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

Good morning, everybody. Welcome to Wednesday. Great to see people here at the Goldman Sachs Healthcare Conference, 44th addition. My name is Chris Shibutani, member of the research team. Team is including some terrific associates, Charlie Ferranti is up here me. The good doctor will also be involved with making sure we prosecute the details and the questions. Revolution absolutely pleased that you guys could be here once again. And we have on the stage with us Peg Horn, Chief Operating Officer; and Steve Kelsey. President of R&D. Professor Steve last year did a didactic. I think we'll have a sort of like next 2023 addition of that to happen this year. So this space that you guys are engaged in with the targeted therapies in oncology focus, there's so many chapters seasons, arcs, right? And I think you guys -- we've known each other for many years, even before the IPO, and thinking about that, the inherent excitement in terms of being able to capture a potential opportunity that everybody had known about in terms of somehow being able to bring therapeutics to such a significant and sort of nettlesome unmet need. Arguably, there was some degree of hype that came about as well. Investors were extremely interested some success, some commercialization finding out that stuff is difficult, nothing is -- commercialization has been kind of a path to navigate doctors are stubborn, they don't always do things quickly and immediately, even though the oncologists will have to give them credit for being very data-driven, very smart, et cetera. And we're always looking for kind of like what else could come. Innovation is relentless, and that's actually where the seat of where the Revolution R&D engine has been about. So with that as kind of a backdrop, Peg maybe you could just give us an overview outline of the company where you guys are at before Dr. Ferranti and Dr. Kelsey go at it.

Excellent. Well, thank you, Chris and Charlie for having us here. We're pleased to join you at the Goldman Sachs Conference again this year. Revolution Medicines is a company for those that are familiar with us and those that are just coming to the story as a company exclusively focused on RAS-addicted cancers. We have a very rich pipeline of inhibitors that are directed at RAS, multiple forms of RAS. And these inhibitors are advancing in the clinic, the first wave and most visible portion of these inhibitors are -- is made up of 3 compounds, one, our RAS multi inhibitor, which some people refer to as a Pan-RAS. We religiously refer to as a multi-RAS, that is RMC-6236, the second in the first wave of our inhibitors is our G12C mutant selective inhibitor 6291 and the third, that is also in the clinic by the way. And the third is our mutant selective G12D inhibitor 9805, which is advancing to the clinic this year and is on pace for our stated goal of treating the first patient mid-year. The collection of inhibitors is distinct in the industry in that these 3 1st wave compounds, they're all related and they're differentiated in that they hit the oncogenic or on form of RAS. And so we think that's very differentiating. They also are all orally bioavailable. So an important distinction from those in the space. And we pioneered this approach several years ago, and we're now collecting the initial clinical data, and we have an exciting year ahead of us with clinical data coming out of the pipeline. And then we have just multiple assets coming behind multiple mutant selective inhibitors coming behind the first 3. So super exciting time for us and happy to jump into the specifics on the program. So I'm sure you'll have lots of questions.

Okay. No, that sounds terrific. And if there's anything that we'll try to inform the ecosystem at least walking away from this, it's for certain to get religion and we're going to use the word multi. Right Charles?

Absolutely.

Multi Okay. I'll turn it over to you.

Yes. Sure. So Peg as you pointed out, this has been an exciting year already so far in terms of clinical data. So recently, the 6236 multi-RAS, you presented a first glimpse of initial clinical data that we were seeing from that dose escalation study. Could you maybe provide some key takeaways from this initial card being turned over during your earnings report a couple of months ago.

Sure. I mean the -- overwhelmingly, the most important message that we wanted to convey was that we could dose a RAS multi inhibitor, which, to be fair, when we say RAS-multi, we mean that this compound is single-digit nanomolar potent against multiple mutant forms of RAS, but also against wild-type RAS. And there was a conventional sort of sentiment in the field that we just wouldn't be able to drug wild-type RAS in the human body without getting unacceptable toxicity and we had a number of reasons for believing that we would be able to achieve a therapeutic index with RMC-6236. And I think we've demonstrated that, and we wanted to get that information out into the public domain as quickly as possible because it doesn't just set a platform for the development of RMC-6236, it also established a precedent for the entire RAS on tri-complex platform, of which there are, as Peg said, now multiple compounds coming along behind it. And it also debunk the theory that you just can't drug -- you can't drug wild-type RAS and get away with it. You can, in fact, and we are and we -- since we disclosed that data to be honest, we disclosed that 80 milligrams daily of RMC-6236 not only induced fairly significant tumor shrinkage well beyond the criteria required for partial response by RAS's criteria, but also was associated with really very startlingly good tolerability. I mean with rash as the only significant toxicity being observed. And since then, we've increased the dose from almost 3x. I mean, we're not dosing patients in excess of 220 milligrams a day, whereas the first responses were observed at 80 milligrams a day. So I think there are a number of reasons why we thought that message was important.

Yes, absolutely. So you mentioned the rash. Rash was probably the adverse event of choice or of interest, obviously, for a MAPK targeting programs. across the board. And so this was something of keen interest with investors. And so going back to that initial glimpse of data that looked up to 120 mg, we were seeing any grade rash 100% of cases of patients who were dosed at 120 mg, but we weren't seeing any maximum tolerated dose. As you pointed out, we weren't seeing any Grade 3. You pointed out that we're now in excess of 220 mg. Is it safe to assume that we've started to see Grade 3 rash at this point?

Well, firstly, let's step back and look at the grading of rash, right? So the grading 1, 2, 3, 4 refers to the severity. Unlike most toxicities in the common toxicity criteria, rash is very unique in as much as, firstly, it's not a single toxicity. It's made up of about 17 different descriptions. So if you look you can ascribe multiple different terms to a rash and it still goes into what we have artificially internally composited all those terms into 1 term, which is called rash. The other thing is that the severity grade has nothing to do with the severity. So it doesn't give you a good description of how troublesome the rash is. It's purely a description of how much of the skin surface area is taken up with the rash. So firstly, so I just want people to understand the context of that. We haven't actually given any further updates on the tolerability or the efficacy. And we will come to that. We did promise that we provide another update sometime sort of in the middle of this year, and we will get to it. But the second thing to say is that we always expected that rash would never be dose-limiting because it's just not troublesome. And we always expected from the preclinical tox that probably gastrointestinal toxicity will become dose limiting. We still have not seen -- we've still not reached a maximum tolerated dose. So we continue -- we dose escalated beyond 220. We're actually now enrolling patients to dose of 300 milligrams daily, whether that will or will not be the maximum tolerated dose, I can't tell. But I don't expect rash to be the problem. Rash isn't the problem. I mean the patients and the investigators tell us that it doesn't really matter how much of the skin surface area is taken up with the rash. It just doesn't bother the patients. And in fact, only half of the patients who have had a rash have actually had any form of intervention for it. Most of them just sort of walk around with a rash, and it's not bothering them at all.

Understood. So the patients who have experienced rash and have been given an intervention to try to treat it. Are physicians or patients describing it any differently than you would see in terms of the rash that's associated with other MAPK-targeting drugs?

Yes, they are. They are beginning to now, the more rash we see, the more diversity of description we get frankly. So some people earlier described it as similar to EGFR inhibitor rash, now they're beginning to -- some people are describing as difference in EGFR inhibitor rash. I think it manifests itself slightly different in different patients and with different phenotypes. And it's really very hard to know. I think we're going to end up calling it a rash associated rash in the end. And frankly, to be fair, this is a question that at some point, you're going to have to put to the investigators who are actually treating the patients because, of course, people accompany, we never actually see the patients with the rash, we see pictures of it. So I think it's -- on balance seems to be a milder rash than has been traditionally associated with EGFR inhibitors, but it's very heterogeneous.

Understood. So now that we're kind of seeing that maybe the therapeutic window for 6236 is wider than others were maybe appreciating, let's focus a little bit on the responders that we're seeing so far. You described 2 out of 3 patients who had received that 80 mg dose having achieved a partial response, 1 of which was previously unconfirmed, the PDAC patient now confirmed. What can you tell us about the composition of these responders that you're seeing so far? I believe they're all G12D tumors. Is that correct?

Well, yes, I mean, again, I'm going to -- we're going back to a snapshot of the data that we shared with you back now, what is 4 months ago. And of course, we've enrolled many more patients since then and evaluated many more patients. And as I said, we will provide a very meaningful update as soon as we can. But to be fair, the G12D bias in the study is a reflection of the epidemiology of RAS mutations. That's all it is. About 50% of RAS mutations across the major epithelial tumor types, are G12D. So that's what we see. We see about 50% G12D. The second most common is G12V. So we see G12V. And we're not enrolling G12C mutations in this study at the moment because we have -- there are plenty of other options for patients with G12C mutations. There's no obvious reason to expect that responses are going to be different across the G12 mutations. That's for sure. We don't expect major differences there. We just expect numerical differences, but we don't expect that to be at the end of the day when we have a big enough data set but the response rate for G12D would be different from G12V. That's not really what we're expecting to see. It is obvious that one of the major determinants of response is histotype, I mean there are certain tumor types that don't shrink as easily as other tumor types in colorectal cancer, the experience from the G12C inhibition that colorectal cancer doesn't shrink as easily as lung cancer and perhaps pancreatic cancer. So I think that's where the major differences are going to play out in the end. And then, of course, you have all the other unknown such as co-mutations. We're not -- it's really not clear whether the number of prior therapies at the moment is a major response or not, I can't tell you, but I'm sure there will be co-mutations ultimately that drive response rates as well.

So you mentioned the colorectal population. Were you surprised that there were no colorectal tumors represented in this initial data.

We did enroll patients with colorectal cancer. We just didn't report them. And one of the reasons we didn't report them is because when -- at the early dose levels, the sort of the first 3 dose levels were sort of below exposures where we have previously seen what we wanted to see, which is significant tumor regressions. And so or most of the colorectal cancer patients were enrolled at those lower dose levels. As the investigators and the company started to see responses in pancreatic cancer and lung cancer. The waiting, the enrollment waiting was very, very much in favor of pancreatic cancer and lung cancer. So the colorectal cancer patients have been, to some extent, not prioritized for the study to date. And at some point, when we get a recommended Phase II dose, there still is in the protocol an option to expand in patients with RAS-mutant colorectal cancer, particularly G12 mutant colorectal cancer, which is the vast majority of RAS mutations in colorectal cancer at that G12 position. And we will do that experiment. I'm not -- generally speaking, and this is -- again, the precedent set by the G12C inhibitors is really important. We don't expect single agent RAS inhibition to be the best treatment for colorectal cancer that cause RAS mutation. I think that's essentially going to be best served with combinations. So you may not see a single agent program in colorectal cancer going forward into sort of registration. It may just be the prelude to a bunch of different combinations.

That makes sense. And we'll get to some combination questions in a moment, but maybe just going back real quick. The high range of that initial cut of data 80 to 120 mg. There's a lot of debate at the time how this level of human drug exposure compared with the preclinical models that you previously reported of the 10 to 25 mg per kg rate...

Yes. We deliberately shied away from it because it's an incredibly complex pharmacokinetic model, and we don't really know how to do the calculation ourselves. All we can say is that if you triangulate the various different ways of comparing cross species PK, we are definitely now in operating in the ballpark of the doses that we used in the preclinical studies that we presented.

And this is in reference to being beyond 220 mg...

Yes. Yes. Well, I mean, I think where we are now. So 220 and above, I think we're operating now. We showed a whole lot of data AACR last year with what we call mouse clinical trials with PDX models that regressed to varying degrees with really quite impressive activity in pancreatic cancer, lung cancer and colorectal cancer, and we're probably operating in that range now. But as I said, because of the unique mechanism of action of the drug, and it's binding to cyclophilin A, it's extremely hard to do accurate cross-species comparison of PK and infer -- you really just have to do it by estimation. And I think all the estimates are just were in the range now.

Absolutely. Allometric scaling, I guess, is complicated enough.

It's very complicated in any way. But when you get into multiple compartment PK with tissue binding to cyclophilin A, it becomes even more difficult.

Sure. You have also commented previously on the possibility of pursuing intermittent dosing as well. And as you're moving up the dose escalation here and seeing a wider therapeutic window? How are you thinking about that possibility?

We're thinking that is probably not necessary to do that. We reserve the right to do that at some point. But I think we always felt that, that would be something we may need to resort to with daily dosing turn out to be too toxic. As far as we can tell, the daily dosing schedule that we have right now at the doses we're giving is still acceptable in terms of tolerability and we're certainly not going to prioritize alternative schedules. We're probably going to move forward with the once daily schedule that we have.

Okay. Good to know. So now maybe a couple of questions that might reflect the potential for combination use with 6236, and as you're looking at, I guess, maybe first of all, as you see a sufficiently wide therapeutic window for 6236, how are you thinking about the potential to pursue 6236 in these mutant specific population. Is there a scenario where maybe the therapeutic window is sufficiently wide that you don't even need a mutant selective inhibitor?

Yes, there is a scenario, but it's not our, if you like, our preferred scenario. I mean, just logically, if you have a mutation, a known mutation in RAS and you have a mutant selective inhibitor like a G12C inhibitor and you have a RAS multi inhibitor, there's really 4 things you can do, right? You can combine them, which I think is our favorite option. And for us, combining RMC-6291, or mutant selective G12C inhibitor with RMC-6236, our RAS multi inhibitor is a very high priority. So a very high priority combination for reasons I'll get into in a minute. So you can combine them. you can figure out which one should be used first and then use the other one second, right? So that gives you 2 options, so you can use a 6291 first followed by 6236 so you use 6236 first rather than 6291. And the third is you just let them compete against each other and you choose the one that's best and don't pursue the other one. But we have so much data now and other people are generating data suggesting that the combination will be superior to either agent alone. And the reasons for that are, I think, very clear. The reasons are that the mutant selective RAS inhibitors are very, very good at really hitting the RAS mutation hard, the original RAS mutation hard. But we now know that tumors carrying RAS mutations are heterogeneous and they have other RAS mutations. And they have other ways of escaping from mutation -- from inhibiting mutant RAS. And a lot of that involves wild-type RAS. So if you can combine with a wild-type RAS inhibitor, which is inherent in 6236, you can suppress a lot of the escape mechanisms. And I think if we do that, we are hopeful that we will extend the time it takes for a tumor to escape from a mutant selective RAS inhibitor. We have demonstrated that, that is true in preclinical models, and we need to go ahead now and demonstrate that, that happens in real people in the clinic.

Sure. And so you just touched on this next question that I was going to ask, which is when you think about these combinations with 6236 and how you measure the benefit of a superiority in this combination approach, it sounds like 1 of those benefits would be an extended duration of response by preventing escape mutant...

Always, I mean our whole premise for 6236 has been that the -- there's a regulatory challenge and a clinical challenge and both of them require that the duration of effect is prolonged. Because right now, if you look at all of those G12C inhibitors that have gone into the clinical single agents in lung cancer, the response rate isn't really the problem. The problem is that progression-free survival is still less than 6 months. And that's why the randomized trial that Amgen did show that the progression-free survival on sotorasib alone was only marginally better than chemotherapy alone. It's about durability. These tumors have an incredibly effective at finding a way around mutant RAS inhibition. You can hit G12C mutations as hard as you want. But after a few months, the tumor has found a way around it and starts to regrow. We've got to deal with that. And so I think the combination and the -- particularly the combination with RMC-6236 is one of the approaches that we think has the highest potential to extend that runway.

Sure. And you mentioned that when it comes to these types of tumors that the response rate is not the issue, but do you still expect that maybe the combination with 6236 might also improve as well...

It could. Again, I mean at the end of the day, different tumors are programmed to respond differently to drugs and some of them blow up and shrink and some of them don't. But in the end, I don't think anyone is going to prescribe a drug or approve a drug or reimburse for a drug on the basis of just the overall response rate. If the duration of effect irrespective of whether the tumor shrinks or not. If the patient is going to progress it in a few months, that's probably just not a good return on the investment. And so I think we just need to get better at prolonging that clinical benefit phase.

Great. Right. That makes sense. And so my last question on 6236 is really just on the pace in the substance of subsequent readouts that we're expecting from the dose escalation trial. Later this year. We've heard references to mid-2023, third quarter, corporate versus medical conference. Just wondering if we could get any color there.

Yes. Let's just try to nail that one. At our earnings release, we said that we would give clinical updates on this in the second half of the year start. And we will do that in a series of presentations. Corporate, scientific, they're going to start in the third quarter. We hope in our August earnings that we can give better roadmap to that to make it clearer for folks. But definitely, it will be a mix and a series of presentations, including scientific conferences because we've heard from many investors that they would like to hear it in that forum.

Right. That makes sense, and we look forward to it. So maybe in the time that we have remaining, we can go into some of the mutant selective -- that you have. So starting with 6291, obviously, we are -- that's the next program to have an initial clinical readout later this year in the second half. As you look at the G12C market as it stands today, we have 2 approvals with in the form of Lumakras and [indiscernible] what can we -- are there any learnings from those launches as they progress in terms of the shape of the market that's out there and where 6291 might fill an unmet need?

Yes, 2 very different answers to both the parts of that question. Well, firstly, look, that space is highly competitive. Now people have worked how to drug G12C, thanks to Kevan Shokat and everyone is in on the act and we've seen now at ASCO, another bunch of KRAS G12C of inhibitors come along. Everyone has their own response rate on a small denominator. And at the end of the day, they're all going to have a PFS of around 5 to 6 months in patients with lung cancers have been previously treated with chemo and pembrolizumab. Great. That's great. The challenge there is that everyone is trying to do experiments in that space is a highly competitive place to do clinical trials. That's the first thing to say. So somehow, you've got to get above that parapet. You've got to show that you have a unique proposition in order to compete in the clinical trial marketplace. And even to actually do the experiments, you need to be unique. And part of our uniqueness, it turns out is the ability to combine with RMC 6236. So that's the first thing. I think the second thing, and we discussed this at this meeting last year, is that the RAS curve is on the same trajectory as all of the other targeted therapies. With regards to the acceptability of testing and the desire Chris introduces whole concept right at the beginning. The willingness of the community to prescribed targeted drugs in a place where they were previously prescribed chemotherapy. There are multiple uphill challenges in that space, not the least of which is that the reimbursement challenges outside the United States are very, very harsh. If you go even in Western Europe, the reimbursement challenges are really harsh. The novel therapies are expensive. They're a lot more expensive than chemo. In the United States, giving an oral drug deprives your treating physician of reimbursements that they get from giving IV therapies. So there are real headwinds in trying to change clinical practice even in a state where everyone is tested and that result is known by the treating physician, which, of course, we know. Even the eGFR curve, it's taken, what, 15 years to come up eGFR curve. Fortunately now, we have much better platforms for doing testing. And so the curve shouldn't be quite -- shouldn't take as long to get up the curve. So that's the general space that we're in. I think there are a lot of people pushing and a lot of people pulling and there's going to be a dynamic tension in that RAS G12C space with some years to come, particularly as we move -- as those inhibitors move into first line of treatment. 6291 has to be better, and there's no doubt about it. It currently is unique. It's the only G12C inhibitor in the clinic that inhibits the on form of RAS. And whether that's enough to make it unique and make it better than the G12C up inhibitors is as an experiment that we will do, and we will figure out at some point. But the real, I think the real utility of 6291 is not just that it inhibits the on form of -- it's not just that it inhibits the on form of mutant RAS. It's a completely different compound. It may have a completely different tolerability profile. And we do expect to be able to combine it completely uniquely with RMC-6236, which no one else has. So we have really 3 propositions for it being best. And it is best, then it will demonstrate itself as best and that will be great. And if it's not, then there's no utility for it, and we will focus our attention on the rest of our portfolio.

And so when we talk about assessing whether 6291 will be best in the G12C field, how should we be framing our expectations with respect to the Phase I monotherapy dose escalation data later.

You're going to have a hard time, I think, let's be really clear. anyone will have a hard, including us, unfortunately, are going to have a hard time determining from that data set, whether it's truly superior. And I think the reality is going to be that the obvious -- the experiments that demonstrate the superiority of RMC-6291 are going to be the ones that are going to be done in combination. And the 2 combinations of interest to us are going to be the combination with an anti-PD-1 inhibitor and the combination with RMC-6236. And ultimately, those work out with the triplet of all 3 of them together. That's really going to be the determinant. It's going to be very hard. I mean, again, like I said, you've seen data sets now for multiple companies where they've given their G12C inhibitor to 50 people and the response rate is 48%, 52%, 39%, 61%, you can't discriminate them. It's just response rate by resist -- there's no durability data. There's no way of discriminating on the basis of PFS. And I don't think we expect to either. There may be some very surprising things that happened with RMC 6291, for instance, like maybe it works really well in people who failed on our G12C off inhibitor. I'm not expecting that to happen. I'm not saying it won't happen. It could, but that's not really an expectation. I think the expectation is that in combination, it will be demonstrably superior. And if it isn't, it isn't. And we -- like I said, we have many other RAS mutant selective inhibitors in our portfolio to be to be spending our time and energy on if 6291 isn't better.

Let me just underscore, Steve said a lot of this, but second-line lung cancer for 6291 is not our goal. Our goal is to identify the profile of the compound in the monotherapy dose escalation and get the combos as soon as possible. When we're in that recommended Phase II dose zone later this year or early next year, whenever it happens, we're going to turn the switch on this and 6291 plus 6236 is by far the highest priority.

So I -- immediately turn to that combo opportunity there.

So we're not going to try to squeeze into that space.

And so maybe in the time that we have remaining, quickly switching over to 9805 with the G12D obviously, we're going into clinical trials here in the middle of this year. And so G12D is obviously a large opportunity, relatively speaking, in the RAS space, just in terms of where you referred to, the prevalence of this mutation. And so maybe could you talk about how you think given the size of this opportunity, multiple players are pursuing G12D at this point. And so how does 9805 maintain a competitive advantage with that in mind?

Well, Yes. I think ultimately, again, the data will determine the clinical data is ultimately going to determine that. Right now, 9805 is going to be the first covalent inhibitor of G12D to go into the clinic. It's distinct from the Astellas degrader because it's given orally. And it's distinct from Mirati's G12D inhibitor 1133, which started dosing a couple of months ago because it has a covalent warhead, which inhibits the G12D pretty effectively. And again, ultimately, whether our compound is better or worse than Mirati's or Astellas's G12D will have to be determined by the clinical experiments. The precedents set by G12C inhibitors will also remain true for G12D inhibitors. I mean these -- we don't expect the ultimately, these drugs just to be used for salvage of patients who have failed chemotherapy and pembrolizumab. We expect them to ultimately be either combined with or ultimately replace chemotherapy in the first-line setting. So there are many, many opportunities for deployment of a G12D inhibitor with different combinations in different lines of therapy, in different tumor types. And plenty of space for more than 1 G12D inhibitor, but whether or not we will ultimately end up being better. I think it's just the -- Mirati have placed their and we've placed ours, and we're happy to -- we're happy to do the clinical trials and see how it pans out.

Great. Maybe one more quick one as we're running out of time. One of the updates from the last quarterly earnings call was an expansion of your commercial team that you have. And so maybe -- can you talk about what the goals are for that team, how they're assessing the space in general across the RAS on programs? And what are the kind of the near-term goals, I guess, for this commercial team.

So we're planning for success and a major portion of that is our RMC-6236 molecule. We see that as a very central part of our thesis going forward. So we are bringing in folks who can start planning for that success, helping us think about that. As you all know, you don't start commercial activities as [ NDA ] that's way too late. So we're planning for success. And that team is thinking about all the pre-commercial planning exercises, interactions that need to take place and helping us also define the clinical development plan that will enable ultimately, we hope, approval and reimbursement.

And then just to close out, Jack isn't here, but just let us know about the healthy balance sheet.

Well, as of the end of the first quarter, we had over $900 million on the balance sheet, I think it's $909 million. So we are in a good position and feeling good about the prospects of the company as we continue through the rest of the year.

Excellent. Peg, Steve, thank you very much for joining us. Charlie, excellent job. Look forward to seeing you on the stage next year and all the updates through the balance...