Associate on Maury Raycroft's team here at Jefferies. I'm happy to introduce Jonathan Lim, Chairman and CEO, and David Chacko, CFO and CBO of Erasca. Thanks for being with us here. Maybe to start, for those who are new to the story, could you please provide a one-minute overview of Erasca and your key programs?
Yeah, thanks. I mean, really great to be here. Erasca is named after our mission to erase cancer and also to eradicate RAS-driven cancer. Our pipeline is entirely focused on the RAS/MAPK pathway. We have a modality-agnostic pipeline really anchored by our RAS-targeting franchise. That is the main thrust of our focus as a company in terms of bandwidth as well as resources. Our pan-RAS molecule, ERAS-0015, is a pan-RAS molecular glue for which an IND was cleared recently, a few weeks ago. Likewise, our pan-KRAS small molecule inhibitor, ERAS-4001, is a switch-II pocket binder. Also pleased that our IND for that molecule was also cleared. Both of those molecules are moving in the clinic this year. I know we will talk a lot more about those. We also have a pan-RAF inhibitor called naporafenib.
That's a phase III program, and that is really focused on NRAS mutant melanoma. We're excited about that program as well, but we're finding a strategic home for that as we announced a few weeks ago. Earlier in the pipeline, we have ERAS-12, which is our one biologic in the pipeline. This is a bispecific antibody that targets both domain II and domain III of EGFR. That is the active confirmation of the receptor as well as the inactive confirmation. Just by way of background, panitumumab and cetuximab, they both are domain III binders, not domain II. We could have the only bispecific that targets both.
Okay, great intro. Congrats on getting INDs cleared for both ERAS-0015 and ERAS-4001.
Thank you.
Have you begun enrolling any patients on these trials yet, or they're still in the early stages of getting the trials up and running?
Yeah, so we do not guide to first patient dosing or anything like that, but we are making really great progress with both of the trials. We actually met with a bunch of investigators that are involved in both studies. AURORAS-1 is our phase I trial for ERAS-0015. BOREALIS-1 is our phase I trial for ERAS-4001. The design is dose escalation for both of those, followed by monotherapy expansions in key areas of interest. All that is going on track.
Great. Are you saying anything on the number of patients you are planning to enroll and how many dose levels you are planning to explore in these two trials?
Yeah, so I think RMC- 6236 is sort of a pioneer and a trailblazer in this particular space for the pan-RAS molecular glue, for instance. If you look at the number of dose levels that they explored, it was about 10 dose levels. I think we'll probably be in that ballpark, would be my guess. In terms of number of patients, we're doing a very robust study for both the pan-RAS as well as the pan-KRAS molecule. It is a dose escalation as a monotherapy, but we're not going to have just three patients at every level, for instance.
Good point on RevMed. I think they enrolled between 10 mg and 400 mg doses, and many of them had like 10 patients or more. Are you planning to have that many patients, or do you think you can be more targeted and with a lower number of patients you can achieve the goal of the phase I?
Yeah, I mean, our goal is really to have an interpretable data set. So I do not think we'll be at three patients, for instance, but we'll have a robust number of patients at every level so that we can fairly interpret what the safety, what the PK looks like at various levels, especially at the higher levels. We'd like to see linearity and dose proportionality without an exposure plateau. So I think that would be really great if we can see that. And then, of course, efficacy at the biologically relevant doses.
What are your expectations for dosing frequency for both ERAS-0015 and ERAS-4001 based on your preclinical data?
Yeah, based on the preclinical PK, we think that, for instance, the predicted half-life of ERAS-0015 should be about 24 hours or so. So that's very amenable to once daily dosing. I think for ERAS-4001, the predicted half-life is shorter than that, but still we should be able to see once per day or QD dosing for 4001. BID would also be a backup for 4001. We don't think that that will be needed for ERAS-0015, but if we need BID, we can explore that for 4001.
Are you enrolling RAS naive patients, or you also include RAS experienced patients as well?
Yeah, for the dose escalation expansion, it's mostly RAS naive.
Your preclinical head-to-head data suggests ERAS-0015 may achieve comparable efficacy at lower doses than Rev Med's drug. Based on these data, do you have a sense of how much lower your efficacious dose might be versus Rev Med's?
Yeah, so if you take the preclinical data at face value for ERAS-0015 versus RMC- 6236, what's interesting is that, just as a reminder, scientifically, we really like our molecule because of the 8-21-fold higher binding affinity to CypA. So what that means is ERAS-0015 binds CypA to form the bipartite moiety in much higher quantity than 6236 with CypA. I call it a Pac-Man molecule, but that bipartite moiety then goes hunting for RAS in the GTP or on state to form the trimer or the tripartite moiety to then take RAS out of circulation. As a result of that higher binding affinity, we see a number of key attributes preclinically. One is in vitro, you see a 5-10-fold higher potency advantage.
To your point, in vivo, we're seeing very good tumor regression at just about 1/10 of the dose of RevMed. If with RMC- 6236, you need 10 mpk or milligrams per kilogram to see tumor regression, with ERAS-0015, you only need 1 mg per kg. We think that advantage is interesting. The other advantage is because CypA is overexpressed by multiple solid tumor types, including the big three tumor types like PDAC, colorectal, and non-small cell lung cancer, there's sort of this depot effect where CypA is just much more prevalent in the tumor and associated tissues. By binding CypA with higher binding affinity, it's sort of soaking up the ERAS-0015 in the tumor. The tumor tissue residence time is much longer with ERAS-0015 than it is with RMC- 6236. The final advantage is really the PK advantage.
When you look at the lower clearance of ERAS-0015, the longer half-life, and then the higher oral bioavailability, all of that gives a stronger preclinical PK profile. The totality of that, what does that mean? To answer your original question, if RMC- 6236, if efficacy was observed at 80 mg, then we are hopeful that maybe at 1/10 of that dose, so at 8 mg, you might start to see efficacy with ERAS-0015.
Great. Any learnings on safety differences based on preclinical data?
Preclinical data are notoriously difficult to translate from that into what would happen in the clinic. I guess the theoretical advantage of having more tumor residence time than, let's say, drug level in the blood is that there's a hypothetical advantage in terms of if that translates into a therapeutic window advantage, then that could be potential upside in safety. I do not want to overstate that because that really has to be shown in the clinic, but at least in a preclinical setting, there's some interesting phenomenon there.
Okay. Have your partner in China filed and cleared IND for ERAS-0015?
Yeah, they filed successfully in China in the fourth quarter of last year. Yeah, that IND has been cleared.
Are you coordinating data disclosure plans with them? Should we expect data from China ahead of the U.S.?
Yeah, so our data guidance, which is 2026, is based on what we can control, which is our data. Now, in terms of China, our partner has rights to disclose their data in their territory. We have rights to disclose our data in our territory, which is everywhere outside of China, Hong Kong, and Macau. We certainly have line of sight into when they might want to disclose their data as well as vice versa. In terms of our guidance and what we can control, it's really based on the ex-China data.
Okay, clear.
That's for ERAS-0015. Just as a reminder, for ERAS-4001, we have global rights for that, so there's not a Chinese partner for that.
Assuming efficacy is observed in PDAC, non-small cell, and CRC, which of these indications would be your priority given the current competitive landscape?
Yeah, I think wherever the most promising data are, we just go. We are moving very quickly. We are taking a comprehensive view of the landscape, both in terms of the big three tumor types as well as the long tail of tumor types. We are sort of doing robust experiments, if you will, to just see where the most promising signals are. We will go after that. We will double down in those areas of interest.
For the phase I, beyond non-small cell, CRC, and PDAC, are there other indications you are considering to enroll within the phase I phase?
Yeah, I think in the phase I, we want to move as fast as possible. If you go to where the patients are, most of the patients are in the big three. It is sort of Pareto principle of 80/20. 80% or more of the patients will be in the big three tumor types. Just to manage expectations, most of the data will probably be in one of those big three or multiple of those big three tumor types.
Okay, that's clear. For ERAS-0015, what do you need to demonstrate in earlier studies to differentiate from RevMed's drug? Is showing comparable safety and efficacy enough, or do you aim to show superiority?
Yeah, I think if you show comparable data and you are fifth in class, then that's probably not enough. If you are second in class, we think that's the unmet need in all of these indications that we're talking about are unfortunately really high. The flip side of that is that enrollment should be fairly brisk, just given how many patients there are. I'd say that's sort of our minimum expectation. Now, there's upside, as I mentioned, on safety. There's upside on PK because if we don't have the sort of pH solubility, pH-mediated solubility issues that sort of cap exposure, and we can maintain dose proportionality at the higher doses, that's upside. That could translate into sort of the third parameter, which is efficacy that everyone also really cares about, and especially patients.
That's something where if we show better efficacy, cross-trial comparisons notwithstanding, then that'll be really exciting, I think, for patients.
Okay. Let's talk about your recent decision to pause the naporafenib development program. From my understanding, part of the benefit here is to extend your cash runway for the RAS programs with less near-term pressure to raise capital. What's your data disclosure strategy for both 4001 and 0015?
Yeah, so I think with napo, we're very excited about that, but we think that that program in the hands of a strategic partner that is really focused on Oncoderm and delivering that product to patients is really the right thing to do. To your earlier point, RAS is just such a competitive space that we really want to, by doing this, we actually ironically become one of the best, if not the best capitalized company in RAS, where we can really fully prosecute the early clinical assessment of both the pan-RAS as well as the pan-KRAS molecules. To answer your question, our data disclosure is basically disclosing monotherapy data for both assets in calendar year 2026. When we go out with that disclosure, it'll be ideally an interpretable data set with robust safety, PK, and efficacy data at biologically relevant doses.
Okay, that's clear. Are you guiding on how many patients you are planning to show data in 2026?
I mean, I can comfortably say it'll be dozens of patients. Yeah, stay tuned on that.
How are you thinking about development timelines for both 4001 and 0015 beyond 2026?
Yeah, we're going to be moving very quickly for dose escalation monotherapy. We'll be expanding monotherapies in key indications of interest. We'll also be starting to look at some combinations.
That would be actually interesting. You have recently done additional preclinical work and also reproduced some of the preclinical data for 0015 and 4001 originally generated by your partners in China. Were there any new insight from this additional work that you have done?
Yeah, so I think first of all, our partners did great work because when we looked at sort of reproducing the preclinical data for both ERAS-0015 and 4001, they reproduced with a high degree of accuracy. That was great to see that everything that we had looked at last year to in-license those compounds, that bore out. I'd say we had sort of key insights for both programs since then. One is the finding that ERAS-0015, like RMC- 6236, works by two mechanisms. One is basically shutting down the effector binding of RAS-RAF in terms of blocking the cascade. The second is by increasing hydrolysis of RAS from the GTP state to the GDP state. In our poster at AACR, we were able to show that that finding is mechanistically of interest and relevant to ERAS-0015 as well, which was great to see.
I'd say the key finding on 4001 is that it is not just a GDP binder, but it also binds KRAS in the GTP state. It is not just an off-state, but also an on-state binder.
You mentioned about the combination strategy. In your phase I studies for both programs, is there a potential to explore combination strategies as well?
Yeah, that's right. We are going to be looking at combinations. You can imagine a range of standard of care options depending on whether you're talking about non-small cell versus CRC versus PDAC. What we'll ultimately be combining with is those standard of care agents across those tumor types.
That data, are we expecting it in 2026 as well, or that's the next step?
The 2026 data disclosure will be the phase I monotherapy data.
Okay. Switching gears, gear two, competitive landscape. Despite the large market opportunity and the RevMed's proof of concept, there are only a few pan-RAS programs in development. Why do you think competition in this space remains very limited?
Yeah, it's a great question. You know, I think just to set the landscape for the audience, RMC- 6236, as Jonathan mentioned, is a leader in this space in terms of having been the first to disclose clinical data here. I think what investors really like about the Erasca molecule 0015 is the fact that we're solidly in second place. There really aren't that many competitors, to your point. Especially as Jonathan mentioned, with all of the various preclinical differentiators around cyclophilin A binding, potency, in vivo activity, PK, all of those lead to a potentially better profile versus what's being seen with 6236. Now, why are there so few players in this space? You know, I think the challenges from a chemistry standpoint in terms of developing a new pan-RAS molecular glue, they're not trivial. It's actually really hard to develop new molecules.
The IP space is relatively limited. You put those two together, it's actually hard to find a molecule that can adequately address the pan-RAS molecular glue space. The way that ERAS-0015 was able to find that white space and still be better in many preclinical respects is really interesting.
It's really interesting because in contrast to pan-RAS, in pan-KRAS space looks very crowded with many preclinical presentations at AACR. Do you see any advantages of pan-KRAS over pan-RAS?
Yeah, so what we see in terms of pan-RAS versus pan-KRAS, with a pan-KRAS, you're sparing H/ NRAS. That may lead to a wider therapeutic window versus the pan-RAS inhibitors. Especially as you're thinking about combination plays, that ability for a molecule like 4001 to combine, especially in certain indications, could be advantageous. I think this is certainly still an open question until there is more clinical data in the pan-KRAS space. What's nice for us at Erasca is that we have both a pan-RAS and a pan-KRAS. Depending on how the space evolves, we have an answer for both.
Although many players are active in pan-KRAS, clinical data are still lacking. How do you view the competitive landscape? Are there any specific programs you are closely monitoring based on the preclinical data?
Yeah, one of the things we liked about 4001 when we brought this molecule in last year, about 13 months ago, was that it had a really good preclinical profile. We still feel that way. We have actually been able to discharge some of the potential risks associated with that molecule. We have been able to file and clear the IND. We feel really good about that. In addition, it was in the first wave and still is in the first wave of compounds soon to be in the clinic to helping patients. To your point, when the field is getting more and more crowded, what you do not want to be is super far behind in the pack. Because we are in that leading wave of compounds to enter the clinic, we feel good about the preclinical profile and its timing.
We are watching others that are in the space. As you mentioned, there are others that are in the space, including the big pharmas like Pfizer and the Lilly's of the world and smaller companies like Jacobio or Alterome as well that are in the space. We are watching all of them closely in terms of their data disclosures. To your point, at this point, it's only been preclinical disclosures, no clinical data to date.
Yeah. With naporafenib on hold, what's next for this asset? Do you anticipate a quick out-licensing process, or could it take time to find the right partner here?
Yeah, so naporafenib, as Jonathan mentioned, is our phase III asset that is in the SEACRAFT-2 study in NRAS mutant melanoma. That study, when we designed it, had a built-in pause between the stage one and the stage two portion of the study. That is actually where we are right now in that built-in pause. This is actually a perfect time for us to seek a partner for naporafenib. Those are the discussions that we're having now. I would say that BD, by its nature, tends to be speculative. It is hard to answer your question about whether it is quick or what. We will continue to engage with partners. We've had some promising discussions to date. Again, BD tends to be speculative, as you know.
You collected some data on the first part of this phase III. Are you planning to disclose that in the near future, or is that going to be the partner's decision?
No, that'll be up to the partner. We are not planning to disclose the napo SEACRAFT-2 stage one data.
With approximately $411 million in cash and a runway into the second half of 2028, what are your key objectives for 2026 and 2027?
Yeah, so on the numbers that you mentioned, $411 million of cash runway into the second half of 2028. As Jonathan mentioned, we are one of the best capitalized, if not the best capitalized company in this space. Having more than three years of cash, especially in this environment, we feel really good about. In terms of key priorities for 2026-2027, it is really about generating meaningful data sets that allow us, as well as the external world, to be able to interpret what the data mean. That is all about very good, efficient execution of the clinical trials as well. As Jonathan mentioned, for 2026, which is what we have guided to thus far, we will have phase I monotherapy data for both the ERAS-0015 pan-RAS molecule as well as the ERAS-4001 pan-KRAS molecule.
Okay, great. Thank you very much for joining us.
Thank you.
Thank you.