Good morning, everybody. Last morning's session today. Thank you for joining me, David. We have Erasca here this morning to talk to us about, well, about a couple of programs, actually. So welcome to Miami.
Thank you. Thanks for having us.
Our pleasure. So before we get into what I think is probably the meat for most folks on the new Pan-RAS, Pan-KRAS programs, let's start with naporafenib, where you're currently in SEACRAFT-2, a pivotal phase two, which will come out next year. Between the old Novartis data, SEACRAFT-1, it seems like you have a really strong base heading into the trial in NRAS mutant melanoma. Maybe can you walk us through where you stand on stage one of that trial, what we should be thinking about in terms of timelines and what the pushes and pulls are to get that earlier versus later in the year?
Sure, so SEACRAFT-2 is our pivotal study for NRAS mutant melanoma for naporafenib plus trametinib, that combination. We initiated that study in Q2 of this year, and what we've guided to is that we'll have data from the stage one portion of the study in calendar year 2025. Now, that study is ranged between 60 and 120 patients because it is open label, where we're evaluating two different doses of the combination of Napo plus trametinib versus single agent trametinib. Plus, we'll be able to look at the 3rd dose of 200+1 of Napo plus trametinib from the SEACRAFT-1 study, which data we disclosed at the Triple Meeting 2 months ago, and from those 3 doses of the Napo plus trametinib combination, we'll be able to choose 1 to go forward with into SEACRAFT-2 stage 2.
And so, because the 1st stage is open-label between 60 and 120 patients, that will in part drive when it is in terms of an earlier versus later readout in 2025, in addition to just the kinetics of enrollment. This is still early stages of the study, given that we just kicked it off in Q2 of this year. But I would say that investigator enthusiasm, site enthusiasm has been really high, just given the historical data plus the additional data that we shared in the SEACRAFT-1 update two months ago. And then I would say also the length of follow-up will be another driver of the timing in terms of when that data readout would happen. Obviously, the more follow-up there is, the longer it'll take to read that out.
So now you already do have a fair amount of data at various doses, given the stuff you've got from SEACRAFT-1, given the initial data you've got already from SEACRAFT-2 part one, as you say, it's open label. What are you looking for? What's the go, no go here in terms of dose selection? I mean, obviously safety and efficacy, but is there a key benchmark that will push you to final dose selection?
Yeah, I mean, I think it is exactly what you said, safety and efficacy. On top of that, so just as a reminder of what the data looked like historically, so when Novartis ran the phase I and II study, they showed very good responses in NRAS mutant melanoma. Specifically, if you look across the 2 primary endpoints for our phase three study of PFS and OS, the PFS pooled data across the phase I and II came in at about five months relative to the historical data for the control arms, which is the approved standard of care, chemotherapy, which has only about one and a half months of PFS. The single agent MEK is used off label per the NCCN guidelines. That is about 2.8 months of PFS.
So already from the phase I and II data from the Novartis run trials, we're seeing about a 2-3 X improvement versus chemo and versus single agent MEK. OS, which is the other primary endpoint of the phase three study. We showed from the phase I and II Novartis data about 13-14 months of median OS relative to the historical data for chemo and for single agent MEK that is around seven months. So about a doubling of the OS there. So we feel pretty good about how that data stacks up against the historical data. Now, the data that we showed at the triple meeting 2 months ago actually in some ways looks meaningfully better.
If I start first with the AE profile, I would say that the 201 dose in Novartis' hands did show good PFS and OS, but tolerability and particularly skin AEs were higher. We instituted mandatory primary rash prophylaxis as part of our SEACRAFT-1 and SEACRAFT-2 studies. Based on the data that we showed at the triple meeting, that looks substantially better than the historical phase one and two data. The rate of Grade 3 AEs dropped from about 35%-36 to about 11%. The rate of discontinuation due to AEs also dropped pretty significantly from sort of the 20-ish% range to less than 10. Then the relative dose intensity, which is a measure of how much drug a patient actually gets versus what they're supposed to get, went from about the 50-60 range in the Novartis run trials to 98.5.
A lot of discontinuations.
Exactly right. And in our hands, that was not happening. So both Napo and Trametinib were getting 99%-100 of the RDI.
It's that RAS therapy that's really keeping people on stage according to.
Yes, that's right, and beyond that, we think that that is also because patients are now able to tolerate the combination better, they're able to stay on longer, which is also leading to better response rates, and so if you look at ORR as a metric, I mentioned the phase I and II pooled data from the Novartis run studies, which showed at two different doses an ORR between 22% and 31. The data that we showed at the Triple Meeting in our hands with the rash prophylaxis. The response rate went up to 40%, albeit small patient numbers, but it's encouraging that that is moving in the right direction, and so not only are we seeing a better AE profile, but potentially a better efficacy profile as well.
Although you mentioned just a moment ago that both your data and the old Novartis data are tracking more or less towards that five-month PFS benchmark for median PFS anyway. That has been my base case expectation going into SEACRAFT-2 into part one. Do you expect to see the differences in dose on something like PFS? Do you need that much follow-up to tell the difference between the doses that you're going to be choosing between?
So I would say just maybe one clarification. The data that we have shared so far with regard to PFS has all been based on the Novartis data, not on our data, because the trials have been run.
You did give DOR.
We gave DOR, yes. Now, what I would say is that with regard to PFS, I think if we're able to show five months of PFS, if we're able to show 13- 14 months of OS like was shown in the phase I and II data, that would be a win. And again, the way.
But do you need to see OS in order to pick a dose and move to stage II?
No, no. In fact, we can actually make the determination based on other metrics of efficacy, as well as looking at safety more broadly as well. I would say that based on the data that we showed with the 201 dose at the triple meeting this year, that is our presumptive go-forward dose. And if there's an upside surprise on how the 400, 0.5 or the 101 dose, the two doses that are being evaluated in stage one, if there's an upside surprise on that, then that's just additional upside. But otherwise, that 201 could be our presumptive go-forward.
Looks sufficient to your expectations. All right, excellent. Let's move on from Napo. I would love to talk in some detail about the 0015 and the 4001 programs. The obvious competitor for 0015 is RevMed's Pan-RAS, the CypA binder, but you've been positioning yours as potentially more potent on a couple of different metrics with also some superior PKPD potential. So can you walk us through what you think are the key features for the class that drive from potency, lab potency from PKPD to clinical efficacy?
Yeah. So just as a reminder, our molecule 0015 and 6236 from RevMed, they both work through a similar MOA in terms of binding to cyclophilin A, and that bipartite complex then goes and finds the RAS protein to form a tripartite complex, and so we think that a key differentiator of our program is the fact that it does have stronger, higher binding affinity to cyclophilin A compared to RMC 6236, so in our hands, in head-to-head comparisons, our molecule is about eight to 20X better binding affinity to cyclophilin A compared to RMC 6236. What that translates to is better in vitro activity as well as better in vivo activity.
So if you look at roughly 15 or so different cell lines that we've profiled head-to-head versus 6236, and these cell lines represent KRAS G12X mutations, G13, et cetera, we show about four to five times greater in vitro potency across cell lines compared to RMC 6236. In vivo, across about a half a dozen different models that represent different mutations as well as different tumor types, we're seeing about 10X greater potency with our molecule compared to 6236. In addition to that, as you mentioned, we think that our molecule also has better PK properties that are in part because of this better binding to cyclophilin A. So across multiple species that represent mouse, rat, dog, monkey head-to-head versus 6236, our molecule has better clearance, better half-life, and better bioavailability. So lower clearance, longer half-life, and higher bioavailability across the species.
Driven at least in part by sequestration on the cyclophilin.
Yeah. So there's evidence that Cyclophilin A tends to reside more so in tumor tissue. And so if you have more Cyclophilin A in the tumor tissue and you have more higher binding affinity to Cyclophilin A, that should be.
You have better tumor residence and better.
Yes. And that's a great point as well, because that's another key differentiator of our molecule. We have looked at dose normalized data of our molecule versus 6236 at two different time points of four hours and 24 hours. And what that shows is that our molecule persists in the tumor tissue between four hours and 24 hours versus the comparator molecule drops off pretty dramatically at 24 hours. So that suggests that we're getting this depot effect in the tumor that should hopefully lead to better anti-tumor activity. And again, that's enabled by this stronger binding to cyclophilin A.
That makes sense. Now, to the tolerability point that I think you just briefly touched on there, would we expect broadly speaking, similar tolerability profile compared to RevMed given some of these PK differences? A lot of the talks that they're seeing, the GI talks especially, that's on mechanism talks for RAS, right?
Yeah. So I would say that the number one AE that they've seen is rash. And to their credit, that's been a high frequency, but low severity event. And rash is on target. So that is probably something that we will also have. We'll see how we can maybe titrate the dose to accommodate a better rash profile, but only time will tell on that. I would say their second most common AE is GI, as you mentioned. And a lot of times that's actually driven by the drug burden in the GI tract.
The fact that they're dosing at 300ml in PDAC and now based on the data that they showed earlier this week, 200ml in non-small cell lung, and the fact that our molecule is more potent, we anticipate that our relevant pharmacologically active human dose is on the order of one fifth to one tenth of the dose of RevMed. So if we're able to have a lower dose in the GI tract, that should actually potentially lead to a better GI.
Insofar as it's drug burden related and not epithelial toxicity.
Yeah, yeah, that's right.
Manifesting in GI. Okay, great. You mentioned the universal prophylaxis with Napo helping a lot with rash. Is that something that could be amended for a pan-RAS as well?
Yeah, that is possible as well. I mean, the typical phase one approach is to not have rash prophylaxis because you want to see how your drug performs in that setting. But certainly later on, depending on what we see from the profile of the molecule, we could institute that as well. And these are relatively simple interventions. So what we did in SEACRAFT-1 and SEACRAFT-2, the naporafenib drug that we got from Novartis, what we did there was basically steroids and antibiotics, oral antibiotics, topical steroids. So pretty simple intervention that was able to dramatically reduce the rash rate there.
Okay. Now you've spoken a little bit about combination strategies. Obviously, that's something that RevMed is very focused on for their program. Do you think they're choosing good combo partners? And are there places that you're looking or you're interested that you think they're overlooking?
Yeah, I mean, so if you look at the epidemiology of KRAS mutant tumors, first of all, there's about 2.7 million RAS mutant tumors that are diagnosed annually around the world. So this is a huge unmet need. The big 3 are CRC, PDAC, and non-small cell lung. And that's obviously the focus that they've been looking at. I think the combinations that you want to consider are chemo, especially in PDAC, Pembro in non-small cell, and then combining with cetuximab or an EGFR inhibitor in CRC. So we're certainly looking at that. We're also looking at the long tail of opportunities.
I think we haven't yet talked about 4001, but I think one potential area where 4001, which is our Pan-KRAS inhibitor, could potentially be positioned is in CRC, where if you already have a high amount of rash with a Pan-RAS inhibitor, and then you combine that with an anti-EGFR antibody like cetuximab, which also has a large amount of rash, does that AE profile become too much? Would a Pan-KRAS like 4001 that spares HRAS and NRAS be more appropriate in that population? Only time will tell. Nobody has disclosed any clinical data yet on the Pan-KRAS class, so only time will tell, but that is a potential area that we could.
There aren't too many folks who have a pan-KRAS and a pan-RAS program under the same roof.
Yeah, exactly right. I'm not actually aware of anybody else besides us. And I think that's.
I can't think of any off the top of my head.
I think that's another advantage that we have is these orthogonal MOAs between a pan-RAS molecular glue and a Switch II pocket binder. Also the non-overlap of the targets in terms of pan-RAS, but also pan-KRAS. And so I think all of that should allow us to have an advantage there. We also have the ability to potentially put both of the molecules together down the road to see if that drives even better inhibition of the RAS-MAPK pathway.
All right. So we've got a couple of different directions to go here, but let's start with more 4001 specifically. And I'd love to return to the combo in just a moment. But obviously the focus is primarily on 0015 because of the RevMed comp. I think that's pretty clear. But you mentioned a couple of places where having an NRAS HRAS sparing molecule could be beneficial. How can you drive that program forward independently? And what are your top priorities for 4001, given you've got 0015 also running at the same time and taking up those big three opportunities?
Yeah. So I will say that 0015 and 4001, we're advancing them neck and neck. So they are our top priorities. And we think that there's really places for both of them. I would say that, as you mentioned, the pan-RAS space, because there is the analog in RevMed, I think that is something that investors certainly recognize the value. I think pan-KRAS is still in its infancy in terms of very few molecules that are in the clinic. Nobody has released any clinical data yet. I think as that clinical data emerges, we'll see if pan-KRAS actually turns out to be a very good and maybe even a more appropriate target to go after, especially in certain indications. And so it's good that we have both because that gives us the optionality to see which one might play better in certain areas and also that potential to combine them.
I think 4001, because it spares HRAS and NRAS, that's a key differentiator there versus the pan-RAS molecules. It's also on the leading vanguard of molecules that are going into the clinic. So we'll be on that first wave of companies that are reporting clinical data to see if this is something that actually in certain tumor types works really well. So we're advancing both of them. We like both of them and we like having the two orthogonal mechanisms.
Yeah. Well, maybe while we're on 4001, you talked a little bit about some of the preclinical differentiation for 0015 versus the comps. How do you feel about the 4001 profile versus some of the other competitors, as you say, haven't released clinical data, but where those programs are starting to develop? How do you view the important characteristics of this molecule?
Yeah, we like 4001. There aren't a lot of structures that have been disclosed in the Pan-KRAS space, so that prevents head-to-head comparisons. But that said, the data that we've generated for 4001 look really good. It's got very good activity across different cell lines that represent KRAS mutations of different sorts, as well as KRAS wild type. It's got good in vivo activity in multiple models, including combinations with anti-PD-1. Its A PK properties look very good in terms of advancing it into clinical development. So we're excited about that. In addition, the molecule also has good activity in terms of its IC50 potency against both the GDP and the GTP state of KRAS. It has more potency, about one and a half against the GDP state.
GTP is a little bit higher at around 6-7 but still very good single-digit nanomolar potency across both GDP and GTP.
Yeah, we've got enough time. I'm going to ask you a biochemistry question. So let's talk about that pan-KRAS, the 4001 binder, binding to both the so-called RAS on, RAS off, both sides of that equation. Do you prevent cycling? It wouldn't be an inhibitor if you didn't prevent the activity of the signaling, but are you preventing nucleoside exchange as well?
Yeah, I think that's still something that we're looking into. But I think if you have activity against both the active state and the inactive state, meaning the GTP and the GDP state, then you actually are probably preventing some cycling, but more importantly, preventing that downstream signaling.
Interesting. Well, I'll look forward to seeing more of the biochemistry in that program as it develops. You mentioned looking at the combo of those two molecules, and that might not be immediately obvious to somebody looking at this from the outside. They're hitting the same or similar targets, similar pathways, certainly. What is going into combination of the two potentially get you?
Yeah, so you could, because of the different profiles of the molecules, especially in terms of their binding, one again is a switch II pocket binder, the other one is a pan-RAS molecular glue. That in and of itself may be a way to shut down the RAS-MAPK pathway even better because you have one approach that's shutting down through CypA binding and then the other one through the switch II pocket binding. In addition, you can imagine a situation where if you have 4001, the pan-KRAS to shut down the pathway primarily, especially in certain tumor types, and then you add on a little bit of 0015 to sort of mop up any additional signaling because these tumors are wily, right? They figure out a way to get around certain types of inhibition.
And so having 2 different ways of shutting down the pathway could actually lead to longer time on treatment, longer duration.
For stalling resistance, you mean?
Yeah.
Great. Well, we're out of time, but last question. Runway cash balance looks relatively healthy right now. You've got it for a couple of years there. But what does that guidance cover in terms of data update, SEARAFT-2 part 2, the phase Is for the new assets? How much dose expansion or combo data do you expect to be able to show under the current guidance?
Yeah. So our most recent filing for the Q3 numbers, we said that we have $463 million in cash. So we are well capitalized. We've got runway into the first half of 2027. What we've guided to in terms of our public milestones for SEACRAFT-2 stage 1, we'll have that data readout, as I mentioned, in calendar year 2025 for the two new RAS assets. INDs will be early part of next year in the first half with the phase one monotherapy dose escalation data for both of them guided to 2026. So all of that is covered within the runway guidance.
But presumably you'd be well into SEACRAFT-2 part two as well, but not through completion of that trial.
That'll depend on how quickly enrollment goes. I mean, but yeah, most likely that will be kind of down the road.
And expansion cohorts or combination cohorts for the pan-RAS?
That is also included in the guidance, but again, depending on the timing of that readout.
May or may not be.
Longer.
Makes sense. Awesome. Well, we are out of time, but thank you so much for joining us.
Yeah, thank you. This was fun.