All right. Thank you, everybody, for joining us. I've got David here from Erasca. Thanks so much for coming down, and let's jump right into it.
Yeah, thanks for having us.
So Erasca, a smaller company entering the RAS space in a very real way. There's been a ton of recent interest in next-gen RAS approaches, other pan-RAS approaches, pan-KRAS, inhibitors, degraders, all over the space. We're seeing a lot of innovation. So can you walk us through how you're positioning your two assets relative to incumbents in the space and other next gens?
Yeah, absolutely. Thanks for the question, and again, thanks for having us here. So Erasca, as you mentioned, we are an oncology company. We're focused on the RAS-MAPK pathway. In fact, our name is not only to erase cancer, but to eradicate RAS-driven cancers. And so both of these RAS agents, which we brought in from China in May of last year, are squarely on target with that strategy. We have two programs. ERAS-0015 is our pan-RAS molecular glue, and ERAS-4001 is our pan-KRAS inhibitor. Now, with regard to both of them, let me take them each in stride. So 0015, the pan-RAS molecular glue, if the audience is familiar with the Revolution Medicines' 6236 compound, the RAS(ON) inhibitor, this one works through the same mechanism of action as 6236, but we think that it has a number of differentiating features, at least preclinically.
Starting first with the fact that it's got better binding to cyclophilin A, which is the first step in forming the tripartite molecule. We've got about 8- to 20-fold better binding to CypA. That leads to a number of advantages, including better potency on the order of about 4- to 5x greater in vitro potency across 15 or 20 different cell lines that we tested. It's also got greater in vivo activity in the form of we need about one-tenth the dose to achieve comparable anti-tumor activity. We also see better tumor PK kinetics in terms of distribution into the tumor, as well as residence time of our drug versus 6236. And then finally, that molecule also has better PK properties relative to the RevMed molecule in terms of longer half-life, lower clearance, and higher oral bioavailability.
So a number of different preclinical advantages that we think could translate into a nice profile in the clinic, and I can talk more about that. Where we see the space evolving is that just given the high unmet need, 2.7 million patients that are diagnosed annually with RAS mutant tumors, and the relative lack of competitive intensity, at least in the pan-RAS space, the fact that there's really RevMed, and then there's us, and then there's a few smaller players. But just that difference of the vast number of patients, but the small number of players in the space can easily support two players like us and RevMed. And therefore, we think the bar for us in this case is not inferiority. And of course, if we can show a superior profile, all the better.
Our second program, ERAS-4001, the pan-KRAS inhibitor, this is a program that we like as well. There is less information from competitors in terms of what clinical structures look like in the pan-KRAS space, as opposed to the pan-RAS space, where we were able to do head-to-head comparisons versus RevMed, but in the pan-KRAS space, without those clinical structures, we haven't done head-to-heads, but we still like our molecule in terms of it's got very good activity in vitro against KRAS G12X mutations, G13, KRAS wild type, which is important when you talk about adaptive resistance. It's got good in vivo activity. It's got good admin PK properties, and then importantly, that molecule is actually built off a different scaffold than most of the other pan-KRAS molecules.
And so to the extent that some of those molecules, if they have a scaffold-related issue, our molecule being on a different scaffold could provide a unique advantage there. So we're excited about both programs. I know we'll talk more about both of them, but that's just the high-level overview of them.
Fabulous. Let's start with the pan-RAS, the molecular glue. You mentioned a couple of different potential differentiating factors versus RevMed. And obviously, the RevMed molecule has some great results, but it's not perfect. So can you walk through the clinical differentiators that you would hope to be able to see in an early-stage study? What would be the first signs of potential clinical differentiation?
Yeah, absolutely, and we think RevMed, they've done a great job in terms of trailblazing in this space. I think hats off to them in terms of just their ability to show that pan-RAS is a viable target to go after and see good results there. There are areas for potential improvement. As I mentioned, the bar for us is not inferiority, and again, the reason for that, just the high unmet need and also the lack of competitive intensity, but I think for us, as we think about our data disclosure, which we've guided to having data for both of those programs, 0015 and 4001 in calendar year 2026, the way to think about those data disclosures, and I'll start first with 0015, is we want to be able to tell an interpretable story, and so think about this being dozens of patients.
We'll share, of course, safety, PK, and of course, everybody is very much interested in what the initial signs of activity look like as well. And so we'll share that as well. I think in terms of a few different areas for differentiation, I think if we're able to show dose-proportional PK throughout the dosing interval, I think that would be a win, just given that there's been more of a flattening of the PK curve.
Probably RevMed is limited on the top of the dosing curve.
That's right. Yeah. I think if we're, from a safety standpoint, if we show comparable AEs, that would be a win, a home run scenario. But I think if we're able to show an improvement in the AE profile, either on GI or skin, that would be a grand slam. In terms of efficacy, one of the reasons that we brought the program in was that we felt that we would be able to achieve comparable anti-tumor activity at a fraction of the dose. And I think if we're able to do that, that would be thesis reinforcing. And then the question is, to what extent, what fraction of the dose are we able to achieve? And so if we're able to, for instance, achieve half of the dose or less of RevMed, that would be the home run scenario.
I think if we're able to achieve a quarter of RevMed's dose or lower, that would be the grand slam scenario. And then thinking about further, as we get to more of the recommended dose, the RD or the RD minus one, and we have enough patients in that set, again, if we show a comparable efficacy profile, that would be a win. And if we show anything above that in terms of superior efficacy, that would be even better.
You mentioned two things that jumped out at me on the safety and the dosing side. And for RevMed, those things do seem very tightly connected to me. There's on-target tolerability issues, and you mentioned some of the skin tolerability issues. But some of the GI tox is surely driven by very high doses that they're giving. Do you have an opportunity to disambiguate the different sources of tolerability in your program so that we can see some differentiation there?
Yeah, it's a great question. So I would say that their number one and two AEs are rash and GI. On rash, that is most likely to be on target, and so we will probably have rash ourselves. GI, it could be related to on target. It could be related to drug load in the GI tract. It could be related to both. And so to the extent that it is related to, at least in part, to drug load in the GI tract, then having a lower biological dose, as we anticipate that we will have, could be an advantage from a GI perspective. So we'll have to see that once we have enough clinical data to be able to make that determination.
And now, of course, there are even otherwise prophylactic kind of approaches that you can do both on RAS, which we have a lot of experience with, but also on GI as well.
One of the other things that always comes up in these conversations is duration of therapy and mechanisms of resistance. Most of the incumbent RAS and KRAS-directed therapies have shown amplification of KRAS as a key mechanism of resistance. It's been challenging to dose through for a lot of the incumbents. I assume that when we see the initial data next year, we're not going to have full duration of response or duration of therapy. But are there ways that we can start to think about the potential for durability or the potential for differentiation on these mechanisms of resistance that are critical to the class?
Yeah, you're absolutely right about the premise in terms of just the RAS-MAPK pathway is so wily in terms of being able to find ways to continue to signal, even in the presence of inhibitors or whatever that we are able to throw at it. And so yes, resistance is a key thing that we're looking at. I think it'll be really important to see what that looks like. Our pan-RAS molecule 0015 has very good in vitro potency against not only certain mutations like the G12X, G13, Q61, but also against KRAS wild type amplification. And so we'll see how that profile translates in the clinic in terms of its ability to prevent some of the resistance, especially through amplification.
And you have both RAS on and RAS off binder?
So the SHOC2 binders like us and RevMed, the 0015 compound specifically, they're more of the on inhibitor. 4001, our pan-KRAS, has activity against both the on and the off state. So it's got single-digit nanomolar potency against both, albeit more potency against the off state, the GDP state. But so KRAS wild type amplification is a very important mechanism of resistance, as are others. We'll see in terms of how our data evolve in terms of the ability of our molecule to shut down the development of resistance either by itself or ultimately if we need to combine it. That has historically been the approach in the RAS-MAPK pathway that combinations are important, and that's also a great way of getting at resistance.
That's a great segue to a topic that we've discussed in the past, which is colorectal, a space where the other molecular glues have trouble because of overlapping tolerability concerns. It's Cetuximab. Can you talk a little bit about how you're approaching colorectal or what your expectations are there?
Yeah, you're absolutely right. I mean, I think if you think about, again, the number one AE with the 6236 compound is RAS, and then you think about combining that with an anti-EGFR like Cetuximab or Panitumumab, then you're probably going to get a lot of overlapping RAS. And so one approach that we have, and we are unique in this regard in terms of, I don't know of really any other company, maybe one or two of the big pharmas that have both approaches in terms of pan-RAS and a pan-KRAS. And so that allows us to really see where the field evolves in terms of my sense is that there's probably certain swim lanes for each of them.
And so that the pan-RAS, for instance, if you look at where RevMed, for instance, has disclosed the most data, it's in PDAC, and it's also in non-small cell lung, very little in CRC. And so maybe there's an opportunity for a pan-KRAS in CRC because it spares H and N. Maybe it has a better RAS profile that allows you to combine with anti-EGFR. We also, as I was alluding to earlier, have a lot of experience not only as a field, but also as Erasca specifically in terms of how to address RAS. The anti-EGFRs have been around for a couple of decades, so doctors have a lot of experience with handling RAS through prophylactic regimens and otherwise.
GERD profile was a key component of the earlier program.
Yes, that's right. We had a pan-RAF program, Naporafenib, that we implemented primary RAS prophylaxis, and we saw profound benefit from doing so, and so there's a lot of things you can do, but of course, if it turns out that either our 0015 molecule or 4001 has a better RAS profile than some of the others in the space.
Absolutely.
Colorectal.
Yeah.
Excellent. So let's segue then into 4001 a little bit. You mentioned data from both programs coming calendar year next year. Can you talk a little bit about what your expectations are for the differences, not necessarily in the molecular profile, but the differences in the patient populations you're going to get in those trials, what you'll be able to share with the street when that data is available?
Yeah, so that update will also be similar to what I described previously in terms of we want to tell an interpretable story. We want this will be dozens of patients as well, of course, looking at PK and safety and tolerability and initial signs of activity. So that will all be very similar. I think in this particular case, because nobody has disclosed any pan-KRAS data, we don't have that comparator to be able to say that this is exactly what the bar should look like. I can give my thoughts on that initially in terms of we want to be able to see dose-proportional PK. We want to be able to see AEs that are in line with kind of the broader class, including the mutant specifics.
We want to see any signs of activity would actually be first in class in this space, just given the lack of any clinical data that's been disclosed. Now, in terms of the patient populations, it'll largely be similar in the sense that if you think about where KRAS mutations are found, whether you're talking about 0015 or 4001, there's generally the big three with CRC, PDAC, and non-small cell. There's also the long tail of opportunities, and those are actually still pretty sizable, tens of thousands of patients in the U.S. that are diagnosed with some of those opportunities. And so the ability for us to enroll across that will probably largely mirror the epidemiology, although we do have the ability to, if we so choose, to put our thumb on the scale and enrich for certain patient populations, especially as we get closer to our RD and MTD.
I'm asking specifically because of the comments you just made about colorectal cancer and the experience that we've seen from the other pan-RASes in the indication. I might expect there to be some possibility that docs would be less enthusiastic to enroll a CRC patient in the 0015 study, but might be more amenable in the 4001 study.
Yeah, that is possible, especially in the early part of a dose escalation where you're trying to get to your relevant doses.
Relevant.
Yeah, but as you get later on in the dose escalation, as I mentioned, we can put our thumb on the scale to enrich.
Excellent. When you share data, would you expect to be sharing both molecules in a similar timeframe? Calendar year next year is a broad window, but would both molecules come together? Should we be expecting to see them next to each other?
Yeah, we put out the data guidance at J.P. Morgan earlier this year, and so that's why it's broad-banded. This was before we even filed the INDs on the molecules, which happened in April of this year, clearance in May. So now that we have a better sense of what enrollment's looking like and how the studies are moving along, we should be able to tighten that guidance soon. Now, with regard to how the data might be released, we can do either. We can either put them together or we can separate them. The goal is that we want to be able to tell an interpretable story, and so if that happens at the same time for both, great. If that happens at different times, that's fine too. Historically, as a company, we've shown that we can do medical meetings.
We can also do R&D days, and so it could come at either of those. All things being equal, we prefer medical meetings, but sometimes you can't always get the timelines to line up.
Now, you mentioned that there's not a good existing data comp for efficacy in the pan-KRAS, but is it fair to think about mutant-specific inhibitors or pan-RASes as a reasonable bar for potential adoption in the overlapping populations?
I think at least initially, yes, that is a reasonable bar. I mean, I think we'll have to just see what the data overall look like. I mean, I think pan-KRAS, just taking that specifically, you would expect with a mutant selective because it should ideally only hit the mutant. For instance, it may have a better AE profile than a pan-KRAS that hits more broadly, including the fact that a pan-KRAS should hit wild type. Now, that could be a liability from a tolerability standpoint, but it could also be a benefit from a durability standpoint, as we were talking about earlier. So at least initially, yes, you can look at kind of the mutant selectives and the pan-RAS to kind of triangulate to where you should be.
But as more data come out, especially in the pan-KRAS space specifically, we'll see exactly what the profiles look like in terms of the safety, the tolerability, and the efficacy.
Now, both of these molecules, you have a Chinese partner, different partners, but there are.
Sorry, just to clarify that.
That's fine.
So on 0015, we have a partner called Joyo. That's our pan-RAS molecular glue. And then 4001, we actually have worldwide rights on that one.
So for the 0015 at least, they're running a study already in China as well in something like parallel with yours, but I believe their study got started a little quicker than yours did. What's your level of visibility into their data, and what are your expectations for their disclosure timelines relative to your own?
Yeah, yes. So we have a Chinese partner for 0015, the pan-RAS molecular glue, a company called Joyo, who we've spent a lot of time with and continue to spend a lot of time with. To your question about visibility, there's multiple levels of communication between the company, CEO to CEO, joint development committee, which I sit on. Our clinical teams and regulatory and other functions meet quite regularly. And so we have a lot of visibility into what's happening. I should also mention on that program that while they do have China rights, we also do have the option for a China buyout, which allows us to convert our territory to worldwide with a one-time payment.
Okay. But the second part of my question, I noticed you didn't answer.
Oh, I may have missed it. Sorry.
What's the likelihood of seeing their data ahead of yours, or do you have any visibility to the timeline?
Yeah, yeah. No, so we are, again, closely aligned with them, and so we know what their plans are. And we can control what we can control. They can control what they can control. That said, because of the multiple layers of connectivity between the organizations, we have a good sense of what's happening.
All right, fair enough. As we're wrapping up here, maybe just a last question. Can you lay out the broader possibilities, broader potential paths going forward in terms of next trials beyond just this phase one? What could development paths look like for these two molecules as we look forward beyond 2026 into 2027?
Yeah, I think this is a really exciting space for us because the unmet need here, as I mentioned, is huge. There are so many different tumor types that have KRAS mutations. And one of the things about our company is that we're well capitalized. We ended the last quarter with $362 million of cash. We've got runway to second half of 2028. What that means is that we've got the firepower to be able to really advance and prosecute these programs where we see the best signal. And for us to be able to really run where we see that signal, if that's in the big three, if that's in the long tail of opportunities, really leave no stone unturned. You can't really advance in this space if you've got a smaller balance sheet, $50 million, $75 million.
It's just not going to be able to give you that same visibility into what a pan-RAS or a pan-KRAS can do. And so because of that combination of both the cash balance sheet, but also the runway, we're going to go very aggressive. We've got multiple dose expansions planned.
All covered in the guidance.
Yes, yes, all guided within that. We've got even the initiation of the phase threes in that as well. So yeah, a lot of things that we can do with these programs and a lot of excitement about where we can go with it for the next operations.
Great. You've got lots of progress, it sounds like.
Yeah.
Fabulous. Awesome. Well, we are out of time, but thank you so much for joining me, David.
Thanks, John.
We look forward to seeing the data next year.
Thank you.