start off, just can give some context for the patient numbers.

Speaker 5

Right now, most of the data has been in G12D patients in part from the epidemiology. Should we You're expecting these next updates to see the POC kind of get broadened out to other mutations in histologies? Or Is this really staying, given the epidemiology, just very focused on G12D? And then I'll probably have a follow-up there.

Speaker 2

Thanks, Mark, for your question. I don't think we can really give you a lot more color around that right now. Obviously, we're still accumulating data. We're still following patients who have been on study. We are enrolling into escalation cohorts and then we're backfilling at doses below the escalation dose.

Speaker 2

So we'll certainly have a larger end. As you know, to a large degree, we think that the patient population represented in the epidemiology broadly, which is that KRAS GKOV is the most common mutation, and that's what we're seeing in the study, but we are seeing additional genotypes. In terms of histology, clearly, we continue to see most patients in the pancreatic cancer and non small cell lung cancer are tumor types, but there are some others as well. So it's hard to say from where we are today, we'll know better as we get closer to that disclosure point.

Speaker 5

Okay. That's helpful. And then, Obviously, the net loss guidance implies a significant growth in expenses kind of here over the remainder of the year. Can you just kind of walk through some what some of those priority trials are that you're looking start. Is that the monotherapy expansion for the multi RAS and maybe the G2C, but Or is that this really the combo work getting underway and kind of what's the priorities there?

Speaker 2

Yes. I don't think today we're necessarily announcing new studies. I think it's more along the lines of plans that we've already had, but the probability for those plans, of course, has gone up because of the progress. And we do feel that there it is justified to increase our commitment to supply, which will supply both this year and continue are providing support into studies that extend into next year as well, as well as expanding the personnel, the senior leadership that we talked about and so on. So I don't think it's really today appoint for us to start disclosing the broader development plan around RMC-six thousand two hundred and thirty six specifically.

Speaker 2

You can certainly expect that we're continuing monotherapy and expanding there and that a priority as well and after we've unveiled more clinical data, then I think it will be more appropriate to sort of combine that with projections about what's coming next.

Speaker 6

Okay. Thank you.

Speaker 2

You're welcome.

Operator

Please standby for our next caller. And our next question comes from the line of Eric Joseph with JPMorgan. Eric, your line is open. Go ahead.

Speaker 7

Thanks for taking the questions. Just on the dose escalation update are now at 220. Can you talk a little bit what you saw in terms of tolerability at 160 that you're Comfortable with widening the dose interval. And I guess, do you think currently Where you are right now that there's perhaps headroom to further dose escalate?

Speaker 2

I think Steve will comment on that.

Speaker 6

Sure.

Speaker 3

The tolerability profile of RMC6236 continues to be what we consider favorable. There have been no qualitative changes in the tolerability profile of RMC-six thousand three hundred and sixty since our last update and so we feel comfortable in continuing to dose escalate. And as we are somewhat laboriously weighted through back in February, even though rash is the most frequent Toxicity remains the most frequent toxicity. It really is difficult to predict ultimately what is going to become dose limiting. We had are articulated, I believe that we would expect on the basis mechanistic studies and non clinical toxicity studies that maybe GI toxicity would ultimately become dose limiting.

Speaker 3

But as of now, That's not happening. And so we're continuing to dose escalate. It's very difficult to predict where we're going to stop with this. I honestly cannot give you color on that. I may do even if I other than that, the program continues pretty well.

Speaker 7

Okay. I don't know if you have visibility on this, but just having highlighted the expectation of being at a medical conference in the Q3, I guess, should investors expect sort of a meaningful difference from the Meaningful difference in the scope of data reading out, sort of midyear from what you might present at the medical meeting with this program.

Speaker 2

Well, I think what we're communicating, Eric, is that our mid year update will be a set of multiple updates, including corporate and scientific meeting presentations that begin in Q3. I don't think we're going to be having an update next week followed by an update, that series that starts in Q3. I think Those are all part of the same series that will begin in Q3.

Speaker 7

Got it. Okay. Thanks for clarifying. Appreciate you taking the questions.

Speaker 2

Yes. Thank you.

Operator

Stand by for our next caller. Will be available. And we have Michael Schmidt from Guggenheim. Michael, your line is open. Please go ahead.

Speaker 8

Hey, guys. Thanks for taking the questions. Question on 6,291. Now that we've seen A few more clinical data sets from other G12C inhibitors at AACR. I guess, what are you looking for in the clinic for your program?

Speaker 8

I guess, what degree of differentiation, be it either on efficacy or safety are you looking for at a minimum relative to the others, which look rather comparable? And then a follow-up question on the switch to BID dosing, just help us understand a bit more what drove that decision to move into twice

Speaker 2

Yes. Hi, Michael. Thanks for your questions. I might just take both of those and Steve can add to it if there's anything to add. So the question of BID dosing, really nothing specific drove it other than the fact that the PK and the daily dosing is turns out to be consistent with what we saw preclinically and preclinically we saw and have reported that The half life of arm C6-two ninety one in animals and now we've seen in people is shorter than a full 24 hour type of coverage from daily dosing.

Speaker 2

We didn't really see much impact of that adverse impact of that pre clinically. In fact, almost all of the preclinical data we reported were from daily dosing. And so the preclinical differentiation that we reported was supported by that daily dosing. But nonetheless, in humans, we want to have every opportunity to be successful here. And there's really not a good argument for are going to staying at daily dosing, twice daily dosing will give us more continuous coverage.

Speaker 2

And if there's a benefit that comes from that, So that's really all there is. There's nothing else from the clinic that drove that decision. And the first question was?

Speaker 8

I was just asking about The degree of differentiation you're sort of looking for in the clinic relative to the other T12C inhibitors out there, which look fairly comparable so far?

Speaker 2

Yes. Well, I think that's the sort of the key point is that the entire RASF inhibitor pool of drug candidates, they look relatively similar. And we that's what we've expected based on the biology of inhibiting The reserve pool of RAS that's in the off state, and that you're always going to be chasing, trying trying to get a leg up, but without much biological ability to do so. So ultimately, we'd like regimens that incorporate RMC-six thousand two hundred and ninety one to give us greater clinical benefit. And as we've talked about in the past, we're not exactly sure whether that's going to be in higher response rates or greater durability response and or greater tolerability, Those are all features that we've seen preclinically and any or all of those could be manifest in humans.

Speaker 2

I think you're asking though, how much of that do we need to see in monotherapy before we start are combination studies since we've indicated pretty explicitly multiple times that our strategy around RMC-six thousand two hundred and ninety one is moving into combination studies as quickly as we can and to focus the long term plan on combinations because I think the puck has already moved past monotherapy, and so we're trying to play where the puck is going to be in the future on behalf of patients. And the answer to that is, we're not really prepared to define for you an answer to that. We're going to move into combination studies as quickly as we can and we need to get sort of the basic profile in monotherapy and we need to compare that to the benchmarks and how much superiority or differentiation we see relative to those benchmarks, we just we don't know. And we're not too concerned about it because we know mechanistically it's going to be it is going to be differentiated qualitatively differentiated. So were not too hyped up about exactly what we see in a relatively small number of patients.

Speaker 2

So I think if we're in the ballpark of the benchmarks, will be going into those combination studies. If we are vastly superior in a way that one could draw such conclusions from a relatively small study, That might allow us to continue down a monotherapy pathway, but we don't really anticipate that from a Phase 1 dose escalation

Operator

stand by for our next question. Will be available. Chris Shibutani joins us from Goldman Sachs. Chris, your line is open. Go ahead.

Speaker 9

Hi. Good afternoon, everyone, and thank you for taking our questions. This is Charlie on for Chris. It's nice to see the CNS activity that we're seeing across the RAS on platform at this So I just wanted to get your take in terms of the potential for that intracranial activity to translate into the human subjects as we proceed and advance further into the clinic. Is there anything In particular, that you would call out about the tri complex mechanism of action that might influence the translatability of that intracranial activity that you're seeing in mouse models so far?

Speaker 3

I don't think so. I think the impact of penetrating into CNS nets is going to be determined to a very large extent by the patient population in which These drugs are being tested. So ultimately, as we get into earlier lines of therapy, as we have the opportunity to control the visceral disease more effectively, then I think that brain metastases are going to be an increasingly large part of the unmet medical need, and that's when you will see the impact to the translatability, so to speak, of compounds getting into CNS metastases. With regards to the Tricomplex technology per se, particularly the mutant selective compounds, which caused these regressions in these implanted tumors, they're highly selective for mutant rats, so there's unlikely to be any translation into CNS based toxicity from any impact in penetrating the normal CNS. We honestly really don't have a very good handle should be how much of these compounds gets into normal CNS.

Speaker 3

All of the evaluations to date have been done in tumors. They're specifically growing within the in the system, I think that's the message that we would like to convey at the moment.

Speaker 9

Great. That's helpful. Thank you so much. And then maybe just a quick one on 6,236 with the profile that's still emerging. Is there anything in particular in terms of combination partners that are you seeing a particular combination partner that's maybe more or less likely to be combinable with 6,236 at this point or are you really seeing A relatively tolerable profile thus far that's leaving all potential combination partners on the table at this time.

Speaker 2

Yes. I mean, I think at this point, everything is open. Obviously, with the RAS multi inhibitor that is suppressing to some degree suppressing normal or wild type RAS in normal tissues, there would in principle be overlap with other inhibitors that also suppress RAS signaling in normal tissues. So for example, a SHP-two inhibitor and a RMC6236, They may be combinable or they may not be, but you would worry more about that combination than you would about combining with something that's highly selective and has are non overlapping mechanistic effect. And an example of that might be PD-one.

Speaker 2

So 6,236 mechanistically targeting RAS and PD-one, not mechanistically targeting it. You can imagine those might in principle be more combinable. Pre clinically, we've combined a lot of things and can see impact in the preclinical models. So I just think it's hard to predict today exactly what will work out best, but we do have some priorities and I've just given you some sort of guidance about how you might think about those priorities.

Speaker 9

Yes, I really appreciate it. Thank you so much.

Speaker 2

You bet.

Operator

Stand by for our next caller. Alex Stranahan joins us from Bank of America. Alex, your line is open. Go ahead.

Speaker 6

Hey, guys. This is John. I'm on for Alec. So just a quick one on 9,805. Obviously, we saw some preclinical data at AACR.

Speaker 6

In terms of getting into the clinic as you dosed the first patient in your monotherapy dose escalation study, What's the kind of like patient baseline characteristics we can expect? And what tumor types are you going to go for in the study. If you could shed some light on that. Thanks.

Speaker 3

Well, right now, as possible and obviously convince ourselves that that's the right dose and persuade other constituencies out there that we have the right dose. So apart from an obvious restriction for patients with tumors harboring KRAS G12D mutation, I don't think you're going to see a lot of difference from the RMC 6236 dose escalation, frankly. We know experience now with 6,236 to get a handle on the types of patients that we're going to get in the Phase 1 study. They're going to be predominantly patients with lung cancer, Cancer and Colorectal Cancer. And I think that's pretty much all we can say right now.

Speaker 3

There is nothing unusual about the Phase 1 plan for this compound.

Speaker 2

Got it. It might be worth adding. I don't know, slightly underlying, it was a question about access to patients, which we sometimes get asked about. There are 55,000 We estimate 55,000 new U. S.

Speaker 2

Cases of KRAS G12D cancers each year. And given that even across multiple companies, studies that might be underway at the same time, you're talking about dozens were at most hundreds of patients. I don't think there's going to be any impact of either competition from others to the extent that there is any versus competition from RMC-six thousand two hundred and thirty six will have plenty of access to patients with KRAS G12D tumors.

Speaker 6

Okay. Thank you. And a quick follow-up to that. You mentioned that CRC is likely going to be are one of the type of patients recruited. So given the complexity of colorectal cancer in general, other than screening for KRAS, the presence of KRAS G12D, are you also going to be screening for the absence of other mutations?

Speaker 2

Well, I think just to build on Steve's comments, The first thing to do with the compound is the Phase 1 dose escalation, and that's not typically a time at which one wants to apply a whole bunch of restrictions. That comes later after you've seen how it behaves and have a good sense of where you might prioritize. So I think Steve mentioned that there will be relatively few restrictions other than sort of conventional Exclusion criteria and then the inclusion is a KRAS G12D mutation, but I don't think we'll be putting in the other genetic, significantly other genetic restrictions.

Speaker 6

Okay. Thank you. Thanks for the color.

Speaker 2

Yes. Thank you.

Operator

And standby. Our next question comes from Ben Burnett with Stifel. Ben, please go ahead.

Speaker 9

Hey, thank you very much. Just want to build off an earlier question. Just about the regulatory path for the RAS multi RMC-six thousand three hundred and sixty six, I realize it's early days, but do you have a sense for how many different sort of genetic variants of KRAS you need to show data on to get a broad sort of mutation agnostic label?

Speaker 2

Hi, Ben. No, we don't know. It will just depend on how much activity there is when we have a more mature data set, and that will ultimately depend on conversation with the people who make that decision.

Speaker 9

Okay. All right. Got it. Thank you.

Operator

And Jay Olson joins us from Oppenheimer. Jay, your line is open. Please go ahead.

Speaker 10

Hey, thanks for taking the question and congrats on all the progress. Can you talk about any feedback you received from physicians following AACR? And also, is the brain penetrant property of your 3 molecules by design or is there a particular reason for the high CNS activity? Thank you.

Speaker 2

So the first remind I was sort of thinking about your second question, but remind me what the first question was. Could you say it again? Any feedback you

Speaker 10

got from physicians following AACR? Thank you.

Speaker 2

And are you asking about Kay, are you asking about feedback on our programs? Are you asking about feedback on other things at AACR? Could you just clarify?

Speaker 10

Feedback on the data you presented?

Speaker 2

I think generally, the feedback continues to be very positive. Our investigators are quite enthusiastic. We've said that previously. We are not able to make available as many investigational study slots as we'd like to be able to make available. They're constrained just by the escalation sort of paradigm, and there's high demand and patients waiting and investigators waiting.

Speaker 2

We continue to receive feedback that so far the compound appears to be well tolerated and active. And so there's quite a lot of excitement about RMC6236. And then now I've forgotten the second question. Was it by design?

Speaker 9

Depends on who you asked.

Speaker 2

Yes. I think in a certain sense, there are Physical Chemical Properties that the chemists at RevMed have determined and also most importantly have figured out how to incorporate those properties into these compounds and those create more drug like molecules. So it is notable, I think, that all 3 of these have this property and all 3 are orally bioavailable, which as somebody who's lived through the history of this, that was not universally accepted as a set of assumptions going into the discovery and development of these RASL inhibitors based Macrocyclic large chemical backbones, but they now have been endowed with these properties through pretty directed efforts. So I think we should acknowledge that the Medicinal Chemistry team with support by many others is able to do that. Whether or not they designed them specifically aiming to get them into the CNS, probably maybe more of a philosophical question than anything else.

Speaker 2

So that means I don't have to answer philosophical questions, I guess.

Speaker 10

Okay, great. Thank you. And if I could, maybe one follow-up on Can you just talk about the next data update and what sort of data you'll have and what investors should expect to learn from that?

Speaker 2

Well, sure. As we've noted, we're following any patient who stays on drugs, we continue following them, so we'll get a much better sense of durability and the course of the treatment for those patients who have already been on drug and who remain on. We're going to get a sense from backfill patients, a deeper sense of tolerability and a deeper sense of antitumor activity from those backfill patients might not have as much Durability data from those, if they're enrolled later in the game. And then, of course, we have escalation data that shows us where we are on the tolerability scale and get a better sense of How, when and at what level we'll reach a recommended Phase 2 dose or candidates for recommended Phase 2 dose. The tumor types are going to be, as we talked about earlier, they are what they are, and the mutations are what the epidemiology dictates them to be.

Speaker 2

And so, depending on how large the total set is, that will determine what's the absolute number of each of those histotypes and each of those genotypes, just too hard to say today. So I think investors should be looking for a larger data set than what we've shown before with more information that's kind of deeper and broader, and we'll see whether the trends that we described earlier, to what degree they continue, to what degree if there are differences, to what degree there are differences, and we'll couple that with, we hope, clarity about what comes next. We've already given you in our body language that we are definitely looking beyond the Phase 1b dose escalation. We're definitely thinking about where this compound needs to go and are sort of scaling up our activities to support all of that, but more detail when we have the data to support it.

Speaker 10

Great. It's super helpful. Thank you so much for taking the questions and congrats again on all the progress.

Speaker 2

Yes. Thanks, Jay.

Operator

Ami Fadia joins us from Needham. Ami, your line is open.

Speaker 11

Great. Thanks for taking my questions. With regards to RMC6236, can you discuss where the 220 milligram dose is relative to The dose that you tested in the preclinical model and how important is it to achieve a comparable dose in order to really reached the ORRs that you were able to see in the preclinical studies. And maybe let me pause here and I'll ask the next question after that.

Speaker 2

Okay. Thank you, Ami. I appreciate the questions. Just to remind you how dose selection is made. There's a dose selection committee, which made up of all the investigators.

Speaker 2

They review all the activity data and tolerability and safety data in a big package that they received before a meeting is called. They look at that, they look at the PK, and if we've cleared the DLT window, then they proceed to dose escalation and they determine, of course, with input from ResMed, how much to increase and they determine the 220 milligram increase versus 160. So just to make sure everybody understands how we arrive at with regard to what dose what exposure level will be at it, 220 milligrams, we'll know after we dose the patients and obtain the blood samples and determine PK. So we don't know. We can't know a priori.

Speaker 2

We have projections around that, but projections are projections, so can't answer that question today. And then your second 2nd or third?

Speaker 3

How important is it going up?

Speaker 2

Yes. I mean, I think we've said in various ways, More is always better. That seems to be the case for most of these compounds, not just ours, but for in most anti tumor drugs. So we'd like to get up as high as we can within the bounds of safety and tolerability. And you're sort of asking a question that Project Optimus is also asking and it's an equally difficult question to answer for Project Optimus, which is how much is enough.

Speaker 2

We're not in that realm right now because as Steve pointed out, we're continuing to see good tolerability. So we're not in that zone where we even have to be worrying about it. But at some point, there will be side effects. It's just hard to conceive of that. There won't be side effects and even more significant side effects than we've seen so far.

Speaker 2

But we're pretty pleased with the exposures we've had at the other dose levels up through 160 and it's we're above what we believe is the equivalent in mouse exposure of 10 milligrams per kilogram, which was very much an active are dose level in the mice or exposure level in the mice. And so we're well above that. We've been above it for a bit, and but exactly where we are 2 20 is hard to say.

Speaker 11

Thank you. I guess my follow-up question is, maybe just what do you at what point Do you think the clinical data will support the sort of superiority to other Get asked off drug that wrap off drugs that you saw in the preclinical data set. And then perhaps if you could in terms of time to respond, Relative to the data set that you shared at the last earnings call, do you expect responses to improve beyond that

Speaker 2

Okay. I think your second Follow-up question there was, do we expect response rates to improve over time as patients stay On drug, I think that's how I heard that question.

Speaker 11

Sure. Yes.

Speaker 2

Yes. Well, we made that statements back at the end of February, we did assert that and we stand by that assertion. We're continuing to accumulate Evidence of anti tumor clinical activity, but we stand by the assertion we made previously and will see over time whether that holds as we dose escalate and when we report it out with the data set, will have a firmer answer as opposed to a preliminary answer at that point.

Speaker 11

Thank you.

Speaker 2

On versus off. Yes. RMC6236 is probably not the best place will be able to test the on versus off because it is unique in its profile as far as we know for any compound that's in the clinic or about to be in the clinic in that is active against so many different genotypes. And so it sort of stands it sort of defines a class of its own And it has to stand on its own. And so it will be compared more to standard of care in each of the histologies.

Speaker 2

I think RMC-six thousand two hundred and ninety one is one where ultimately the treatment regimen must show differentiation from standard of care and standard of care at least in second line now includes our targeted KRAS G12C OFF inhibitor. But that is likely to come from us in the form ultimately of combination strategies. That's what convey this our vision for the RMC-six thousand two hundred and ninety one program. And in the combination, we'd like to have the very best RAS inhibitor that there is, And we think RMC-six thousand two hundred and ninety one is a candidate to be the best KRAS G2C inhibitor in large part because of its on mechanism. But that will be additive to whatever combination play is put together when it's tested in a Phase 2 kind of context.

Operator

Okay. And standby for our last question. And it comes from the line of Jonathan Chang with SVP Securities. Jonathan, you're on the air.

Speaker 4

Hi, guys. Thanks for taking my question. Just one for me. What do you see as the competition for RMC6236? Thank you.

Speaker 2

Thanks, Jonathan. That's a good question. For most of the indications, The competition is standard of care. That's what we're going up against. For example, for G12V or any of the other G12X mutations, Aside from C, there aren't other compounds in the clinic today.

Speaker 2

For G12D, Obviously, there are some other compounds that have entered the clinic. And so in principle, those are competitive for that population, the KRAS G12 phenotype. That's not a Those would have to be considered competition.

Speaker 4

Got it. Thanks for taking my question.

Speaker 2

You're welcome.

Operator

And that concludes our Q and A. I would like to turn it now back to Doctor. Mark Goldsmith, Chairman and Chief Executive Officer for closing remarks.

Speaker 2

Well, thank you, operator, and thank you to everyone for participating today and for your continued support of Revolution Medicines.

Operator

Thank you for your participation. This does conclude the program. You may now disconnect.

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Earnings Conference Call
Revolution Medicines Q1 2023
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