Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have Erasca, with CEO, Jonathan Lim, and CFO, David Chacko. Welcome. Thank you. Great to be here, Jeff. So for those who may not be as familiar with Erasca, can you provide a brief introduction? Yeah. So Erasca is named after our mission to erase cancer and also to eradicate RAS-driven cancer. So we have a pipeline that is really led by three main priorities. Our top priority is ERAS-0015, which is a pan-RAS molecular glue that works by cyclophilin A binding modality, similar to another molecule called RMC-6236. Second priority is ERAS-4001, which is a pan-KRAS inhibitor. That's a switch-II pocket binder, a small molecule. Both of those are preclinical and on track for H1 and Q1 2025 INDs, respectively. And then our third priority is actually our lead clinical asset, it's naporafenib, and this is a pan-RAF inhibitor that is in phase III, so we're really excited about that, and that's for a very focused indication called NRAS-mutant melanoma. I know we'll talk more about the SEACRAFT-2 trial, and then it's also being explored in a phase I-B trial called SEACRAFT-1 for KRAS, basically, RAS Q61X solid tumors. So that's our pipeline, and you know, we really have a great team that's very experienced across the drug development spectrum. Really a world-class scientific advisory board. Our focus as a company has always been on the RAS/ MAPK pathway, to try and shut that down with single agent as well as combination approaches, and so we're still very excited about having the pipeline to be able to achieve that goal one day. Great. Now, before diving into the programs, I wanted to ask, and, you know, about pipeline development and prioritization. You know, a few months ago, you in-licensed the pan-RAS and pan-KRAS, while deprioritizing some of your other pipelines. Can you just talk about your overall strategy when it comes to pipeline development? Yeah. So, you know, we basically were founded in 2018 on a backbone of drug discovery, and so we were pursuing structure-based drug design to go after RAS. At the time, we had some interesting approaches that we developed with Dr. Kevan Shokat from UCSF. And so, while that approach ultimately didn't pan out the way we had hoped, we also supplemented our in-house discovery with inorganic sort of business development efforts. And so, through a series of in-licensing and acquisition agreements, we've brought a number of different molecules, all united by this biological focus on the RAS/ MAPK pathway. Now, one of the hallmarks of the company is that we've been very nimble and data-driven, so we move fast. When we see science and molecules that we like, we work very quickly to in-license them, and so, for instance, you referenced the pan-RAS and pan-KRAS molecules. You know, from our first trip to China to the successful announcement and closing of those deals, that took 17 weeks, so when we see what we like, we move very quickly and we move forward. But we also have been data-driven, so to your point, in terms of portfolio prioritization, we had an ERK inhibitor, and we had a SHP2 inhibitor, and while we still really like those mechanisms, the clinical trials that we had developed those molecules in didn't show activity that warranted moving forward with the next step. And so we're still exploring those molecules in the preclinical setting for other combination settings that we might pursue in the future, but for now, our clinical focus is really on the pan-RAF with naporafenib, and then ultimately, the pan-RAS and pan-KRAS molecules. Great. Maybe starting with the ERAS‑0015, can you just provide an overview of the profile and what you saw in the preclinical activity that you found attractive? Yeah, ERAS‑0015 is a really interesting molecule, 'cause first of all, the pioneer in this space, we have a lot of respect for what they've done. You know, Revolution Medicines has really opened a lot of eyes, in terms of what RMC-6236 can do for patients, especially with pancreatic cancer. So we're just thrilled for the entire space of sort of RAS targeting, and then more meaningfully, for patients that clearly seem to be benefiting from that molecule, which is moving into phase III. I think what excites us about that mechanism is, first of all, that you can have reasonable safety and tolerability. I guess, you know, five years ago, it wouldn't have been intuitive that you can give a pan-RAS inhibitor that basically hits K, H, and N RAS mutations, as well as wild type, and have a you know, a reasonable therapeutic window. And so the fact that you can do that is super exciting for the field. Now, that mechanism, a cyclophilin A or CYP A binding, is also very interesting. And so our molecule, relative to the comparator molecule, which in this case is RMC-6236, ERAS‑0015 has a fourfold higher binding affinity for CYP A, and that translates into a number of interesting attributes. First of all, it's about tenfold higher potency in vitro and in vivo models, and this is across G12D, G12V, G12R, various models that have been tested. And then because of that preferential binding to CYP A, it also translates into a longer tumor tissue residence time. And so, for instance, in vivo models, we've seen at four hours and 24 hours, persistently high levels of ERAS‑0015 in the local tumor tissue environment, which could translate into better target coverage. And then finally, the PK characteristics of ERAS‑0015 in terms of the lower clearance, the longer half-life, the higher percent of oral bioavailability, all of those, as well as maybe less solubility limited absorption that's predicted from the preclinical characteristics. We think all of those bode well for having a molecule that could have a shot at being best-in-class in certain indications. We're really excited about the totality of the preclinical data for this molecule, where reproducibly across different G12D, G12V models, you only need about 1/10 to 1/5 of the dose of the comparator molecule with ERAS‑0015 to achieve the same tumor growth regression. Can you just talk a little bit about what you're hoping or expecting to see in the IND tox studies that will be completed this year? We're hoping to not see a signal. Yeah. ... that is, that's rate limiting. And so I think the good thing is that, you know, the two main things that we need to achieve between now and IND is really in the realm of GLP tox, as you mentioned, and then also CMC or chemistry, manufacturing, and controls. And so with both of those, we don't... you know, we remain on track for the publicly stated goal of filing an IND in the first half of next year. But within GLP tox, the main thing is to test a low, medium, and high dose in both large animal and small animal species. And then that really, you know, whatever you see in the most sensitive species in terms of tox, then helps you set that starting dose in the clinic, and, and from there, you dose escalate. And so we haven't. You know, we're, we're on track in terms of we don't give a play-by-play update on where we are with tox per se, but we can say that we're, we're on track for the publicly articulated IND filing timeline. Okay. And then the pan-RAS and pan-KRAS spaces, they're, it's increasingly competitive. You know, how are ERAS-0015 and ERAS-4001 differentiated from other candidates that are out there? Yeah, so I think with the. Let's talk about the pan-RAS molecular glue space. It's really just Revolution Medicines and us, and then there is a Chinese company that's in earlier preclinical development, and so it's really just three molecules. And we think that, you know, ERAS‑0015 is differentiated in a number of ways, preclinically. Now, this needs to be borne out in the clinic, of course, but we are very excited about its preclinical profile, and ability to potentially differentiate. In the pan-KRAS space, that is pretty crowded, as you mentioned, but even then, there's been no clinical data that have been disclosed. And we think for the pan-KRAS class, there likely will be clinical data that's presented sometime in calendar year 2025, and so we'll be watching that closely, and with anticipation. But in the meantime, you know, we're really focused on getting ERAS-4001 into the clinic, so that we can then see what that molecule can do. Especially, the key features of theoretical differentiation is the fact that it is K selective, and it spares H and N. So it does hit KRAS mutations, as well as KRAS wild type, with a high degree of potency. But because of the H and NRAS sparing, the question is: Is there a wider therapeutic window? Because you may not see as much rash that could be mediated by either N or HRAS. More likely, N is the suspect there for driving a lot of the rash. And so by sparing N and H, can you have a better tolerated molecule, especially as you look at different combinations of what that could be combined with? Now, in July, Revolution Medicines reported updated monotherapy data. Any read-throughs that you saw for your programs? Yeah. First of all, we were super excited. I think for patients, it was great to see meaningfully higher PFS, and if you look at the lower bound of the OS that they reported of eight and a half months, and the data were immature, I think that's really great for patients in an area of significant unmet need. And so I think the read-through is really. I'm bullish for that class of compound of, you know, that mechanism of a pan-RAS cyclophilin A molecular glue. I think that bodes well then for other molecules like ERAS‑0015. And then the fact that you had reasonable response rates, you know, in the twenties versus historical standard of care that's in the single digits. I think you're seeing a meaningful advantage across the board, as a monotherapy, which is really great. Later this year, they'll report updated non-small cell lung cancer monotherapy data. You know, what should Erasca investors be looking for, if anything, from their data to confirm the potential differentiation of your programs? ... Yeah, I mean, I would say that it certainly will serve as a useful benchmark. I mean, obviously within non-small cell lung, you'd like to see something with higher response rates above 30%. The question is, will you get all the way into G12C territory? Will you get higher? I think that's probably less likely based on the early data that have been reported, but can you be on par with G12C, or at least in the similar ballpark with that molecule and that approach? And then I think it just serves as a benchmark then for what we could look at for ERAS‑0015. Irrespective of where that lands, I think, you know, the question is: do those different areas of potential differentiation, whether potency, tumor residence time, PK, solubility, absorption, do any of those translate into upside? I think the fact that there's a number of different attributes gives us some reason for potential optimism there. Great. And how are you thinking about the possibility of combining ERAS-0015 and ERAS-4001? You know, do you see potential for synergy? Yeah. I think the sort of hierarchy of focus would be, can you apply pan-RAS broadly across different indications? And clearly, pancreatic seems to be high on the list of promise based on the data, and that's where we've seen the most data, and so there's a lot of promise there. To your point, we'll see what lung cancer looks like, and then down the line, you'll also wanna see colon and other solid tumor types. I think where the pan-RAS falls short, then you will wanna explore where pan-KRAS can play. And are there areas where pan-RAS doesn't work, where you can really dial up pan-KRAS to really hit the target very hard in terms of KRAS itself. And KRAS really is about 80%-85% of all of RAS-driven tumors, and so that's really where a lot of the unmet need is. And so giving a pan-KRAS molecule with a potentially wider therapeutic window, and then having pan-RAS on board to mop up for any of the resistance mechanisms or any of the isoform switching or mutations that arise elsewhere within RAS, whether NRAS, HRAS, or certain KRAS mutations. Just having the pan-RAS on board, as well as the fact that you have the RAS GTP or RAS on ability to shut that down with ERAS‑0015 will help complement ERAS-4001, which works better on KRAS in the GDP state as opposed to the GTP state. So that combination is really intriguing, based on conversations we've had with KOLs, including our SAB. Okay, great. Let's shift to naporafenib. Can you just talk about its profile, what you've seen on safety? Sure. So I'll take that, and thanks for having us here, Jeff. So naporafenib is our pan-RAF inhibitor that we brought in in December of 2022. It is the most advanced pan-RAF inhibitor in development. It's been dosed in over five hundred patients to date, which includes both monotherapy as well as combinations with various agents. In terms of its preclinical profile, it has very good potency against BRAF and CRAF, which are the two isoforms that you wanna hit from an efficacy standpoint, and then relatively less potency against ARAF, which we think it will help from a safety and tolerability standpoint. It also has a clean kinome scan relative to other pan-RAF inhibitors. And the fact that it's been dosed in the 500 patients that I mentioned just really establishes a wealth of clinical data around safety and tolerability, as well as efficacy where there have been intriguing signals in both melanoma, which we're exploring further within our SEACRAFT-2 study, as well as non-small cell lung. And so as Jonathan mentioned in his opening remarks, we're exploring the combination of naporafenib plus trametinib in the SEACRAFT-1 study, which is a RAS Q61X study that includes melanoma and lung cancer, but also other tumor types where RAS Q61X is highly prevalent. And then SEACRAFT-2 is our study with naporafenib plus trametinib in NRAS-mutant melanoma, which is the pivotal study that we initiated earlier this year. Can you just talk a little bit more on the unmet need in NRAS melanoma, and then for SEACRAFT-2, can you just talk about how patient enrollment is progressing? Sure. So in terms of the unmet need, you know, I think about it in terms of two things. Number one is, you know, number of patients, and then also what are the comparator therapies. So in terms of number of patients, you know, if you look at the funnel of. You know, starting with the top of the funnel, and then you cut by line of therapy and metastatic disease and other sorts of cuts, you know, you're probably talking about a few thousand patients in the U.S. and probably a comparable number of patients in Europe and other parts of the world. So that gives you a sense of the size of the population, so it's a reasonable number. And then in terms of the available therapies, these patients in NRAS melanoma are initially treated in the front line with IO. After IO, the treatment options are pretty poor, actually. So, this approved standard of care is chemotherapy, like dacarbazine, for instance. Single-agent MEK inhibitors are used off-label, but both of them actually have pretty poor metrics. So for instance, PFS, progression-free survival for the chemotherapy is only about one and a half months, and for single-agent MEK, it's slightly better at about two point eight months... versus in phase I and II studies, the naporafenib plus trametinib combination showed about five months of PFS. So about a doubling of the single-agent MEK, about a tripling of the chemotherapy. And then likewise on OS, we shared this data earlier this year because the data from the phase I and II study reached a level of maturity where we were able to analyze it. The data that we showed earlier this year was about 13 to 14 months of median overall survival for the naporafenib plus trametinib combination, versus what we think are the most relevant benchmarks for the SEACRAFT-2 control arm, coming in at around 7 months for those comparators. So there you're seeing potentially a doubling of the overall survival, and so we'll have to see how that bears out in our SEACRAFT-2 pivotal study in terms of both PFS and OS, but the early phase I and II data give us good confidence about that. With regard to the second part of your question, we initiated this study in Q2 of this year, the phase III study, and so it's still early days. Enrollment is moving along. It's still early days, but it's hard for us to, you know, give guidance on enrollment kinetics at this point, but we are still on track for our publicly stated guidance to have a Stage I readout from the phase III study in calendar year 2025. Now, ahead of the randomized Stage I readout, next year, you know, how are you framing expectations around the dual primary PFS and OS endpoints, and how should we be thinking about the bar for success? Yeah. So, just as a reminder for the audience, the phase III study has a dual primary endpoint of both PFS and OS, and that was agreed upon with the regulatory bodies in the U.S. and Europe and other territories. And as I mentioned, the data from the phase I and II studies suggest that we do have a benefit in both PFS and OS. Now, per our discussions with the regulators, it would actually be sufficient to win on one, not necessarily both endpoints, but we have a reason to believe that we could win on both. Now, with regard to the Stage I readout next year, what we're guiding to here is that we will share efficacy data, including overall response rate. I think measures of durability, like PFS and OS, generally take a little bit more time to mature. PFS is a little bit faster than OS, typically, and so, you know, we may be able to share some data around PFS, depending on the maturity of the data and you know, how that's trending, but OS, I think, probably will be a little bit early to share next year. Okay. And then what are the next steps for Stage II? And you kinda touched upon this, but what has feedback been like from, you know, regulatory agencies, on the path for potential approval? Yeah. So the plan that we proposed to the regulatory bodies, and it was in the second half of last year that we were having these conversations, was ultimately more or less the plan that was agreed to with them as well, and so that was to have this dual primary of PFS and OS. It's to have this Stage II or two-stage design, where Stage I is a dose optimization stage, where we're looking at two different doses of the combination of naporafenib plus trametinib, especially in light of things like Project Optimus from the FDA, and then comparing that against single-agent MEK. That is an open label study, so that with as few as 60 patients or as many as 120 patients, we may be able to then say, "Okay, we've got a dose that we like," that we then wanna meet with the FDA and other regulators to inform them of what we're seeing and get their buy-in that, "Yes, we like dose X the best and wanna move forward with that." And then we'll be able to put that dose into Stage II, which will ultimately then be up to 350 patients for that, potential approval. For SEACRAFT-1, with data expected in the fourth quarter, you know, what are you looking for to decide between pursuing a tissue-agnostic or a tissue-specific approach for the mutation? Yeah. And as a reminder, SEACRAFT-1 is enrolling patients with RAS Q61X solid tumors, and those that mutation shows up in about a half a dozen tumor types, including melanoma and non-small cell lung, where Novartis has already demonstrated some data there, but also other tumor types like CRC, pancreatic, head and neck, thyroid. And so what we're doing in SEACRAFT-1 is enrolling across the spectrum of where RAS Q61X is highly prevalent. What we'll look at in terms of the data is, you know, essentially, are we seeing a signal that supports a tissue-agnostic label versus potentially something that's more tissue specific? And so depending on what that data look like later this year, we'll then be able to make a call about whether we are seeing a promising signal truly across the board versus in a more narrow, you know, set of populations. And then be able to move forward with, you know, wherever it is that we're double down, essentially, where we're seeing the signal. Great. Maybe one last question. Can you just remind us how much cash you have in the runway? Yeah. So as of Q2 filing, we reported $460 million of cash. And with that money that we were able to raise in Q2 of this year, we were able to extend our runway into the first half of 2027. So we're well capitalized. We've got a number of readouts for naporafenib from SEACRAFT-1 and SEACRAFT-2, as well as from the two new RAS assets that we talked about, between now and that dry well date. Great. We'll leave it there. Thanks so much for your time. Thank you. Thank you. Good to be here.