Let's kick off the next session. I am pleased to welcome David Chacko from Erasca for our next presentation. David, welcome. I believe this is the first time that I met you in person.
Yes.
We also host you at the Goldman Sachs Conference.
That's right.
Thanks for being here. I'll kick it off to you for opening remarks.
Yeah, thank you for inviting us. It's been great. We've been coming to the Goldman Sachs Conference for a few years now, previously covered by Chris Shibutani, as you know. It's great to be here with you again. Maybe just a brief overview on the company. I'll start there. The company Erasca, our name is our mission to erase cancer as well as to eradicate RAS-driven cancers. RAS is mutated in up to about a third, to maybe even up to half of all cancers that are diagnosed annually. It's a really important driver between RAS itself as well as the rest of the pathway. Our company was really focused around that mission to eradicate RAS-driven cancers. Over the years, we've built what we believe to be one of the most comprehensive pipelines in the industry going after this pathway.
Right now, our 2 RAS programs are ERAS-0015, which is a pan-RAS molecular glue, as well as ERAS-4001, which is a pan-KRAS inhibitor. Both of these molecules we licensed in May of last year. They have been in our hands now for about 13-14 months. We have made tremendous progress on both of them, having filed and cleared INDs on both of them within the last several weeks and are now off to the races in terms of those programs. We also have ERAS-2, and I know we will spend a lot of time talking about both of those programs. We also have ERAS-12, which is a bispecific antibody targeting domain 2 and domain 3 of EGFR.
All of the approved EGFR inhibitors like panitumumab and cetuximab target the inactive state, which is the domain 3 state of EGFR, versus our molecule has the ability to go after both the active and inactive state. That's an earlier stage program, so we don't spend as much time talking about those. Certainly, the two RAS programs, ERAS-0015 and 4001, are where most of the focus is today.
Got it. Sounds great. Maybe just a little bit about, help people who are newer to the story, including myself, to understand why choose the RAS and the KRAS, because these are two highly competitive markets. Where do you see you guys fit in and where the unmet needs are?
Yeah. We are really interested in these RAS programs because we think the unmet need here is huge. I mean, there are millions of patients that are diagnosed annually, as I mentioned, with these RAS mutant tumors. We think that having 0015 and 4001 allow us to go after the huge unmet need here and to be able to help patients. We think that both of these programs exhibit competitive profiles. 0015, we think, is a best-in-class pan-RAS molecular glue. That space is actually relatively open, so to speak, in the sense that there's one competitor ahead of us, Revolution Medicines, with their RMC-6236 compound. They've done an incredible job of blazing the trail in this space. Because of the chemistry challenges as well as the IP challenges associated with making a new molecule, this space is actually relatively uncrowded, as I mentioned.
Pan-KRAS, on the other hand, that one does have more players in it. What we like about our program, in addition to its profile in terms of its in vitro activity, its in vivo activity, its adenine PK properties, we also like the fact that we're on the leading edge of molecules to enter into the clinic in this space. You're right that it is becoming increasingly crowded. Being in that first wave to enter the clinic and then to be able to show data should allow us to differentiate on this program as well. The unmet need here is huge. We think that having a best-in-class molecule in 0015 and a potential first-in-class molecule in 4001 positions us well here.
I see. Got it. First of all, congrats on a recent IND clearance for both programs.
Thank you.
Maybe just we might ask, what's the path forward from here? What's the timeline looking like in terms of entering the clinic? And then what's the path forward to hopefully commercial?
Yes. So yeah, we were very pleased to have IND clearances for both 0015 and 4001 in the month of May. Getting 2 INDs cleared in the same month is incredible and great work by our team in terms of really executing well to make that happen. Especially, as I mentioned, the fact that we brought these assets in in May of last year. Really call it about a year after in licensing the molecules to have their INDs get cleared is just a really great feat. Our official guidance on those 2 programs were that we would have filed the INDs by mid Q2 in the case of 0015 and by Q2 in the case of 4001. We were actually able to beat our own guidance in that respect.
Our next guidance on both programs is that we will have phase one monotherapy data for both programs in calendar year 2026. Next year will be a big year for us in terms of having the clinical data on both of these programs and seeing what the monotherapy data look like there.
I see.
At that point, we'll move forward into various paths depending on what the monotherapy data show us. We can continue to evolve our clinical development plan accordingly.
OK, fantastic. You guys presented some new preclinical data back at AACR. Maybe walk us through the data. What are some key highlights? What got you excited looking at that data?
Yeah. So a few things in that data. One is that we were able to replicate a lot of the data, pretty much all of the data from the licensors. When we brought in these molecules in May of 2024, there was a set of data that we had looked at from the licensors. With both 0015 and 4001, we were able to replicate that data. That is in large part what we presented at AACR. For instance, on 0015, we showed that it binds very well to cyclophilin A. Just as a reminder on the mechanism, this molecule works by binding cyclophilin A to form a bipartite complex. That bipartite complex then goes and searches for the RAS protein to form the tripartite complex, similar MOA as the Revolution Medicines 6236 molecule.
We were able to show that our molecule has very strong binding affinity, about 8-20-fold higher binding affinity to cyclophilin A compared to 6236. We were able to replicate the in vitro data that show about 4-5x greater in vitro potency compared to Revolution Medicines 6236. We were able to show good in vivo data that show our ability to dose at about 1/10 of the 6236 dose and still achieve comparable levels of anti-tumor activity. Likewise, on the adenine PK side, we were able to replicate some of that data as well. On 4001, which is our pan-KRAS molecule, again, we were able to replicate the licensor data around adenine PK in vitro and in vivo activity as well.
In addition to that, we also showed combination data of both of those molecules, so 0015 with Cetuximab as an anti-EGFR combination, as well as 4001 in combination with Cetuximab. That was also good for us to be able to show the in vivo activity both from a tolerability standpoint, but of course from the efficacy standpoint.
I see. Got it. So you mentioned that 0015 was able to show something similar to 6236 at a much lower dose, right? I mean, is that sort of the direction you want to go into? Would that translate to a lower dose in a clinical setting?
Yeah, that's the idea. We think that based on our PK modeling that we've done so far, that our human dose will probably be on the order of about one-tenth of what we're seeing from the comparator molecule in terms of its clinical dose. That is good from a number of perspectives in terms of allowing for potentially better GI tolerability. Our molecule also seems to be more potent, which can lead to enhanced efficacy potentially. Of course, all of this will need to be borne out in the clinic. It gives us reason to believe that our molecule does have a differentiated profile potentially from both an efficacy and a safety tolerability standpoint.
Great. In these preclinical models, what do you think is, my guess is that you would take a couple doses forward into the phase one study and all that stuff. Have you established what you think is the minimal efficacious dose going forward?
Yeah. I mean, ultimately, that will be determined by what we see in the clinic. We are pleased with our starting dose actually for both molecules. The starting dose is informed by what we saw in GLP tox. We are pleased with the starting dose. As we escalate both of those molecules, we'll see where the human efficacious dose lies. As I mentioned, in the case of 0015, we anticipate that that'll be probably about 1/10 of where Revolution Medicines is.
I see. OK. Also in your corporate presentation, I think you guys showed some adenine and tox profile for both of these ERAS assets. So 0015's potency against CYP2C9 seemed to be pretty high there. Any concerns there? Any concerns about DDI?
The short answer is no. We're not concerned. 2C9 is a CYP2C9 P450 that is generally not as clinically relevant as some of the other ones. That is the main reason that we're not that concerned about it. The other thing that I would say with regard to that value is that DDI tends to be evaluated in a sequential manner. First you do your in vitro studies, which this one is. You have your in vivo studies as well. Then you have ultimately your clinical pharmacology. We will continue to investigate both of our molecules. We've done that historically with all the molecules that we've had previously. We'll investigate the DDI risk in a sequential manner. What we've seen so far, even with 2C9, we're not that concerned about.
I see. What about potential combination partners or things that you think about? I think you mentioned Cetuximab.
Yeah. So I mean, we'll ultimately look to combine with various standard of care agents. I think you're asking in the context of DDIs. We'll look at that as we develop the data. At least right now, we're not anticipating that to be a major issue given that CYP2C9 is not as clinically relevant to CYP450 as other forms of the protein.
I see. OK. And then for 0015's PK profile, it seems to have a longer half-life and a lower clearance compared to 6236. Are you guys anticipating 0015 to be given as a daily pill? Or what's the dosing regimen potential here?
Yeah, most likely it will. Just as a reminder for the audience, we characterized 0015 versus 6236 across four different animal species, both small and large animals. We showed a good profile in terms of its PK properties. We also showed across three metrics in particular that all three were favorable for us. As you mentioned, we had lower clearance, we had a longer half-life, and we had higher bioavailability orally. All of those should favor the QD dosing and also favor the profile of the compound relative to the comparator. We anticipate that that should actually help us in terms of the continued advancement of the program.
I see. Is there any concern that because of the longer half-life and the lower clearance, that the drug could accumulate over time in the body and increase the risk for tox? Since I think for RAS inhibitor, we have things like drug-induced liver injuries and hepato-tox. Just any thoughts there?
Yeah. So that's of course something that we're going to be watching as we are in the clinic. I would say that accumulation in and of itself is neither a good thing nor a bad thing. It's just a natural consequence of repeated dosing in humans. That's true for really any drug. That's something that we're going to be watching because obviously you want the optimal balance of the enhanced efficacy that you get from the drug being on board and having good exposure, but also, as you're pointing out, that there could be some tolerability challenges if you have too much drug on board. As with any oncology drug, it's about finding that optimal balance. We will continue to monitor that and make sure that we find that optimal therapeutic window for the drug going forward.
We do not anticipate that accumulation in and of itself will be an issue for this drug. Now with regard to your question around the DILI and hepato-tox, that tends to be seen mostly, at least in the RAS space, with the KRAS G12C inhibitors, which were covalent binders and led to haptenization in the liver. I think that is what drove a lot of that liver tox. Our molecule does not follow that same binding form. We do not anticipate having that issue for us either.
I see. OK. For the pan-RAS, for the 0015, have you characterized sort of the inhibition across the various types of RAS? Because there is some HRAS and NRAS that could lead to some safety and off-target tox effects. Just curious if you have looked at across the RAS, different types of RAS, and the binding to these different ones.
Yeah. We did look. Our molecule binds RAS actually in all three isoforms, binds it really well, which is actually what you want for a pan-RAS molecule in terms of potential for acquired resistance and other sort of ways that the cancer can adapt. We have looked at that. We do not actually see anything both in our in vivo studies, but also in the GLP tox studies. We do not see anything untoward. We are again pleased with where we landed in terms of how that drug is progressing through the preclinical studies and now as we have cleared the INDs on 0015. Now with regard to kind of going forward, I think that we will continue to watch that and see if there is any issue.
The nice thing is that Revolution Medicines has largely de-risked the pan-RAS target and shown that you can actually safely administer, in that case, RMC-6236, but in our case, 0015, and have a pretty reasonable profile both from a safety and an efficacy standpoint. The other advantage that we at Erasca have is that we have 4001, which is our pan-KRAS inhibitor. That molecule is specifically designed to spare H and NRAS. To the extent that you do see toxicities that are driven by H and NRAS, then a pan-KRAS inhibitor should theoretically provide you with even a better therapeutic window. We will be able to test that hypothesis given that we have both 0015 and 4001.
The nice thing is that if you ask the field as a whole, nobody yet knows whether pan-RAS or pan-KRAS will be better or whether one will be better in a certain setting and the other will be better in a different setting. Regardless of how that field evolves, the nice thing for Erasca is that we're well positioned having both. We have an answer either way.
I see. OK. So you guys guided the two initial phase one data for 0015 and also for 4001 in 2026. Sort of what's the status in terms of kicking off these studies and any concern about enrollment? Because again, just being some of these studies could is in a competitive field. Any concerns regarding enrollment? How do you guys think about it?
Yeah. We have guided to phase I monotherapy data, as I mentioned, for both of these molecules in calendar year 2026. We are not that concerned about enrollment. As you have mentioned, this is a competitive space. The unmet need here is huge. The number of patients that are diagnosed annually with these RAS mutant tumors is ginormous, right? I mean, you are talking about 2.2 million patients that are diagnosed annually with KRAS mutant tumors and 2.7 million if you include HRAS and NRAS as well. The prevalence of the incidence as well is tremendously high. We do not anticipate there being issues from an enrollment standpoint. Since bringing in these molecules in May of last year, I have been talking to all of the leading centers and all of the leading KOLs in the space.
They're very excited about the profiles that we have for both our 0015 and 4001 compounds. There are more sites and more PIs that want to be part of the study that unfortunately can't just given the size and scope of a normal dose escalation. We don't actually anticipate there being issues from an enrollment standpoint.
I see. Are both studies going to be mostly in the U.S.? Is it going to be part of Europe and U.S.?
Yeah, mostly in the U.S., especially for the phase one monotherapy dose escalation portion. As we expand out, we'll expand territories as well too.
I see. OK. So in your view, what is the bar to aim for, especially when you look at 6236? Is it more, I mean, are you looking at both the efficacy, safety, and sort of what is the bar that you think you have to achieve for that go and no go decision?
We view this space as it's not a zero-sum game. We actually view this more as a rising tide raises all boats. We are actually cheering for Revolution Medicines to be successful because I think their success is ours and our success is theirs. Just given the huge unmet need in this space, it can easily support two players, if not even more than that. Given the huge number of patients that are diagnosed annually with these types of tumors, there is just a tremendous lack of available therapies right now, especially approved therapies in this space. We think that ultimately there are a couple of ways to look at it.
I think even if we show that we are equivalent to Revolution Medicines, and we actually think that we'll be better in many respects, as I kind of alluded to earlier, but even still, it's such a large number of patients that we can potentially split between the two companies versus if we truly end up being differentiated across whether it's efficacy, whether it's response rates, whether it's some measure of durability, whether it's the PK profile, whatever it might end up being, we think that then the potential just becomes that much larger for us. Because again, this is not a zero-sum game. Certainly, there are some spaces where every patient that company X enrolls is that much fewer patients that company Y can enroll. That's not the case here. Unfortunately, there are just too many patients that need these therapies.
That is why we think that this is a kind of a rising tide raises all boats kind of situation for us.
Interesting. A lot of times when we think about ontologies, mostly we're going to take most, maybe not all, but take most type of market. This is a market that you don't think that's the case. You think you can kind of, what, they coming from behind, if you don't achieve best in class or better than Revolution Medicines, that there still could be two winners.
Yeah. Again, I think that our base case is that we assume that our preclinical profile looks differentiated. We are hoping to show that as well clinically. I think there are examples in oncology where you have a second or a third to market that ultimately does end up becoming the market leader. I think there are many examples of what you are describing, but also of the other where a second or third player can actually come in and still do quite well.
Got it. What about 4001? That's a little more competitive. What's the bar there that you need to show for, again, your own internal go/no go decision based on these phase one studies?
Yeah, the bar there I think is a little bit more difficult in the sense that there isn't any clinical data that's been released to date for the pan-KRAS class. It's hard to know what others may see. We'll know more about the bar once there are clinical data in the space. What I can say is that if you look across the board at others that have released data, whether it's in the G12C space, in the case of some of those first-generation molecules from the likes of Amgen and Mirati or now even DevaRASib, or if you look at the G12C space, there was some of that data last week or two weeks ago at ASCO, that gives you a sense of where we might want to be.
Now granted, those are mutant specific molecules going after just a segment of the population as opposed to pan-KRAS that can go after a broader swath of patients. That gives you a sense of what some of the initial data are shaping up as. As we have clinical data in the pan-KRAS space, we can ultimately see where it is that we need to be as well.
I see. Got it. So you alluded to this earlier about combination potential and therapies and stuff like that. Maybe give us your preliminary thoughts on that. Obviously, we see combination with PD-1s and for NSCLC and then EGFRs for CRC. What's your current thinking about combination therapies, maybe timeline for that, like when you would expect to do these types of studies?
Yeah. Yeah, I mean, I think ultimately we're going to be looking to combine with standard of care across different indications. I think that'll be an important part of our clinical development plan just given the ability of RAS, MAP kinase tumors to adapt around whatever you throw at it. In some ways, you have to be thinking about combinations to comprehensively shut down the pathway. I think as well, one other point that I'll mention here because you brought up the combination with Pembro. As the audience knows, Revolution Medicines showed data in December of last year in non-small cell where they showed the combination of 6236 plus Pembro.
For us, that was a good sign because what they showed is that you can combine the pan-RAS molecular glue class with Pembro, especially going back to one of the earlier questions you asked around drug-induced liver injury. That was a question mark for the class, especially in light of some of the early data from the KRAS G12C space. We felt that our molecule should be able to be combined with anti-PD1. Now having seen the Revolution Medicines data, we have even more conviction about that ability for us to combine there. Ultimately for us, in terms of timelines, we have not given specific guidance around timelines. Obviously, we want to move as quickly as we can. I think this year, 2025 and 2026 will be years of execution for us.
We've already shown that with the two INDs getting cleared last month. Now it's off to the races in terms of getting these trials through their monotherapy and then ultimately into combination.
I see. OK. And then both of these assets, I think you mentioned that you brought those in last year.
Yep.
Maybe remind us about some of the applications from the deal that you made, like the royalty applications, milestones.
Sure. Yeah. We struck two deals in May of last year. One, I'll start first with the pan-RAS molecule, which is ERAS-0015. That one, it's a traditional license arrangement. We paid an upfront. There's also various milestones and royalties. The upfront on that deal was $12.5 million. The total deal value before royalties was, if I remember correctly, around $189 million or so. Most of that is actually back-ended in terms of sales-based milestones. There's a low to mid single-digit royalty on that. That particular license agreement that we struck was actually for ex-China rights. The licensor actually maintains rights in China, Hong Kong, and Macau. We have worldwide rights excluding those three countries. At our option, we have the ability to buy out China, Hong Kong, and Macau from the licensor by making a one-time payment.
The amount of that one-time payment depends on whether we do it prior to a certain date or after that date. With that option, we have the ability, again, at our election to convert our territory to full worldwide. The other molecule, ERAS-4001, the pan-KRAS inhibitor, that is also a traditional license. That one, we actually do have worldwide rights on that program. There, the upfront was actually even lower. It was only $10 million. The total deal value on that deal, if I remember correctly, was around $170 million, most of that again being back-ended in terms of sales-based milestones and a low single-digit royalty on that as well.
We're pleased with both deals in terms of being able to acquire what seemed to be very good assets and to be able to do so in a way where the upfronts were very reasonable. We only paid a total of $22.5 million for both assets in terms of the upfront payments. Most of it is back-ended. The royalties, as I mentioned, are quite reasonable.
I see. Got it. Prior to these two assets, you have a pan-RAS inhibitor. That was in a pivotal phase three study. You paused that study. I think you went to a strategic decision to focus on these RAS, these two new RAS molecules. What drove that decision? Where are you now with the pan-RAS in terms of thinking about partnering and the partnership?
Yep. So just as a reminder, the pan-RAS inhibitor, we brought this in from Novartis. It's called Naperafnib. We brought this in from Novartis in December of 2022. And we enrolled this in a couple of trials that we referred to as CCRAFT 1 and 2 study. CCRAFT 2 is the one that you're referring to, Richard, in terms of it being that phase three study that was actually a two-stage design with a stage one and a stage two and a built-in pause between stage one and two. Where we are right now is actually in the middle of that built-in pause between stage one and two.
Ultimately, our decision to look for strategic partners on Napo, it came down to the fact that there seems to be, with our RAS assets where they are in terms of having brought them in last year, seen what they can do in our hands over the course of the last year, successfully going through GLP tox, filing the INDs, getting those cleared, and now being off to the races in terms of the clinical development, this felt like a good time for us to reevaluate our portfolio. Since these RAS assets have just a tremendous potential, it felt like the right decision to make. Ultimately, Napo also has its going after high unmet need population of NRAS mutant melanoma. That population is smaller than the RAS populations.
I would say that if you look at the historical phase one and two data that Novartis generated, it actually showed a tremendous improvement. The combination of Naperafnib plus Trametinib showed a tremendous improvement relative to standard of care chemo or single agent MEK that's used off label. Ultimately, these are smaller markets compared to what we're going after with the pan-RAS. This felt like a good time for us to seek a partner for whom Naperafnib could actually be better in their hands than in ours and to put our focus and our attention and our resources on the RAS programs.
I see. Will you continue to show any more data, any additional data from either CCRAFT 1 or enrollment status or something for CCRAFT 2 going forward?
No. What we announced at the same time that we made this strategic reprioritization is that what we had previously guided in terms of a second half data readout in this year on the CCRAFT 2 study that we would no longer be doing that. We are not planning to provide an update. What I can say is that the enrollment, the site enthusiasm, the investigator enthusiasm was quite high. Napo clearly was filling an unmet need. Doctors and patients wanted to be on this drug to see what it could do in that NRAS melanoma population.
I see. OK. And then going forward for Naperafnib, what type of partnership are you looking for? And is there a timeline for that?
Yeah. In terms of partnership, I think we're flexible in terms of finding really what is the right home for Napo. That's our ultimate question. We can be flexible with potential partners in terms of what that potentially looks like, whether that is something that we throw over the wall to them and they can run with it, assuming that they have the right team and capabilities to be able to take Napo from a running start and continue with it, or even to do something else that allows us to stay a little bit more involved if that's something that would be advantageous to a partner, given just how much we know from a clinical and regulatory and non-clinical perspective program. We're open on that. In terms of timeline, no, there isn't a definitive timeline on it.
As you know, BD by its nature tends to be speculative. Ultimately, we want to find the best partner. We are not in a rush to find somebody immediately just for the sake of finding somebody. We ultimately want to find the right partner.
I see. Got it. What's been the feedback from shareholders on the strategic decision? Also, what's the biggest pushback that you've been hearing from investors?
Yeah, quite positive has been the feedback. In mid-May, we announced not only this reprioritization where we would look for a partner for Napo, focus on the RAS programs, that we had cleared the IND on 0015, as well as filed the IND at that time on 4001, ultimately now cleared. We also, in that same announcement, announced that we had extended our cash runway guidance to second half of 2028. We have more than three years of cash. I think it's a special kind of environment. Cash is king. To be able to have that kind of runway was really well received to be focusing on the RAS assets. Especially given the, even though they are early stage programs, there's been a lot of de-risking that has happened in the space. People know that these are validated targets.
They are excited about us advancing those programs. I would say that really it has been quite favorable in terms of the feedback that we have received around that announcement.
The runway guidance, what does it include and not include?
Yeah. So included in there is these RAS programs that I mentioned. Napo was in there previously. As part of this, we've actually removed Napo. It's worth noting as well that if we're successful in executing a BD deal on Napo, that would just be additional upside to the budget. We're not factoring in any success yet on a Napo BD transaction in terms of that cash runway guidance. If we do get it, then that would just extend runway even further.
I see. Anything else in the pipeline that you also factor into this runway? Is there any?
Yeah. As I mentioned at the start of the conversation, we also have our ERAS-12 molecule, the bispecific molecule. That's still in early stages. That is in the budget. It does not consume that much cash either.
I see. OK, got it. Fantastic. This is a very exciting time for you guys. I guess we'll look forward to continued future updates.
Thank you.
Before we conclude, I turn it to you for final remarks.
Yeah. No, I mean, again, we are excited to be at this conference. I think this is a really exciting time for Erasca, just where we are with these two RAS assets, as I mentioned. Even though the programs themselves are relatively early, the field as a whole is just evolving so fast. There is a lot of really exciting progress that is being made. We are very excited that we are part of that as well. With the features of our pan-RAS molecular glue that we think allow it to be best in class, we are very excited about what that can show for patients. Then 4001, which is very close behind in time relative to 0015, I think that molecule is also making tremendous strides.
As we as a field learn more about the benefits of pan-RAS versus pan-KRAS, we feel that Erasca is well positioned to be able to have an answer for both, as I mentioned earlier. Now with the runway, with that force versus balance sheet, to be able to really have ample time to read out on these assets and show their potential, we feel that we're in a really good spot.
Fantastic. David, it's been fun hosting you.
Thank you.
Thank you for coming to our conference.
Absolutely. It's been great.
Thanks, everyone.
Thanks.