All right, so welcome to this Fireside Chat with Erasca. I'm Michael Schmidt, Senior Biotech Analyst with Guggenheim. And with me today I have David Chacko, CFO and Chief Business Officer. David, welcome. Thanks for joining us. Yeah, thank you, Michael. Thanks for having us. Maybe just starting out with a little bit of a higher-level question. At Erasca, you have streamlined your pipeline a little while ago, now primarily focusing on your two RAS inhibitors, both of which recently entered phase one clinical studies. Maybe provide a little bit of background on what were the key criteria in the support of your choice for each of those assets, which were in-licensed a little while ago. Yeah, absolutely. Just as a general overview, Erasca is a precision oncology company. We're based in San Diego. Our name has a dual mission. We're not only trying to erase cancer, but eradicate RAS-driven cancers. Both of these assets that we brought in in May of 2024 fit squarely within that strategy of eradicating RAS-driven cancers. In terms of the specifics around the molecule, I know we'll get into the differentiation, but it has to do both with the differentiation of each molecule as well as the high unmet need in the space right now, just given the number of patients that are diagnosed annually with RAS mutant tumors, about 2.7 million patients that are diagnosed around the world with these RAS mutant tumors. With 4001, our pan-KRAS, as well as 0015, our pan-RAS molecule, we think that we'll have the ability to help impact patients' lives quite positively. I think the space itself is getting increasingly crowded, for sure. What I really like about our programs is two things. Let me talk about the pan-RAS, 0015, and then 4001, the pan-KRAS. I would say that overall, the pan-RAS space is actually relatively uncrowded. It is basically Revolution Medicines has the molecule that is most advanced in the space, and then us right behind that. There are a couple of smaller companies that are even further behind. Essentially, I think what investors really like about our story is that we are solidly in second place in a field that is relatively uncrowded. I think that creates a scarcity value. If the pan-RAS space continues to play out the way that it has, that could be a real benefit. In the pan-KRAS space, that one is becoming a little bit more crowded, but nobody has disclosed any clinical data yet to date. Whoever it is that discloses that first will be on the leading wave. I think that gives us the potential to still be a very viable competitor in the space in terms of potentially best-in-class or first-in-class type of profile. Yeah, no, makes sense. Totally. Yeah, maybe starting out with 0015, your pan-RAS inhibitor, which essentially is sort of directed at competing with RevMed's direct and RAS, as you mentioned. Talk a bit about the preclinical data and what some of the differences are that really make that an attractive molecule. Yeah. We think that the space is certainly big enough to support multiple players, let alone two players in the space. That said, our molecule does show very good preclinical differentiation versus RevMed across a number of different factors. I'll start first with the fact that our molecule binds to cyclophilin A, which is the first step in forming the tripartite molecule. It binds to cyclophilin A with about 8- to 20-fold greater binding affinity compared to 6236. That enables a lot of benefits, including the fact that our molecule is about 4- to 5x more potent in vitro across maybe 15, 20 different cell lines that represent a variety of mutations, a variety of tumor types. It also translates into better anti-tumor activity in terms of seeing really with about one-tenth the dose in vivo, we're able to achieve comparable levels of anti-tumor activity. We also see better tumor PK kinetics in terms of longer residence time, as well as better distribution of our molecule into the tumor. Finally, from an admin PK standpoint, the molecule looks really good in head-to-head comparisons in terms of better clearance, longer half-life, and higher bioavailability across both small and large animal species. A number of different differentiation points from a preclinical standpoint. Now that we're in the clinic, we'll generate data there as well. Right. I guess which of these preclinical characteristics do you think are most important in terms of driving potential clinical differentiation? I would say that a lot of them are important, but I would say that it starts first with that better binding to cyclophilin A. The fact that we have that 8- to 20-fold better binding to CypA, the fact that there is more CypA in tumor tissue, that leads to sort of a depot effect where we are able to get our drug into the tumor to potentially lead to really good anti-tumor activity. I think a lot of it starts with that. I think what I really like about the profile is that we are not hanging our hat essentially on one form of differentiation. It has to do a lot with multiple areas of differentiation across, again, the better binding to CypA, the better in vitro potency, the better in vivo activity across multiple cell lines, and then the better admin PK properties as well. Right. Are there any specific types of, any specific tumor histologies or any specific types of KRAS mutations where you think those differences may play out more meaningfully or to a greater degree than in others? I think at this point, it's probably, I mean, the nice thing about a pan-RAS molecule is that it has such broad applicability across so many different tumor types. The epidemiology does support the big three of CRC, panc, and non-small cell lung. There is also a long tail of opportunities. Those long tail opportunities are still 10,000 patients or more in the U.S. across several of those long tail opportunities. There are a lot of places where this molecule can play right now. Okay. RevMed, I think as well now that they had with the multi-RAS inhibitor, they did have sort of, I would not say DOTs, but they did run into sort of on-target AEs at higher doses, especially the rash, I think has been most limiting in terms of going to higher doses. How do you expect that to play out? Do you worry about some of those on-target AEs being more pronounced with a more potent molecule? Yeah. Rash is something that is most likely to be on target. We will likely also have rash. Now, what I will say is to RevMed's credit, what they showed in their various data disclosures is a molecule that has a high frequency of rash, but low severity. That is one of these ones where physicians have a lot of experience. If you look at the anti-EGFR space, as an example, they have a lot of experience dealing with rash. We also were advancing our NEPA RAFNIB pan-RAS program in a different indication. As part of that trial, we actually implemented mandatory primary rash prophylaxis. That actually really helped the rash rate in that trial. We have a lot of experience as a company as well in terms of how to manage rash. I don't anticipate that as RevMed is also able to move forward despite having, as you mentioned, some amount of rash, I don't anticipate that that should be an issue for us as well. We'll see what the data look like in terms of how that actually plays out. Do you anticipate any differences around combinability of 0015 with chemo or with other agents? Yeah, I think one of the reasons that we brought in the program amongst others is the fact that we anticipate that we'll have a lower clinically active dose than where RevMed is at. If that proves out, that will be thesis reinforcing for us. One of the benefits amongst others is that that could lead to better combinability when you're talking about other agents. If you have a lower dose of Drug X, in our case, 0015, compared to 6236, that just helps you when you think about combinations with drug Y as well. Right. Maybe before we talk about the clinical studies, just shifting over to 4001, your pan-KRAS inhibitor. Again, how could that potentially be differentiated? We obviously have not seen clinical data yet on any pan-KRAS inhibitor. Not sure how much preclinical data there has been disclosed on some of those molecules, but maybe speak to its sort of key features preclinically and how you think those could potentially be translating into the clinic. Yeah. Whereas in the pan-RAS space, where there is the structure of 6,2,3,6 available, and therefore we were able to do head-to-head comparisons preclinically, there really hasn't been much in the way of data disclosures or structure disclosures in the pan-KRAS space. That makes it harder in the pan-KRAS space, as you're saying. Now, that said, what we like about 4001 are a number of different things. The molecule itself has very good in vitro potency, particularly against mutations of interest, certain G12X mutations, G13, KRAS wild type as well, which is really important when you think about resistance mechanisms. On top of that, it also has good activity against both the GDP and GTP states of the molecule, so the on-and-off state, albeit more so against the GDP state. The molecule has good in vivo activity across multiple preclinical models. The admin PK properties also look good. We like the profile of that molecule. Investigators have also been enthused by that profile as well. It is interesting. I mean, it seems to be technically challenging, I think, to make a potent and selective pan-KRAS inhibitor, just given that we have not seen a lot of industry data in the space yet. Anything you can speak to how you guys have solved that issue? Yeah, that's a great question. I think there are certain companies that have been in the clinic for a little while and there still has not been any data disclosures. I think the silence is deafening there. I think with our molecule, we're excited about its profile, as I mentioned from some of the things that I just said. I think the other thing too that could differentiate us is that most of the pan-KRASs are built off of the same scaffold. Ours actually has a different scaffold. To the extent that some of the issues that have come about with some of those pan-KRASs is driven by that scaffold, having a different one could be an advantage for us. Gotcha. Okay. There's a little bit of a debate out there. Some folks think that hitting NRAS and HRAS is actually beneficial. Obviously, your 0015 product does that, presumably, especially around duration, perhaps. I'm just curious where you stand philosophically in terms of what is the opportunity for a pan-KRAS inhibitor to differentiate, perhaps, relative to the pan-RAS inhibitors? Yeah. You actually hosted a great panel earlier this year with David Hong and Ryan Corcoran talking exactly about this. I'll do my best to kind of provide my thoughts on it as well. I think there's multiple areas where you think about pan-RAS versus pan-KRAS. You can think about, for instance, the isoforms. You mentioned the fact that ours, as well as RevMed's, hits K, H, and N versus our pan-KRAS only hits K. That could be an advantage from an efficacy standpoint to hit all three isoforms if there is isoform switching. A pan-K, because it spares H and N, could be a gentler, kinder version in terms of the tolerability profile. I think if you look at the mutational spectrum as well, the pan-RASs tend to hit across G12, G13, Q61 reasonably well. The pan-KRASs hit G12X, but maybe not as much G12R. They also do not hit Q61 as hard. The third point I will mention is the MOAs. These are orthogonal MOAs of pan-RAS, which is a CypA binder versus pan-KRAS is a switch two pocket binder. There are different ways that these molecules may work in terms of how we can think about targeting them to different populations. The nice thing for Erasca is that we are one of just a few companies that actually have both. Regardless of the way that the field evolves, if it turns out that there are different swim lanes for the pan-RAS versus the pan-KRAS, we have got an answer for both. Right. So it sounds like it will be less of a decision in the future whether to select one of the two versus the other as opposed to finding differential opportunities for either, the way I think about it. Is that right? Most likely that'll be the case. Obviously, this is going to be data-driven. If we see phenomenal efficacy from one molecule and terrible efficacy from the other, which I don't anticipate, we'll obviously make a data-driven decision. Yeah, I think at this point, it's most likely that they'll each have their own swim lanes. Obviously, you do have two phase I studies up and running since earlier this year. Maybe comment a bit about how far into dose escalation you are at this point and how you're tracking perhaps towards reaching active dosing ranges or anything along those lines. Yeah. We filed and cleared INDs for both of these molecules in May of this year. We have guided to having data for both of them, phase one monotherapy dose escalation data in calendar year 2026. Enrollment has been going well. Investigators are enthused about both programs. I think it just speaks again to the unmet need in the space as well as the specific profiles of these programs. We are on track for that 2026 readout. In terms of what that readout, or I should say those readouts, because we will have one for each, will look like, we want these to be interpretable data sets. You can think about dozens of patients in each of them. We will, of course, be looking at safety, tolerability, PK, initial signs of efficacy as well. We want to be able to tell an interpretable story around them. Right. Could you comment sort of what types of patients do you see enrolling in the studies? Are there certain histologies that are more frequent than others that you see enrolling? Is it the same for either of the two studies? Yeah. The epidemiology of these RAS mutations, they tend to fall into that big three that I mentioned earlier of CRC, panc, and non-small cell lung, and then the long tail of opportunities. In a dose escalation, and especially at lower doses, you do not really select for any particular tumor types. You just want to get to your dose as quickly as possible and establish safety and PK. As we get further into the dose escalation, we do have the ability to put our thumb on the scale if we want to enrich for certain tumor types. Right. Do you allow prior K RAS inhibitor therapies in other studies? No, we want patients to be naive. Right. Okay. Yeah, any predictions based on your study scheme when you might be hitting efficacious doses or RPTD even? I would say that we as a field know a lot more about the pan-RAS space, just given that RevMed's out there. We know, for instance, that they saw their first signs of efficacy at 80 milligrams. That was their fourth dose level. I would say that we as a field know a lot less about the pan-KRAS space because nobody's disclosed any data in that space. We have more ability as a company to sort of forecast our 0015 pan-RAS clinical plan, just given that there is that predecessor as opposed to the pan-KRAS. We are on track for that data readout for next year. Gotcha. Maybe a little bit early here, but are you planning dose expansion cohorts? If so, which ones? Yeah, we are. Of course, that'll be a data-driven decision as well for us. Depending on what we see, we have our hypotheses about where we're likely to see efficacy and where we want to go. Of course, based on what we see from the dose escalation, that'll inform the dose expansions as well. If we maybe step back again and think about the broader landscape, fast forward to, let's say, the end of 2026. At that point, the Jurex and RASEB is probably approved in PDAC, best case. The field's sort of advancing in lung cancer as well. There's multiple G12C inhibitors on the market and in development. How would you position either molecule in a bigger development landscape going forward? Yeah. Great question. I think what you were mentioning with respect to 6236 is specifically in second line PDAC that I think they've shown great data there. I think it depends what our program looks like in terms of its profile. Let me start first with if we show sort of a comparable profile, and then I'll talk if we are able to show a superior profile. In terms of a comparable profile, it may not make sense for us to go after second line PDAC if RevMed is already approved there. I think there's still a lot of white space opportunity for us in first line PDAC, in all of non-small cell, in CRC, in the long tail opportunities. I think there's a lot of white space that's still available for both the pan-RAS as well as the pan-KRAS molecule. Now, if we're able to show superiority with either or both of our programs, that leads to not only those white space opportunities that I mentioned, but also the potential for that second line PDAC opportunity. I think for us, if I talk about 0015 specifically, part of the reason, amongst others, that we brought in this program was because we think that we're able to achieve, call it comparable level of activity with a fraction of the dose. If we're able to do that, I think that'll be a win scenario for us. If we're able to see signs of activity on our 0015 program at a fraction of where RevMed is, that would be a win. Depending on where exactly we are, like let's say we're at half the dose of RevMed, I think that would be a home run. If we're at maybe a quarter of the dose of RevMed or less, I think that would be a grand slam for us. If we're able to show comparable safety, that would be a win for us. If anything that we're able to show on top of that, like an improvement in the RAS rate or the GI rate, would also be a nice outcome for us. Right. There is always a range of combinations that one can do, obviously, with standard of care in each of the target indications and then also with novel agents, right? Do you have any prospective plans around combinations? If so, what are you thinking about? Yeah, absolutely. I mean, right now we're in the monotherapy dose escalation, but we do have our hypotheses around areas that we want to look at combinations, both with standard of care agents as well as with investigational agents. I mean, I think one of the most obvious examples, if you're thinking about CRC, you almost always have to combine with an anti-EGFR antibody. I think that would be a great combination partner to look at. In particular, that's probably more of a pan-KRAS type of combination, just given the rash that's associated with a pan-RAS, like 6236, and the rash that's associated with an Anti-EGFR. Perhaps that may be too much from a pan-RAS plus EGFR combo. Right. Maybe lastly, just picking up on a thing you said a minute ago, you said a win would be for 0015 if it had comparable activity and tolerability at a lower dose. Is that right? I think that would be a win for sure, just given the high unmet need in the space, given the potential benefits in terms of having a lower dose from a combination standpoint, given the benefits potentially of RevMed's number one AE is rash, their number two AE is GI. To a certain extent, that could be driven by drug load in the GI tract. A lower drug load could actually lead to a better AE profile. I think there's a lot of advantages even if we're comparable. Of course, if we are better than comparable, if we're superior, that just opens up the world for us even more. Gotcha. I know there's still a ways to go to the sort of phase one data disclosure next year. Do you anticipate providing visibility on duration or time to event endpoints as well, or will it be mostly a focus on response, right, and safety initially? I think it will largely depend on when it is in 2026 that we ultimately report out the data. Obviously, the earlier it is, the less follow-up that we'll have versus the later in the year, the more follow-up that we'll have. It is still TBD. Right. In terms of just, sorry, going back to combinations, there is some interesting combination that can be done combining the pan-RAS or pan-KRAS inhibitors with mutant selective inhibitors. Do you have any plans of looking into that? Yeah, everything is on the table for us in terms of potential combinations. We're going to be data-driven about that. I think the nice thing for us is that we have shown a history as a company of combining with the best agents, whether that's internally developed or external agents. If we see a combination that we want to go after, whether that's a selective, whether it's standard of care, whether it's investigational, whether it's whatever, we have shown that history of finding the best molecule and trying to combine with that. Great. Thank you, David. That is all I had for questions. I really appreciate the time. We will all look forward to the phase I disclosure next year. Thank you. Thank you.