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

Good afternoon. My name is Peter Lawson. I'm one of the biotech analysts at Barclays. Welcome to Lawson's Lunchtime Deep Dive with Revolution Medicines. Goal of these calls is to help preview upcoming data and we've been doing it for the last 3 years at Barclays and Revolution Medicines [ attending ] our series, and I think we've got the 4 left this year for the series. And I hope you find them useful and of course, [ II season ] and so we very much appreciate all those are support. And just as a way of orientation, this is a 30-minute call, if you have questions, do e-mail me directly. So at [email protected], you can get me on Bloomberg. I'm on Bloomberg, so you can pass me that way. And -- the others -- and it gives me great pleasure here to introduce Revolution Medicines. We don't cover the company, so uncovered. So thanks so much, Mark Goldsmith, CEO. Thanks for your time today and you have time permitting, we'd love to cover the multi-RAS inhibitor updated data in the second half and then your G12C. And then of course, the SHP2 inhibitors we ever realize is a clear distinct read through for us.

So with that, maybe the first question would be there's multiple KRAS players. You've got a kind of unique approach with this kind of multi or pan-RAS inhibitors. So just curious on how your approach differentiates from other KRAS players within the space?

Well, thanks, Peter. We really appreciate the chance to talk with you today. Our approach as a company is differentiated in that, essentially the entire company is focused on RAS-addicted cancers that creates a great deal of internal know-how and crosstalk leverage that we think will ultimately help us to feed RAS-addicted cancers. The core of our pipeline is a very large collection of RAS inhibitors that bind selectively to the activated or (ON) form of RAS, which is in fact the oncogenic state for RAS. And when we began doing this work several years ago, we acquired a company called Warp Drive Bio that had made some early breakthroughs with regard to drugging the activated or (ON) form of RAS. We incorporated their technology into our platform and since then have created really a vast collection of highly selective inhibitors of the RAS (ON) state and some of those inhibitors are uniquely active against a particular oncogenic variant of RAS and some of those are active against multiple forms of RAS. And the compound that you just spoke to, RMC-6236 is something we call a RAS multi-ON inhibitor, multi because it inhibits virtually all forms of K and HRAS that we've tested to date, which is essentially all forms of RAS and it has activity against essentially all mutant variance of those isoforms of RAS. So that's why we call it RAS multi, and we call it (ON) because it is active only against the (ON) state of the RAS proteins.

Got you. And then the data you showed earlier this year, sort of safety looks really encouraging. Well, I think you're at 220 milligrams now and 80 milligrams was theoretically active dose and it seems to be well tolerated. Kind of when do you think you hit DLTs and kind of if you could talk about the rash and if you think that could become a dose-limited toxicity and if that could even preclude the use of the drug in any way?

Right. So RMC-6236, the RAS multi-ON inhibitor has been presumed to be one that would be difficult to use in humans under the theory that inhibiting wild-type RAS would cause intolerabilities. Our approach to it assumed that inhibiting wild-type RAS would actually contribute to antitumor benefits since RAS-addicted tumors will recruit any form of RAS in the cell that they can find in order to stay alive. And therefore, inhibiting all forms of RAS could be more active as an antitumor agent. Preclinically, RMC-6236 was highly active at dose levels that were also well tolerated. And we put out very extensive data sets across many different tumor models that showed how active RMC-6236 is with animals able to tolerate it for many months, on end we've had mice treated for 100 days without any difficulty. So the question really was, would that translate into humans. That's always a question in moving from mouse models into human. And what we reported back in February, about 6 months into the study, is that the very first dose level, which was 10 milligrams in human was already pharmacologically active, and we have been dose escalating from there and the data we showed on tolerability included patients up to 120 milligrams. And as you point out, it actually was quite well tolerated. No patient had come off of drug for intolerability and really the most common side effect was and remains today rash and a rash that both investigators and patients have reported is manageable, is not really a cause of intolerability and in fact, as far as I'm aware, maybe only 1 patient over even had a dose reduction associated with the rash. Now since that early report, we've disclosed that we continue to dose escalate above 120 milligrams. We went to 160 milligrams per day, and then we cleared that dose level, and we went to 220 milligrams per day. And I can now share with you that since then, we have cleared the 220-milligram dose level from the DLT window and have moved on to 300 milligrams per day. So it's moving along quite well in terms of antitumor activity. We began to see really objective antitumor evidence at 40 milligrams and above, but even much more so at 80 milligrams. And 80 milligrams is roughly the equivalent of -- in the ballpark of 10 milligrams per kilogram in the mouse, which is the dose level at which we began to see significant numbers of tumor regressions. So really, I think, 80 milligrams, we kind of hone in on as a threshold for shrinking tumors. And now we're already 3x that dose level. And we've seen continued increases in exposures associated with the increases in dose levels.

How far do you think it will be able to go up? I know it's difficult triangulate between the mouse studies and the human studies based upon the dynamics of the interaction in the molecule. But kind of...

We sort of -- we'll know when we get there, to be honest, if we don't clear a dose level, then we know that, that dose was above the tolerated dose level. We just don't know it until we're there. We have all sorts of betting tools internally and so on. But I just don't really know the answer to it. Clearly, we did clear the DLT window for 220 milligrams, and we'll see how 300 milligrams plays out.

Got you. And as we think about efficacy, you saw a number of encouraging responses in the original release. And just -- do you expect the patients that are on drug, stay on drug of they come off? It sounds like one had a dose reduction, just anything you can kind of help us frame kind of the second half expectations around response rates and what you want to see?

Well, generally, with RAS inhibitors, more is better from the point of view of antitumor response. I think that's true for virtually every RAS inhibitor that's been tested, and it is true for RMC-6236 as well. So we'd like to be able to deliver to patients as much drug as they can tolerate and still stay on drug. It's not a very effective drug if patients have to stop taking it. So it is important that there'll be continuity in taking the drug. And we just don't know what that dose level will be, but the higher the better from an antitumor perspective. What we've disclosed is that we've continued accumulating evidence of antitumor activity, and we haven't given any more detail than that. Yet, we'd not like to do that sort of piecemeal, we'll do it. This starting in Q3, we'll introduce a series of presentations, both corporate and scientific meeting presentations that will put together the whole package for people to see rather than just bits and pieces. But we're very encouraged by what we're seeing feedback from investigators is very positive, very encouraging. There tends to be a waiting list to enter this study at our clinical sites, which is both a sad indicator of how much need there is for it, but also a very encouraging indicator that, that amongst patients and investigators it's viewed as a high priority drug candidate. So we're excited about that. We have no trouble getting patients into the dose escalation cohorts. And we will present as much data as we can when we start that series of presentations.

Got you. And then I know you saw kind of a dose response relationship in the earlier doses. Do you see a similar kind of thing pan out? What to say?

Yes, I can't really comment, of course, on clinical data as subsequent to our February release. The 1 thing we did report in May that, although it's only a single data point, I think it is indicative of general observations. The general observation is that the longer a patient stays on drug, the more likely that they will convert to an objective response. And we had already indicated back in February that, that was the case for the patients who had shown responses. In particular, there was a patient we described who have metastatic pancreatic cancer -- late-stage pancreatic cancer, had failed multiple other therapies, began on RMC-6236 at 80 milligrams and on their first on-treatment scan, which is 6 weeks after they started treatment had a modest but noticeable reduction in tumor volume, and I think it was around 17%, not enough to trigger RECIST criteria for a partial response, but nonetheless notable. Subsequently, the patient had a second scan, which was after 12 weeks of treatment, and they converted to a greater than 30% response. So that became a partial response considered unconfirmed at that stage. And then in May, we reported that, that patient after another 6 weeks on the same dose had a greater than 80% reduction in tumor volume and really by scans some people look at it and say it looked like a CR. But formally, it was read as an 80% or 82% tumor volume reduction. So I think that is evidence that at least at those doses at that dose that the longer one stays on drug, the more likely one can convert to an objective response. So that's quite exciting, quite encouraging. And the fact that the compound has been generally well tolerated means that there is a greater chance that one could stay on drug long enough to seen an objective response. And then beyond that, we're, of course, monitoring patients longer term. And as long as they're staying on drug, we're interested to know what's the durability of the response and durability of benefit.

And then I had a question around the speed of response. How does that compare to peer molecules?

Well, there is no peer molecule for RMC-6236. There's really nothing to compare it to because it is the only RAS multi (ON) inhibitor in the clinic that we know of to date. So there really isn't a peer molecule. Some people try to compare it to adagrasib or sotorasib, which I'd consider the pioneering RAS inhibitors and the only 2 approved drugs. Of course, those are mutant selective for KRAS G12C, they're covalent inhibitors and only inhibit G12C. With regard to those, I'm familiar with sotorasib, which showed that the mean time to an objective response was around that first scan or median, I'm sorry, was around the first scan. And what that means is about half the patients did not show an objective response on the first scan, but showed 1 subsequently. So I don't think it's unusual that it may take time for responses to occur. But it's also the case that all of our patients who have shown a response required multiple cycles to show a response. So it's not a fixed characteristic. It just says that if one doesn't have an objective response on the first scan, one shouldn't be discouraged. If there's some evidence of tumor reduction that may well convert subsequently to a PR.

Got you. And then as we think about those data releases, in the second half. Is that going to be medical meetings or on earnings calls, just have you...

I think it will be a combination of corporate and scientific meeting presentations. We certainly understand the value of peer-reviewed settings. At the same time, sometimes peer-reviewed settings only provide a amount of time, and there's a lot more information. You can imagine now that this study, which has been underway now for roughly a year, we've accumulated a lot of data, a lot of different types of data and can be hard to squeeze into even a podium presentation. So we'll do some combination of corporate and scientific meeting presentations. And I think in -- at our next earnings call, we ought to be able to lay out a more precise time line of which settings and at what times people should expect these data to be shared.

Got you. The approach here and how should we be thinking about potential registrational pathways and kind of which tissues you go after, which cancers?

Yes. Well, it's an exciting question. I mean if you think about this a year ago when we first introduced 1.5 years ago when we first introduced RMC-6236, most people's immediate reaction was that it would never be tolerated enough to provide any clinical benefit. And now we're talking about what kind of registration path might be possible. And I think that's honestly an appropriate question because the early evidence that we shared in February was quite encouraging. And of course, people will have to look at the additional data layer to decide if they feel that way, but we feel very excited about this compound. And as I've indicated, feedback from investigators continues to be very strong. And I believe even patients have been reporting their own -- self-reporting results in various settings that is consistent with what the investigators are telling us. So let's see what the data look like, though, when we present it in the late summer and into the fall. In terms of our registration strategy, that's clearly something our development team is intensively focused on these days. We do believe that there is encouraging evidence of monotherapy activity in settings where there are significant unmet needs. And recall that all of the patients that we are treating today with RMC-6236 are patients for whom there is no targeted RAS therapy available. In other words, we're working an entirely white space. The mutations that are permitted in this study are all mutations for which there are no -- not only no approved targeted therapies but no known experimental targeted therapies that have shown activity yet. So we're really at the vanguard in this field, and that creates opportunities to pursue monotherapy from a registration perspective if the data support it. And we would obviously lean heavily into that as supported by the data. Beyond that, Beyond that, though, I want to be really clear, and we've said this consistently for many years now, and I want to stay on this point that really to defeat RAS-addicted cancers in the long run, for the most patients to get the deepest and most durable responses, one is likely to require combination strategies. RAS is an essential component of -- for these tumors and any attempt to suppress them even very effective attempts like RMC-6236 effective biochemically is going to elicit some form of resistance mechanism that will require a second or even a third component. We just know this from all the experience in the RAS field to date. And so we would expect that there will be combination strategies that will build on the monotherapy activity in order to provide distinct patient subsets with the best therapeutic options.

Do you think your multi-RAS ends up being kind of early line versus a more targeted, say, G12C, et cetera?

Well, that's a great question. I mean that's a really complicated question. It's very hard to give a straightforward simple answer. There aren't enough data -- clinical data to answer that. Preclinically 6236 is really the most active compound we've ever tested full stop. So we're very heavily invested scientifically in this idea. And it leads to the possibility that RMC-6236 could become a broadly applicable drug on to which 1 adds additional drugs, for example, combining a G12C selective inhibitor with RMC-6236 or combining a G12D selective inhibitor with RMC-6236, and we've shown a pretty good body of preclinical data that supports that idea, and we're quite excited to pursue it. And as soon as we feel that we're even in the zone of a recommended Phase II dose for RMC-6236, we expect to bring forward into combinations at least one of the mutant selective inhibitors with RMC-6236. And that -- the first mutant selective inhibitors is most likely to be RMC-6291, which is our KRAS G12C inhibitor, that is also in the clinic and making progress now.

Got you. And then so on your G12C kind of how should we be thinking about when you get the recommended Phase II dose? Is that kind of a second half thing or early next year? And...

Yes, we're making good progress on that. We've shared less information about it than RMC-6236 and the only reason for that is it's a crowded space. And so the bar is simply higher and giving an early look just doesn't provide enough information for people to judge it. So we indicated by the end of the year, we'll -- we expect to share some data around RMC-6291. But it's going well. Dose escalation is going well. It's been very well tolerated, and it too is an extremely active compound. We reported at AACR and various other settings, much more detail over the last 6 months about that compound, including its chemical structure and its entire profile. And it's really a remarkable KRAS G12C (ON) inhibitor. So its differentiation is that it inhibits the (ON) or active state of KRAS G12C, unlike the other compounds, so sotorasib, adagrasib and the other 10 RAS (OFF) inhibitors that are out there today, which all operate by binding to the off or inactive form of KRAS G12C. So it is a highly differentiated molecule, which means that it has the potential because of its mechanism of action to deliver a different biological impact. And of course, we're banking on that and testing that hypothesis.

Do you think that the data we see year-end will have enough to see whether there's a differentiation on safety or response rates or how long do you think that takes the [ pan out ].

Yes. So safety is much easier for us to accumulate evidence on because, of course, every single patient that comes in becomes part of a safety database. And -- so I think we will have good evidence around tolerability and safety by the end of the year, proving that it is differentiated from efficacy standpoint or an antitumor activity standpoint is higher bar. And what we've seen so far with the first half dozen KRAS G12C (OFF) inhibitors, the first-generation inhibitors is that they all seem to confer a roughly 30% to 50% objective response rate in second-line non-small cell lung cancer caring KRAS G12C mutation. So we know kind of a benchmark that we have to at least be in the ballpark of that number. But that's not the number we're looking for true ultimate differentiation. What we're really looking for is progression-free survival and then ultimately overall survival because at this stage, with 2 drugs having accelerated approval, the game is really all about true long-term clinical benefit. It's no longer about objective response rates. That's just not an important parameter anymore, and we're not likely to focus on objective response rates. We just want to make sure the compound is behaving at least as well as others in that regard. And then you're going to see us really doubling down on how do we really smash these tumors and combining 6291 with 6236 is a high priority study for us to pursue. And as soon as we're in the dose -- in the range of recommended Phase II dose for 6291 and 6236, which may well be later this year, that's when we'll pull the trigger on a combination study, a lot of work going into that combination study as we speak now. So we fully expect to be able to pull that off.

And that would -- that would be the priority for the combination study, your RAS -- multi-RAS and your G12C versus the PD-1 combination?

Well, that's a very important question. We've spent a lot of time talking with investigators about what they think because that's an important part of our own considerations is learning from investigators who have been around all of these compounds now for the last several years. And we sense a very strong excitement about the 6291, 6236 combination, which mirrors our own preclinical data and our own assessment. With regard to PD-1 ultimately in first line, one is likely to have to play with PD-1 and have it be part of your regimen, but a single agent combined with PD-1 that is a single G12C inhibitor combined with PD-1 just may not be sufficient to move the needle. And so we are really going more for the 6291-6236 combination and then eventually bringing in PD-1 into that combination as well. And so that might be really a fantastic combination where you take advantage of all the immune benefits of the RAS (ON) inhibitors plus the PD-1 checkpoint inhibitor and put all those together into a package. And if patients can tolerate it, if that regimen is tolerable, it has real promise.

Got you. And then would that be an accelerated approach randomized? How should we think about the...

It's hard to say that a doublet or triplet will be an accelerated strategy even if you mean lower case accelerated, that is a little bit of a slog from an operational point of view. I don't think we're that focused on accelerated approvals, and I think the field of oncology is generally needs to be much less focused on accelerated approvals, given the FDA's posture on it. Right now, the endgame for us is to develop the most active beneficial therapeutic regimen we can on behalf of patients and let the registration time line just work itself out. Now along the way, we might generate sufficient data for the FDA to consider whether something should be approved on an accelerated basis, but it's really -- it's not our priority. Our priority is to get the best regimen optimal dosing into the right patients.

I'd love to move on to the SHP2 kind of, I guess, initially, how do you see the differentiation of your molecule or your combination versus, say, the Roche Relay combination and others out there?

Well, we were among the earliest to bring a SHP2 inhibitor into the clinic. We invested a great deal of time in optimizing the dose regimen for RMC-4630, which is a very clean and active SHP2 inhibitor, very well behaved, but it does carry with it the same general side effect profile of RAS/MAP kinase pathway inhibitors, which is that normal tissues don't like to have their RAS pathway suppressed, and that can lead to gastrointestinal manifestations, skin rashes, edema, a number of different things that are well described for the BRAF inhibitors for MEK inhibitors for ERK inhibitors. So we worked very hard on the dosing regimen to try to design a strategy that would maximize antitumor effect, but minimize impact on normal tissues, and that led to an intermittent dosing regimen we landed on a day 1, day 2 weekly schedule. So for example, Monday and Tuesday, patient takes a dose on each of those 2 days and for the rest of the week doesn't take a dose. And that leads to very high Cmax and above IC50 exposures for many days of the week and then allows normal tissues to recover towards the end of that week cycle when the drug concentration dips below the IC50 and then we hit the tumor again the next week with the same regimen. And we think that, that is the best approach for RMC-4630. No other compound has been tested with such an intermittent regimen other SHP2 inhibitor. There may be differences in the inhibitors themselves, but I think the dosing regimen is probably the most differentiating feature. And now we are in the throes of accumulating data from a combination study with sotorasib, so RMC-4630 plus sotorasib, both dosed at their optimal doses and regimens and we expect to read that out later this year. And we will see whether the tolerability benefit of our dosing regimen translates or whether the combination with sotorasib is tolerated sufficiently for patients to stay on drug long enough to get the benefit. And if so, what level of benefit do they receive. And we've set a reasonably high bar for that. I mean there's no reason for somebody to take an additional drug if it's not really moving the needle for them clinically. So we're looking with response rates, but also more importantly, even duration of response, and we'll have a good sense of that later this year.

Okay. Do you think it -- that benefit plays out in depth of response? Or is it duration?

I think duration is the most important thing. I'm not sure patient would be able to tell if they had a 32% response or a 45% response. I'm not sure that would matter much but whether or not that response lasts for 6 months or 12 months or 18 months makes a real difference. So I think we're most interested in durability of response. And one of the limitations of sotorasib and adagrasib has been that only a fraction of patients even show a response. And then when they do, it's not a particularly durable response. So I think durability is the main thing for us to try to extend and the data will tell us whether it does that or not.

Got you. And then for Phase III, would you continue with Amgen? How does that work? Would you slip -- you add your own G12C in?

Yes, of course, our pipeline is designed ultimately to have intra-pipeline combinations. And now we have 2 RAS (ON) inhibitors in the clinic. We have our KRAS G12D selective RAS inhibitor called RMC-9805, which is about to enter the clinic. And so we will be a company with 3 RAS inhibitors in the clinic plus 2 companion -- potential RAS companion inhibitors. We're clearly most focused on developing our pipeline, but we have a very good relationship with Amgen. And if the data are supportive, we'd be certainly open to talking with them about what the next steps would be.

Got you. And then how -- where do you think you are versus competitors for generating, whether it's Phase III data or a potential approval with a SHP2?

SHP2 compound, well, it all comes down to what the Phase II study shows. As far as we know, this is the most significant Phase II study design and trial underway. So we think it will be a very important readout. And it just depends on what it shows. I don't have the answer today. But once we know that, we'll be able to answer your question about where does that lead.

Got you. And what's the bar to continue to move that forward in the sense of duration since that's the key aspect here?

Well, progression-free survival by sotorasib treatment in second-line lung cancer is something like 6 months. So it's not -- it's not yet providing the kind of benefit that as a monotherapy really moves people. So that's what we want to improve upon and what's the number to achieve that improves upon that. I'm not going to get into that today, but I think it will be pretty obvious whether or not there's something to continue pursuing.

Got you. And I've got a, I guess, final question and the same bond question is just going back to the rash, how severe is that? And in clinical trial sets very different in the real-world setting could that preclude the use of your multi-RAS?

We see no evidence that it would preclude the use of it, as I mentioned, with as far as I know one patient having a dose reduction, if you look across all drugs and particularly all the KRAS G12C inhibitors, they are far more patients discontinuing drug for dose-related side effects than the number I just mentioned to you. We -- there's a lot of experience with RAS pathway mediated rashes, including EGF receptors, all of which whether it's an antibody or a small molecule, we've had decades of experience with those. And most patients do develop rashes. And for most patients, it's tolerated and for most patients, for many patients that actually results on its own in the historical experience. So I don't think we have any reason to expect that it will be materially impactful in terms of patient treatment.

Got you. Thank you so much for the way past the development of the [ asset ]. So thank you so much, Mark, for your time today. Next up for us is because we've got a [indiscernible] on ovarian cancer, which is -- appears to be really timely, and that's 8:00 tomorrow. And then next Tuesday, we've got Tango Therapeutics for a fireside chat. So Mike, once again, thank you so much for the time today.

Thank you, Peter. Appreciate it.