All right, so welcome to the next Fireside Chat with Erasca. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and it's my great pleasure to welcome Jonathan Lim, Chairman and CEO, as well as David Chacko, CFO of Erasca. Welcome. Thanks for joining us this year. Thank you, Michael. So jumping right into Q&A, Jonathan, Erasca has, or you guys have streamlined the pipeline of Erasca this year, and now primarily focusing in on development of naporafenib and also your pan-RAS and KRAS inhibitors. So yeah, maybe just talk about how investors should think about the key value drivers in the pipeline strategy for Erasca today as it stands. Yeah, we're really excited because we stand at an important threshold of value creation for patients as well as investors. So I'd say 99% of the focus these days is on our RAS targeting franchise. I know we'll dig in a little deeper on that, but really the lead molecule there is ERAS-15, which is a pan-RAS molecular glue that is on track for an H125 IND filing. So that's sort of the next value driver for that program. And then ERAS-4001, which is a pan-KRAS switch-II pocket binder that's on track for a Q125 IND. So both of those are neck and neck moving along. Then we had an exciting update a few weeks ago at the Triple Meeting in Barcelona on naporafenib and showing in the SEACRAFT-1 NRAS mutant melanoma cohort. We saw very high response rates of 40%, which compares nicely relative to historical response rates of the low 30s in the phase I, phase II setting and a very good tolerability. So we're excited about that read-through to the SEACRAFT-2 trial, which is underway. It's a phase III trial that we'll talk about as well in two parts. Right now we're in the dose optimization phase, and then we'll be segueing into the stage two, which is the randomized pivotal portion. Great. Yeah. So maybe then starting out with naporafenib, and then we'll go to your RAS inhibitor franchise after that. So yeah, just talk a bit more about naporafenib and some of the data from the Triple Meeting and how it really validates its profile and opportunity in the SEACRAFT-2 study. Sure. So I'll take that. So naporafenib is our pan-RAS inhibitor. It's the most advanced pan-RAS inhibitor in development. We're really excited about this program, especially in light of the data that we showed at the Triple Meeting a couple of weeks ago. So that data showed, as Jonathan mentioned, about a 40% response rate in the first 10 patients. So that was encouraging to see, especially relative to the standard of care, which is chemotherapy, which has a response rate of about 7%. Even single agent MEK that is used off label has a response rate of about 15%. And in the historical data from when Novartis ran the trials with naporafenib plus trametinib, they saw response rates in the 20%-low 30% range. And so this data update that we showed at the Triple Meeting with response rates in the 40% looked very good from an efficacy standpoint. I think even perhaps more importantly is the fact that the primary rash prophylaxis that we made mandatory in our SEACRAFT-1 and 2 studies seems to be working to improve the rate of rash. So you saw the rash rate decrease from about the mid-30% in the Novartis-run trials to about 10%-11% in our trial. You saw the rate of discontinuations due to an AE dropping off pretty significantly as well in our trial relative to the Novartis-run trial. Then also finally, the relative dose intensity, which is a measure of how much drug the patient receives in actuality relative to what the intent to treat is, that improved quite significantly from about 67% in the Novartis run trials to 98%-99% in our hands, so that totality of data where we saw improvement in the response rate, improvement in the tolerability, as well as further conviction around the melanoma cohort coming out of SEACRAFT-1, that has now given us additional conviction around the SEACRAFT-2 study, which is our pivotal study that's ongoing right now in the NRAS melanoma population. I know there was a little bit lower activity seen in non-melanoma patients. Any explanation for that or any mechanistic hypothesis for that, just given that they also had the RAS Q61 mutations? Yeah. So if you look at the spectrum of tumor types in terms of what tends to be more responsive versus less responsive to targeted therapies and what tends to involve perhaps other additional pathways, melanoma tends to be a more sensitive tumor type compared to something like CRC, where there tends to be other feedback activation pathways. And so I think the data that Novartis had generated showed the most promising signal in melanoma in the RAS Q61 space, some preliminary POC in the non-small cell lung space. And what we wanted to do was really explore whether there was a path forward from a tissue agnostic approach. And ultimately, what this showed us is that the most promising approach was in the melanoma population, which again gives us that further conviction around SEACRAFT-2. Gotcha. And then so what else do you need to do in SEACRAFT-2 before initiating the randomized phase III portion? So where are you in your dose selection process? Yeah. And maybe just one clarification. The phase III study actually has two portions, the stage one and the stage two. So we're actually already in the phase III portion of the study, but in that stage one portion, that's a dose optimization. There we're testing two different doses of Napo plus trametinib. Those two doses plus the third dose that was tested in SEACRAFT-1, we will have data for those three doses next year in 2025, where we will then be able to make a decision about which dose it is that we want to move forward with in stage two of the phase III study. Now, based on the data that we showed a couple of weeks ago at the Triple Meeting and the fact that that 201 dose, which was tested in SEACRAFT-1, looked really good from a tolerability standpoint, that could be our presumptive dose going forward. We'll see what happens in the SEACRAFT-2 stage one portion with the two other doses to see if there's an upside pleasant surprise there. But otherwise, we have a pretty good go-forward dose with the 201. Just to build on that, the mandatory primary RAS prophylaxis really seems to have boosted the safety and tolerability, as David mentioned. We think the 201 dose, whereas in the phase I II, that looked like it was borderline tolerable. Now, with the relative dose intensity shooting up to 99%-100% for Napo and TRAMI respectively, it's looking like a very promising dose. Just remind us of the other two doses that you're evaluating in the stage one portion. Yeah. So the two doses that we're evaluating in SEACRAFT-2 stage one are 400 of Napo plus 0.5 of trametinib and also 10 1. And so if you take those two doses plus the dose that was tested in SEACRAFT-1, which was the 200 plus one, so 200 of Napo, one plus trametinib, we think that that gives us a nice bookend. If you look at the preclinical and clinical pharmacology data and where the most likely efficacious doses are of both drugs in combination, this allows us to essentially bookend the high end of Napo and low end of Napo with the high end and the low end of trametinib. Gotcha. And then the selection will be based on efficacy and RAS predominantly, or what are the assessments that would you just pick the winner of the three arms or what are the outcomes that are important in that regard? Yeah, I think it'll be sort of looking at the totality of the data, but of course, efficacy and tolerability will be two of the big aspects that we're looking at. And again, I think with the 201 dose showing what it did already, we feel pretty good about having at a minimum, that's a very good go-forward dose. And then we have the other two as well. Okay. And then just on stage two of the SEACRAFT-2 study, I have two questions where outcomes presumably are PFS and OS as opposed to response rate. Sort of what are expectations there for control and perhaps one of the treatment arms? And then just talk about the overall commercial opportunity in that setting. Sure. So first on the dual primary endpoint of PFS and OS, the reason we're looking at that specifically is that it's a good metric of how a patient is doing over a longer period of time. And especially in this population where you're talking about end of line patients, having the even long-term stable disease is actually a pretty meaningful outcome for these patients. So that's why we wanted to look at PFS and OS as opposed to response rate in the phase III study. Now, with regard to what the benchmarks look like, unfortunately, it's pretty abysmal in the post-IO setting. So the approved standard of care is chemotherapy, which has only about one and a half months of PFS. Single agent MEK is used off label, and that has about 2.8 months of PFS. So neither one is that great. Naporafenib plus trametinib in the phase I and II setting showed about five months of PFS, so pretty meaningful doubling to tripling of the benchmarks there. On top of that, if you look at OS, we did an analysis earlier this year of the phase I and II data because that data reached a level of maturity where we could analyze the OS data, and we showed about 13 to 14 months of median OS for the naporafenib plus trametinib combination relative to historical benchmarks for chemo and for single agent MEK that are more appropriate comparators for the control arm of about seven months, so you're seeing about a doubling there on the OS side, and so on both PFS and OS, based on the historical data, we feel pretty good about the trajectory of the study. With regard to your final question on the commercial opportunity, we think that NRAS melanoma is a reasonable opportunity. It's probably a few thousand patients in the U.S. and similar numbers in Europe. So you're probably talking about peak revenue for this in the several hundred million range. And one other point is that NRAS melanoma is about 25% of melanoma. To put that in perspective, BRAF melanoma is about 50% of melanoma. So this is about half of that. Gotcha. Okay. Super helpful. And then, yeah, maybe shifting over to your RAS inhibitor portfolio. And so you obviously have in license these two new molecules earlier this year. One is a pan-RAS inhibitor, as you mentioned. One is a pan-KRAS inhibitor. And so, yeah, there's ongoing debate, I suppose, among some of the KOLs in terms of what is the preferred mechanism of action, pan-RAS versus pan-KRAS. And so where do you stand on that topic? We love both, and that's why we have both. So thanks for teeing that up. I think for the pan-RAS CypA molecular glue, what's really cool is that that mechanism has been validated by Revolution Medicines. So I think their data in pancreatic carcinoma is really compelling and showing just the power of taking RAS out of circulation. Now, what's really exciting is a Nature publication that came out last month showing that there could be a dual mechanism of action. So in addition to sort of decreasing the RAS-RAF effector function by removing RAS from circulation, it also looks like it's increasing the hydrolysis of RAS GTP. So in doing so, you can actually have that dual mode of action, which would put this pan-RAS molecular glue in rarefied air because it's hard for any traditional small molecule to achieve the same twin mechanism of action. So I think that's very exciting for the class of compounds where it's really a short list of players that are in that space. Now, the pan-KRAS space is a little more crowded, but I think the benefit there of being K-selective is that you can spare H and NRAS, which also could then translate into a potentially wider therapeutic window. Right. And so on your molecule, ERAS-0015, how is it mechanistically differentiated or perhaps similar to the Revolution Medicines' compound? Yeah. So same mechanism, but the differentiation, the secret sauce of the differentiation has to do with the CypA binding. So by our orthogonal assays, we've shown that ERAS-15 has an 8 to 20-fold higher binding affinity to CypA than does RMC-6236. So the way to think about that is you've got this moiety that goes hunting for CypA to form these bipartite moieties that then go hunting for RAS to form a tripartite complex. And so if you have an 8 to 20-fold higher binding affinity, you form a lot more of these bipartite moieties that then go hunting for RAS. So that differentiation then translates into an 8 to 10-fold higher potency in vivo across multiple in vivo models, including G12D, G12V, G12X, even other isotypes of RAS. And then beyond that, we also see advantageous PK properties. One of the most unique properties is the fact that the tumor tissue biodistribution for ERAS-15 is much higher than for 6236. In different in vivo models, we can see persistently high levels of ERAS-15 in the local tumor tissue microenvironment at four and 24 hours versus the comparator that drops off at 24 hours. That enhanced tumor tissue residence time could potentially offer upside in terms of therapeutic window as well. Okay, and then with higher potency, to what degree do you worry about on-target side effects becoming limiting in a way since we know that there was some rash at higher doses with the RevMed compound? If you hit the target harder, wouldn't that become a limiting factor as well? Yeah, I think the limitation is more around the linearity of PK. And so if you can dose and maintain dose proportionality at higher doses, then you can translate into potentially better target coverage. Now, to your point, if you're hitting it harder, are you going to have worsening rash and other on-target effects? First of all, we agree rash is probably an on-target mechanism. So we wouldn't predict any difference from our approach versus 6236. We do think that if you're delivering less drug to patients, there could be a benefit in terms of GI tolerability. But as far as rash, we do think the tumor tissue concentration could be a potential benefit in that if you wanted to match, let's say, the rash frequency and severity of what's being observed with a comparator compound, for that given AE rate, you're probably going to have better tumor tissue coverage. And then vice versa, if you want to match the tumor tissue concentration, you might see lower rash. So it's a very simplistic way to look at it, but we'll have to see whether that principle translates in the clinic. Right. And then, yeah, so can you talk about your preliminary development plans for ERAS-15 sort of relative to what's out there in the landscape? Yeah. First of all, the unmet need is unfortunately really significant. There's millions of patients that suffer from RAS mutations globally. I think there's the big three of pancreatic, non-small cell lung, and CRC. We'll be looking at all three of those. We'll also be looking at other tumor types outside of that. It's a pretty long tail, but there's certainly more than enough unmet need for more than one compound. So as the second pan-RAS CypA binder to enter the scene, we're really rooting for Revolution Medicines' success because we just think it's great for the entire class. And then we think there's more than enough room for more than one player. Right. And so the IND is going in the first half of next year? That's right. First half of next year, we've finished the in-life portion of the GLP tox for that molecule. And the CMC is the other sort of long pole IND enabling activity that's on track also. So we're reiterating our guidance for H1 of next year for the IND. And then for ERAS-4001, the pan-KRAS, we're on track for Q1 of next year. All right. And so for 4001, we talked just a minute ago. So there are other pan-KRAS inhibitors out there. Lilly is now in phase I, as is a Boehringer compound and a few others. So yeah, anything you can share about differentiating features or unique attributes of 4001? Yeah, I think we are, first of all, in the vanguard of all the pan-KRAS molecules. I think the ideal molecule, you want to see single-digit nanomolar potency against the different variants of D and V, especially, as well as G12X. You also want to see GTP state as well as GDP state activity. And then you want to see very good in vivo tumor regression across multiple models. And then you want to see very strong inhibition of both KRAS wild type as well as KRAS mutations and spare H and NRAS. So what I can say is that our molecule unequivocally checks all of those boxes. And so we really like the features of our molecule, which also in terms of the race into the clinic, I'd say that we are in the vanguard of all of the different players looking at that space. Right. And then there's also, I think the question still out there, sort of the on versus off inhibition, or the GTP versus GDP inhibition. How important is that, or in what areas is that most differentiating, perhaps? And how do you plan on taking advantage of that? Yeah. Well, it's really important because both G12D and to a larger extent G12V, which are the most common mutations, both of those more commonly reside in the GTP state rather than the GDP. So you do want to have not just take those mutations, inhibit them when they are in the off state, but you also want to inhibit them in the on state. So it is very important to have both. And the nice thing is that against D, for instance, ERAS 4001 has low single-digit nanomolar potency against the off state or the GDP state. And then it has mid-single-digit IC50 or nanomolar potency against the GTP state. And then in terms of the phase I study, so any thoughts? Will it be similar to the pan-RAS study or different in any way? Yeah, we'll do the same dose escalation. We'll do expansions in similar cohorts, I would say, as we start thinking about combinations, especially when you look at sort of the rash rates of the pan-RAS approach. I think by being KRAS selective, there could be slightly better tolerability when it comes to rash. And so as you think about potential combinations with anti-EGFR compounds, for instance, 4001 might behave better or play better with the anti-EGFR approach. Gotcha. And then as you think ahead in terms of future development, is there a point where there's a selection process? Either 4001 or 15 will advance, or is there a different opportunity for either of the two drugs? Yeah, I think it's probably the latter rather than the former. I think there's sort of a chessboard, if you will, of all of the different tumor types as well as mutations across the RAS spectrum, and then I do think that each molecule will declare itself within that chessboard. Sounds good, and then any other I know you have some companies built on a licensing model to a large degree. Any other pipeline expansion plans as we think about some of the midterm? Yeah. So I mean, we're very excited about our pipeline right now with naporafenib in its phase III study with the two new RAS assets that we were just talking about. And we just got those in May, so we're still very much moving those forward. And I think it's all about execution. So we have gotten a lot of inbound interest, especially since announcing those deals back in May. But the bar has always been very high for us. And I would say the bar is even higher now in terms of bringing anything.