All right, great. Well, I'm excited to kick off day two of the Guggenheim Oncology Conference. The first company this morning is Revolution Medicines, and we have Mark Goldsmith with us, CEO. Mark, welcome, and thanks for joining us.
Thanks, Michael.
Maybe just starting off with a high-level question, Mark, Revolution Medicines has obviously generated a portfolio of mutation selective RAS inhibitors targeting the GTP-bound or active form of RAS, which is differentiated from currently approved KRAS inhibitors. Could you talk about the scientific mechanism of why RAS(ON) inhibitors could potentially be differentiated from the currently approved agents?
Yeah. Thanks, Michael. Thanks for the opportunity to speak here. You know, there's just one form of RAS that is oncogenic. It's the RAS(ON) or GTP-bound form. It seems from first principles that that's what you'd want to inhibit if you wanna disrupt oncogenic signaling. The reality is that people have been trying for decades to inhibit the RAS(ON) form. There just hasn't been a drug discovery strategy that opened that up. The RAS(OFF) inhibitor simply came out of Kevan Shokat's laboratory that came up with a way of doing it to the RAS GDP-bound or RAS(OFF) state. Quite remarkably, that works.
It doesn't work fully, and it allows many tumor cells that are dependent on RAS to evade the RAS(OFF) inhibitors by shifting the pool of RAS proteins from off to on, they no longer can bind the RAS(OFF) inhibitors, and then they can therefore escape the inhibitory effect. We think on first principles, inhibiting RAS(ON) is the better way to go. Empirically, several years after we started doing this, I think the cumulative evidence is very supportive of that, of that theory.
Our preclinical work, which has been quite extensive and much of which we've put out in the public domain, has shown quite consistently that inhibiting the RAS(ON) state, drives a much more, or induces a much more, deep, and robust, meaning sustained, suppression of RAS signaling and therefore tumor growth, inhibition. That's what we've seen so far across the entire collection of the RAS(ON) inhibitors that we've developed.
Right. Maybe let's talk about some of those. RMC-6236 is your most advanced clinical stage, RAS inhibitor. Could you talk about, you know, about that drug, what makes it unique, and how is it positioned within your portfolio, in general?
Right. RMC-6236, we call it a RAS multi-inhibitor. It's often casually referred to as a pan-RAS inhibitor, roughly the same thing. It's a very bold concept, and that is to target not only the known initial mutant driver of a RAS-dependent tumor, but also to target all the other forms of RAS that are carried in the same cell because, in reality, those other RAS proteins can be recruited to contribute to the oncogenic process, and I think the evidence for that is now very strong. If you think about it, there are three different forms of RAS or isoforms, KRAS, NRAS, and HRAS, that are present in almost every cell, and each of those has two gene copies.
If you have a mutant, let's say a G12D allele, only one out of the six alleles in a tumor cell is that G12D, and the other five represent other forms of RAS. Because those other five can be recruited by the tumor cell to help support its growth, we believe that there is risk that a pure mutant-selective inhibitor that targets just the initial mutant driver will not have a sustained suppressive effect and will eventually be overcome by the tumor. That, in fact, is what we've seen in the clinic. The RAS-off inhibitors typically don't provide very sustained benefit, and one of the multiple reasons why that occurs is because other forms of RAS are recruited. RMC-6236 is intended to cover the entire collection of RAS proteins in a cell.
It is a very attractive from an efficacy perspective, but of course, the reason I said it's bold is because there are wild-type forms of RAS proteins in every other cell in the body, and this compound, RMC-6236, will, to some degree, inhibit all of those RAS forms in normal cells. It's a race between efficacy and safety or tolerability, and we believe, based on preclinical work, that there will be a therapeutic window, but we're trying to maximize the absolute level of tumor suppression rather than just the relative level. The key question in the clinic is will humans reflect what we've seen preclinically, and will we be able to get to that level of suppression without inducing intolerable side effects?
Right. You know, that's obviously an obvious, you know, debate, or not debate, but maybe a concern to some.
It's a debate.
Right. What, I know you've made some comments recently about the ongoing phase I trial, which is underway.
Yeah
... just remind us of, you know, how that study's been going so far and, what you expect to share later this year.
Right. Maybe just to continue the thought on this sort of debate about will this be tolerable or will it not. You know, the history in targeted oncology therapeutics actually has not been focused on mutant selectivity, even though in recent years that's started to emerge. If we go back to the compounds like erlotinib, Tarceva, in the early days, which was a very successful drug in lung cancer. It targeted the EGF receptor, but not just the mutant form. It targeted the wild type form. In fact, it was accompanied by, it is accompanied by side effects such as skin rash, GI toxicity manifests as diarrhea, maybe bone marrow suppression, these sorts of things which we consider RAS side effects.
Yet, if you had an EGFR-driven tumor, a mutant EGFR-driven tumor, taking erlotinib was very likely to give you some clinical benefit. It was a wildly successful drug. The next generation, osimertinib, came along and said it's mutant selective, and now we're gonna give you more bang for the buck. It turns out osimertinib in humans is not mutant selective either. It also inhibits the wild type forms of EGF receptor because of an active metabolite that is, has lost its mutant selectivity. Osimertinib has taken over the market. It's a multibillion-dollar drug. It's widely used by patients with EGF receptor mutations driving their cancers, those patients often have side effects. They have, they can have skin rashes or diarrhea. That's quite common, yet patients benefit from it.
I want to sort of level set that. The concept of pure mutant selectivity has emerged much more recently than that. That gives us some reason to believe that in the clinic it is possible actually to inhibit all the forms of RAS, as I mentioned with RMC-6236, and as I mentioned preclinically, that's what we've observed, is that the animals can tolerate it, and we can have dramatic effects across many tumor types. Your question was about what have we seen in the clinic so far, I did mention just last month at an investor conference that dose escalation in humans has been going well so far. It's generally been well-tolerated. It's behaved well. It's behaved like a drug. It has proven to be orally bioavailable.
We're getting good plasma exposures, very consistent with what we had predicted preclinically. We're seeing dose-dependent increases in plasma exposure. These exotic compounds, these we call them tri-complex inhibitors, they're larger than typical small molecule drugs, and they have a mechanism of action that's different from others in the field, are nonetheless behaving like fairly like traditional small molecules. We have not yet reached a maximal tolerated dose. We haven't declared a recommended phase II dose, so we just haven't gotten to that level yet where we're seeing enough side effects that that would be a problem. In the multiple dose levels that we've tested so far, it has actually been generally well tolerated.
We'll continue seeking to reach a maximal tolerated dose. Of course, we wanna report on this. We've indicated that midyear this year we expect to be able to provide an initial data readout from this study. It would be, you know, in roughly in the timeframe of about a year since we started at the time that we provide that dataset. It should include not only drug exposures and tolerability and safety, but whatever we're seeing in terms of early clinical activity.
Can you talk a bit about, what types of patients have been enrolling in the study?
Yeah.
Also just given, how the molecule is designed, you know, what level of efficacy one would expect perhaps relative to your more single mutant selective agent?
Yeah. With RMC-6236, so far what we've talked about is how it also hits wild type forms of RAS, but what we didn't emphasize, and I think your question really invites now, is that it's also inhibiting every mutant form of RAS that we've ever tested, which is virtually, you know, we've probably tested 95% of the known RAS mutants that cause human cancer or maybe even 99% of them. It has the potential to be active against all those mutant forms, all those mutant drivers of cancer as a single molecule. It's, it's quite astounding and in every genotype that we've tested in an in vivo model we have seen antitumor activity. It has potentially very broad activity, you know, quite exciting. It will have limits.
Just to be clear, I'm not suggesting that there won't be an MTD. There will be a dose at which we can't, patients won't be able to tolerate more than that. There will be a ceiling, and we're just trying to navigate getting in the active range without hitting that ceiling. Your question was what are the tumor types that are enrolling in the trial or the patients with tumor types? You know, what we're seeing is what you'd predict. The most common mutation, RAS mutation that causes human cancer is KRAS G12D. That's the most prominent mutation that's showing up in patients who are enrolling in the trial. The next most common is KRAS G12V. That's roughly the most, second most common mutation that we're seeing in the trial, and so on.
I think the genotypes roughly reflect the epidemiology in the population, roughly speaking, and the histologies also reflect where those genotypes are, which is your major epithelial tumors: lung cancer, colorectal cancer, and pancreatic cancer, and then a smattering of other things, but those are the most common for sure. The unmet needs across all of these mutations are very, very high. I mean, there are no targeted agents for any RAS cancer driver other than KRAS G12C. At the moment, we exclude patients with KRAS G12C from the trial. That's really a logistical decision that those patients have available to them now, two drugs that have accelerated approval in the U.S. Asking them to participate in the early dose escalation of a RAS multi-inhibitor doesn't make sense to us.
They'll come back in later as once we hit a recommended phase II dose and schedule, we will be in a position to start thinking about how do we also address the KRAS G12C population.
I guess how active would you expect RMC-6236 to be in a clinic relative to the mutant selective inhibitors?
Mutant selective inhibitors.
... how may that affect your development plan for the drug?
Yeah. It's really, really hard to answer that question. I mean, I think we've probably spent millions of dollars in vivo experiments sort of trying to figure out how these things work relative to each other. You know, all of them are so active that finding resolution that differentiates them so far just really hasn't been very easy. For example, if we compare our KRAS G12C inhibitor, RMC-6291, with our RAS multi-inhibitor 6236 in a KRAS G12C model system, you wouldn't be able to tell, at least we can't tell. Maybe you, maybe others in the audience would, I can't tell or at least our team can't tell what's the difference. They're very, very active. There's...
There seems to be a trade-off here between the dose levels for RMC-6236 will be probably lower than they might be for a mutant-selective inhibitor because of the potential tolerability effect. I would guess that. You might argue, well, if the total exposure's lower, you're getting less target engagement, somehow that's gonna lead to less effect. We haven't really seen that. You know, we can dose those preclinical models at, you know, 10 mg/kg. and have just dramatic antitumor effects with RMC-6236. I don't think we know. The upside of 6236, as we said right from the beginning, is that it's hitting all the other RAS in the cell. It's actually more active, but it also carries this tolerability risk.
I don't think we know the answer. You know, maybe another way to look at it though is that with the mutant selective inhibitor, assuming you don't have off-target effects, which maybe we could come back to in a moment, but assuming you just have a really clean compound that's only hitting G12C, so far no such compound has been reported by the way, because patients are experiencing a lot of side effects. Let's just suppose you had the perfect pure G12C inhibitor and that had no other side effects. In principle, you could dose that drug much higher than you could a RAS multi-inhibitor, and therefore you could just pound away and just really crush that G12C. You'd leave open all the other forms of RAS, but at least you'd really hit that G12C hard.
In theory, you might argue a mutant selective inhibitor could be more active, but I don't think in practice that's gonna be the case, and preclinically that's not what we've really seen.
Okay. The fact, I guess, how close are you to... You said you have reached an MTD yet. You hope to report clinical activity by midyear. Does that suggest you're in an active dosing range at this point?
I'm not gonna comment on what it might suggest or what you might infer. I'm gonna leave it at that. We've escalated through multiple dose levels. It's gone very well. It's gone smoothly. We continue doing that. We've not reached an MTD, so we're somewhere between the earliest dose level and our recommended phase II dose and schedule, and obviously we'll report on that when we're able to make, you know, a more fulsome disclosure about it.
All right. Well, we look forward to that. Maybe a couple of questions on 6291, which is your G12C inhibitor.
Mm-hmm
that's also in phase I.
Yeah.
You know, again, you made some comments a couple weeks ago as well. It sounds like the trial is lagging a bit behind the 6236 trial. Perhaps talk a bit about, you know, how the study's been rolling, what are you seeing in terms of patients that are coming-
Yeah
... into the study and how you see that evolve over the rest of the year.
Yeah. I'm still a little reluctant to use the term lagging behind. It actually started a quarter behind RMC-6236, and I'd say it's sort of keeping pace. I'm not sure it's lagging. We started it after the 6236 trial, and one difference that I did state, and maybe you're capturing this in your question, is that the interest level of 6236 by investigators and patients has been quite extraordinary. It's extremely high. The clinical sites we have open have very long waiting lists by patients to get in, and that doesn't really make me happy because that means that there are a lot of patients who desperately need, you know, a drug. We have no trouble enrolling cohorts.
The cohorts are typically screened and ready to go by the time we release the slots. The investigators already know which patients are going into those slots, so that it's very competitive in that sense. That's not true for RMC-6291. It's a, it's a very lovely G12C selective inhibitor. It works by the RAS(ON) mechanisms. It's extremely active in preclinical studies, and it's the first compound to go into the clinic in the G12C space that is highly differentiated from all the other G12C inhibitors. It's really in a, it's in a class of its own at the moment. Investigators are interested in it for that reason. They've kind of come around to think that all of the KRAS G12C RAS(OFF) inhibitors are pretty similar, and I think that's what the data so far that's been released publicly suggests.
They're hopeful based on the preclinical work that RMC-6291 may actually be clinically differentiated, and that's what we're there to test. They're not uninterested in enrolling patients, but there are fewer naive patients, that is not previously treated with a G12C inhibitor, available in the U.S. Despite the commercial constraints that Amgen has seen so far, the fact is a lot of patients are getting the opportunity to get on sotorasib, and that will happen with adagrasib too. There are just fewer patients available. We actually allow pre-treated patients into the trial in this early stage just to make sure we're able to get going on dose escalation. We're seeing a mix of some non-previously treated and some pre-treated, and we're dose escalating. It too has proven to be orally bioavailable. It's been well-tolerated.
We are dose escalating, have escalated through multiple dose levels, and we expect to be able to report something later in the year.
Okay. Then how do you think about RMC-6291 development longer term?
Yeah
... just in the context of probably, you know, fully approved, inhibitors in a second.
Right
line lung cancer setting, maybe colorectal as well? Yeah.
Yeah. Right. you know, coming in as the eighth or eighteenth G12C inhibitor, I'm not sure what the number's gonna end up being, it sure better be differentiated in some way. That is our ambition. I think we've been very open about that. We're not interested in being, you know, the eighth or ninth in class. It's not in class. It's a very distinct molecule. We think it has the potential really to move to the head of the line. However, I wanna just sort of set expectations. Conceptually, the field has moved on from monotherapy and G12C treatment, even though what's p-approved right now is only monotherapy. Conceptually, everybody knows we're gonna need to be in combination strategies, that's what people are already working on with sotorasib and adagrasib.
In fact, we are working with Amgen on sotorasib and combining with our SHP2 inhibitor, and there are a few other things going on as well. to play where the puck is going to be, to use the old, you know, hockey analogy, you know, we're planning to be in the combination realm, and I think it's probably the case that RMC-6291 won't be pushed as a monotherapy strategy simply because we need to really move the needle here. We need to make a real difference for patients that goes beyond what's been reported for sotorasib and adagrasib monotherapy. a combination strategy is gonna be likely the way to do it.
One of the most exciting combinations that we have in mind here, this may be a head spinner for folks, but it is combine our RAS multi-inhibitor, RMC-6236, with our RAS G12C inhibitor RMC-6291. We have seen pre-clinically that that can overcome some tumor resistance that causes relative lack of sensitivity to either of the agents alone, but when combined translates into quite dramatic antitumor responses. This is a chance for us as a still relatively small company to be combining two assets from our own portfolio. Each of those assets is currently in the clinic, we hope to get to a point maybe later this year where we can begin putting these together to treat non-small cell lung cancer and potentially other other tumor types.
We believe that has real potential, to go beyond what the monotherapy can do.
You know, commercially less relevant, but thinking about the phase I study, I guess, would you expect 6291 to be active in patients that have progressed on a prior KRAS inhibitor?
Yeah. In some, very likely to be the case. There are multiple mechanisms that allow progression on KRAS G12C monotherapy, KRAS G12C inhibitor monotherapy. There's a range of different things that go on in cells that permit that. Some of those RMC-6291 will clearly overcome. That's what we've seen pre-clinically, and some of which RMC-6291 will not overcome. Let's go back to the point I made at the beginning. If wild-type forms of RAS have been recruited into the tumor and are now contributing to tumor genesis, RMC-6291's not gonna help that because it's very G12C selective. That sort of points to why we would think about combining what we think will be a very good G12C inhibitor, RMC-6291, with a very good RAS multi-inhibitor, which we think is RMC-6236.
Yes, it will probably affect some patients, but we'd like to provide the most impactful combination strategy that we can.
Right. All right. Great. The data you said will come around year-end. Is that correct?
Later in the year.
Okay.
We haven't, you know, been more specific than that. Obviously, we're still in dose escalation, so it's hard to be too precise about that. You know, it's coming along fine.
Sounds good. In the last couple minutes, maybe just touching on 9805-
Yeah
... which is your G12D inhibitor. You recently disclosed the molecular profile of that candidate.
Yeah.
It is a covalent inhibitor, I understand. Maybe talk about some of the key characteristics and why it is so interesting or differentiated.
RMC-9805 is our KRAS G12D entrant. It is highly mutant selective, which is something we achieved through covalency. No drug known to humans, or at least known to us, has ever targeted an aspartic acid residue in a protein through covalency. It has been said as recently as last year, I think at AACR, a speech was given by a very prominent individual who said it's not possible to do that. Well, we had already done it by that point, and we had used our really remarkable chemistry platform to do something that frankly we didn't even think we could do.
We put a team on it, and they were determined and found a way very smartly to engage that aspartic acid, and they've designed a molecule that engages only that aspartic acid. It doesn't work on KRASG13D. It's only covalently bound to KRASG12D, just to give you a sense of the specificity. We think that's powerful because that provides for very sustained effect, and of course covalency has been very useful in the G12C inhibitor, so it's really the same thing now playing out. KRASG12C accounts for 15% of all RAS tumors. KRASG12D, much higher % than that. In fact, D and V together account for 40% of all. You know, it's G12D is a much more common driver of human cancer.
Great. That's going into the clinic this year, I believe?
Yes. We expect it to be in the clinic, mid-2023. I'm thinking about we're already in February. Mid seems like it's almost tomorrow. I mean, we're there. We're now doing the work to get together for the FDA, et cetera.
Great. Thanks. Unfortunately, our time is up, so we need to wrap up. I know you also did, guide to presenting data from your SHP2, Lumakras.
Yeah
by year-end, correct?
Yes. We are on track for that. We're more than 80% rolled into that global phase II trial. We will see what it shows, and that will help determine what's the path forward.
Thank you, Mark. Really appreciate it.
Thanks very much. Yeah.