Okay, apologies for getting underway a little bit late, but very excited to be here. Thank you and welcome for joining us today on the Goldman Sachs Healthcare Conference. My name is Chris Shibutani. I'm a member of the Biopharmaceuticals and Biotech Teams, and we're very excited to have Erasca join us today. Jonathan Lim, CEO and Chairman, and David Chacko, Chief Financial Officer and Chief Business Officer. A lot of strategic optionality here, a lot of horsepower, experience. Let's level set. Tell us about Erasca. I ask that this year in particular because there's been an evolution. Science is difficult. You guys are targeting some ambitious and very important pathways, and you make some very bold choices. As a result, the recent pivot has really reframed Erasca. We are here today, mid-June, Goldman Conference. Tell us about the Erasca of now and going forward.
Yeah, thank you, Chris. Great to be here. Thanks for the invitation. So Erasca is a portmanteau for our twofold mission. So one is to erase cancer. The second is to eradicate RAS-driven cancer. And so that remains our unrelenting focus. That hasn't changed from our founding in 2018 to today. And we are entirely focused on the RAS/MAP kinase pathway. So historically, in fact, an investor today told us there's been sort of a few reinventions, if you will, of the company, as you alluded to. So in the early days, we were focused on sort of downstream and upstream nodes with our ERAS007 ERK inhibitor and our ERAS-601 SHP2 inhibitor. We ran a number of different trials and saw interesting data, but not enough to move forward with that. We then, in December of 2022, brought in Naporafenib, which is our lead program We continue to be excited about that. That's going to be a phase III clinical program shortly, and David will talk more about that program today. Then the new reinvention, which is bringing in two amazing RAS-targeting molecules, ERAS-0015, which is a pan-RAS molecular glue, and then ERAS-4001, which is a pan-KRAS small molecule Switch II pocket binder. Very excited about both of those programs. We do take a modality-agnostic approach to targeting the RAS/MAPK pathway. It's worth noting that we have also ERAS-12, which is a bispecific antibody for EGFR. We think that could be very interesting for different indications that are driven by EGFR, such as colorectal cancer and other solid tumors. The recent news was very exciting. It was really catalyzed by bringing in exclusive license to both of these RAS-targeting agents. I know we'll talk more about that.
Then also we did a reprioritization of the pipeline to focus on Naporafenib as our lead clinical program and then the pan-RAS inhibitors. We also did a concomitant $184 million financing with that.
Right. I brought up the notion of being CEO and Chairman. You bring to bear a lot of experience from your prior academic expertise, also being part of leadership of a company that went through all sorts of strategic decisions. So what was the dialogue between Jonathan, the CEO, and Jonathan, the Chairman, as you had to make this difficult decision about really kind of reshaping in a very concrete way your approach? I bring this up in part because typically people who have ambitions in science have to almost be true believers to an extent that the word passion project often gets invoked here. When you have that kind of sort of energy behind things, it can be hard to pivot and to change. So what was that conversation like for you?
Oh, we talk to each other all the time, Chris.
Absolutely.
But I'd say, look, to be honest, the last three years have been really hard on the industry, and it's been hard on us. I just think it's tough when really good science goes unnoticed. And we've been doing really good science trying to drug a really tough pathway. So RAS/MAPK is not for the faint at heart. And I'd say you just really have to be data-driven. So first of all, there's no sacred cows. So as a team, we're data-driven. We've done several prioritizations, reprioritizations, really to try and navigate in a very challenging environment that is not entirely driven by fundamentals. So to be fair, I mean, we were joking earlier today that the Fed decision has more of an impact on our sector than sometimes some of the science that we do. And that can be just an interesting place to operate.
So you have to constantly visit and revisit plans and programs and what you're doing. I'd say we've landed in a place where Jonathan, the Chairman, and Jonathan, the CEO, feel really good about where we're at today versus where we were at, let's say, six months ago. And so I think we've landed on a place where we want to play in an area that is competitive, but where we feel like we have a shot at being successful. And I'd say six months ago, that may not have been the case.
Those of you on the webcast who aren't seeing a video sitting in these armchairs, we're all comfortable because we're all armchair economists, which is absolutely true. You have to be an indispensable skill for the biotech industry. Let's talk about Napo, lead asset. Remind us about the history of this program here and just frame the opportunity set.
Sure. So I'll take that. Thanks, Chris. So in terms of the history of the asset, as Jonathan mentioned, this was an asset that we brought in from Novartis back in December of 2022. Novartis had already generated some compelling data, proof of concept data in NRAS mutant melanoma across phase I and II studies that I'll talk more about. They had also generated some preliminary proof of concept data in other RAS Q61X solid tumors, for instance, non-small cell lung. And so that totality of the data there got us very excited about bringing this asset in. The molecule itself had been dosed in over 500 patients to date at that point, which established just a wealth of data, not only around the efficacy side, but also around the safety and tolerability side.
We have continued to advance the molecule pretty aggressively in two different indications, what we refer to as SEACRAFT-1, which is our RAS Q61X solid tumor study, which initiated in Q3 of last year and is on track for a data readout in Q4 of this year. And then also our SEACRAFT-2 study, which is a pivotal phase III study in NRAS mutant melanoma, which is on track to initiate in the first half of this year with data from the stage one portion of the phase III study in calendar year 2025.
Can we get a little bit more specific about the 500-patient data safety aspect of it? This is a very important part of, I think, the calculus that investors have about thinking about how de-risked is this asset.
Absolutely. So the molecule has been dosed in over 500 patients to date, as I mentioned. That's across both monotherapy as well as various combinations. So Novartis did a very full package here in terms of their interrogation, where they looked at combinations with trametinib, their MEK inhibitor, which proved to be the most promising. But they also looked at combinations with an ERK inhibitor, CDK4/6 inhibitor, and others as well. And so this molecule has shown good safety and tolerability, especially in combination with trametinib. The AE profile is consistent with the pathway. So the main AE that we see is rash, which is to be expected when you hit the RAS/MAPK pathway. Other AEs from a treatment-related adverse event standpoint are mostly in the grade one and two range. So largely this looks, from a safety and tolerability standpoint, to be a very good asset.
We are taking steps to improve the rash even further. So for instance, Novartis did not have mandatory primary rash prophylaxis as part of their phase one and two studies, but that is something that we are implementing in our studies. There's literature out there from the EGFR space that with primary rash prophylaxis, you can decrease the rate of grade two and higher rash from in the 60% range to in the high 20% range. So that seems to be a promising avenue to potentially improve upon the safety profile even further. Then, of course, the efficacy profile of the compound in combination with trametinib looks very good, particularly in the NRAS melanoma setting.
Right. And is that the whole notion of trying to prosecute really further down the entire MAP kinase pathway with a MEK inhibitor combination there? Can you talk about the market opportunity then and its potential to maybe have a tissue-agnostic label as well as an NRAS mutant-specific label?
Yes. Maybe I'll touch upon your first point about targeting the downstream part of the pathway, which I think is really important in this particular case because Naporafenib is very potent against BRAF and CRAF, which we think are the two isoforms that you want to target from an efficacy standpoint. It has relatively less efficacy against ARAF, which we think helps from a safety and tolerability standpoint, but it does allow for some oncogenic signaling to get through at the ARAF node, which is why we think that you need to have a MEK inhibitor downstream like trametinib to mop up any oncogenic signaling that gets through. And that's why we think that it's so important to have a combination approach in these indications.
Now, with regard to your question around the potential market opportunity, NRAS melanoma, if you look at the top of the funnel in terms of total number of patients that are diagnosed annually in the U.S. and Europe, it's about 50,000 patients. When you cut that for line of therapy and metastatic disease, you're probably talking about a few thousand patients in the U.S., for instance. The RAS Q61X solid tumor population is much larger. It's about 3 times larger if you include the 6 or so tumor types where RAS Q61 mutations are highly prevalent. So things like melanoma and non-small cell lung, which is where Novartis generated the early POC data, but also thyroid, head and neck, and GI malignancies as well.
Talk about the competitive landscape, obviously important targets. Others are going after this. Then help us a little bit with maybe some benchmarks so that we can have a sense for how to measure the data that you'll be developing.
Sure. So in terms of the competitive landscape, this is one where we believe that we are first in class, particularly in NRAS melanoma. And when I talk about the benchmarks, that will become a really important point. So I'll come back to that in a second. In terms of others in the field, I would say that the next closest competitor behind us was probably belvarafenib from Roche Genentech. But earlier this year, they actually deprioritized that program. And then others are in the space as well, including what used to be exarafenib molecule, which is now in the hands of Pierre Fabre. And then there's many other assets from the likes of Jazz Pharmaceuticals and Black Diamond Therapeutics and others that are either late preclinical or early clinical. But I think being first in class in this space is particularly advantageous.
And that gets to the second part of your question, Chris, around what do benchmarks look like. So for instance, in NRAS melanoma, the approved standard of care right now is chemotherapy, which was approved with only 1.5 months of PFS as an example. Single-agent MEK inhibitors are used off-label with about 2.8 months of PFS. What Novartis was able to show across phase I and II, regardless of the doses that they looked at, was about 5 months of PFS. And so you're seeing sort of a doubling of the single-agent MEK, a tripling of the chemotherapy benchmarks, which we think was really nice. On top of that, we shared data earlier this year in March that showed that we are also showing a benefit in OS.
So the phase I and II data that Novartis generated, which actually only reached a level of maturity earlier this year because of the censoring that would have happened earlier from an OS standpoint, that reached a level of maturity earlier this year that we were able to finally analyze that data set. And we are seeing about 13-14 months of median overall survival for the combination compared to what we think are the most appropriate historical benchmarks that are in the 6-7-month range. So about a doubling of the overall survival there. And back to the earlier point around the competitive landscape, this is where this is particularly important because what we are able to do in our randomized study, our SEACRAFT-2 randomized study, is to be able to compare against either single-agent MEK or chemotherapy as the benchmark.
If we're able to reset that standard of care for patients with our combination of Napo plus trametinib, then anybody coming behind us would then potentially have to compare against us as that new standard of care. So this is a class where being first is super important.
You guys have shared some of the pooled phase I/II data with Napo plus trametinib. If I'm correct, some of the response rates have been clearly trending in the right direction. We're talking response rates in the 22%-31% range, if I have that data correct. And this is in comparison to sort of the high single-digit to mid-teens range that might be expected with chemo or with trametinib alone. Obviously, overall survival is the gold standard here. Talk about when you expect that data to potentially mature.
Yeah, that's right. So in the phase I and II setting, the response rates are, as you've mentioned, the PFS data are, as I had mentioned, in terms of the 5 months across the 2 different dose levels from the phase I and II, and about 13-14 months in terms of median OS. So that data has actually now matured from the phase I and II study. And it was on that that we were able to actually raise an equity financing back in March of this year, which is distinct from the financing that Jonathan mentioned that we did in May of this year around the RAS targeting assets. And so we feel pretty good about the data that have been generated to date for the Napo plus trametinib combination.
In addition, what I'll mention is that we gained alignment with the regulatory bodies in the U.S. and Europe in the second half of last year around what the pivotal study for NRAS melanoma would look like. They agreed with our proposal that it would be a dual primary of PFS and OS. So those are the two benchmarks that we're watching the closest because I think, especially in this late line population, of course, the response is great, but even long-term stable disease is pretty important, which is captured by the PFS metric. That's what we're looking at. The numbers that I mentioned in terms of doubling the binimetinib or trametinib benchmark, tripling the chemotherapy benchmark in terms of PFS are really important for us.
The vocabulary, people are very attentive to being the specificities for dual primary endpoint of PFS and overall survival, correct? In terms of what you need to achieve to sort of give the thumbs up overall on the study would be.
Yeah. And actually, good point that you're bringing up because in addition to those being the dual primary, the other point that's important to mention here is that we actually gained alignment that PFS could be acceptable for the potential initial approval. So we wouldn't actually necessarily need to win on both benchmarks. We would only need to potentially win on one benchmark. Of course, we'll look at the totality of the data. And if we're able to win on both benchmarks, that's obviously even better than just winning on one.
Then because we're junkies for execution and success, remind us of when you think the timeline to initiate this phase III could be. Are we still possibly on track here for the first half? What's the latest thinking?
Yes, we are on track to initiate the pivotal study for SEACRAFT-2 this quarter, which would mean this month. And then we are on track to have a data readout as previously guided for this trial in 2025.
Okay. Perfect. It'd be ideal for us to be sitting down again a year from now and for me to be pushing to see if we can get some insights there. I think Napo has been such a very foundational part of the story recently and then especially going forward, right? Having that diversification of the pipeline towards later stage assets, which certainly is very attractive from the standpoint of the investor community as a public company. So let's talk about the new kids on the block here. Additional pipeline assets here, which are now part of the important profile of the company. Introduce us to them respectively. You get to pick which kid is favorite.
All right. So I mentioned that there's 2 of them, ERAS -15 and ERAS- 4001. This was the culmination of, I would say, a year-long of different opportunities, both inbound and outbound. Formative announcement that we had on May 16th. And so ERAS- 15 is a pan-RAS molecular glue. So by that, we mean it works by the same tripartite mechanism of binding to first cyclophilin A, followed by RAS to form a tripartite moiety, much like RMC6236 does. Now, the features of ERAS- 15 are that it's about 5- to 10-fold higher potency, both in vitro and in vivo versus the comparator compound. And it also has higher bioavailability and superior sort of ADME PK properties in animal models. So we're very excited about that program. And then ERAS- 4001 at a high level, I mentioned it's a switch to pocket binder.
So it's a reversible small molecule inhibitor of pan-KRAS. But that includes both KRAS mutations as well as KRAS wild type. So for instance, KRAS wild type amplifications can be a source of acquired resistance. This does not bind to HRAS or NRAS wild type. So that HRAS and NRAS sparing, if you will, could potentially lead to a wider therapeutic index for that molecule. So we think both molecules are exciting for different reasons. But those orthogonal, if not complementary mechanisms of action, I think allows us to enter into the RAS space in a meaningful way, including with a unique ability to combine these in the future.
I think that's an important distinction. People tend to sort of listen and there's waves here. There's pan-RAS and there's pan-KRAS here.
That's right.
So talk about sort of like the advantages of doing a pan strategy versus mutant selective. Let's start with the RAS. Then if there's any distinctions as you think about that from the KRAS standpoint, because perhaps there's been so much attention to the mutant-specific KRAS domain there and maybe fewer progress points across the pan-RAS side of it. So I probably just jumbled the alphabet soup, but I am looking for insight into making sure that we come away with a little bit of an aha in terms of thinking strategically about approach for those.
So let's talk numbers and then let's talk data and science. So in terms of just sheer numbers or the math, there's about 2.7 million patients with RAS mutations, solid tumors in the world. And of that, 2.3 million have KRAS-mediated mutations. The balance, 400,000, have H and NRAS. So just in terms of pure numbers, the number of patients with RAS mutations, irrespective of K, H, or N, is pretty significant. But for a pan-KRAS molecule, you could still have an addressable patient population of up to 2.3 million patients. So that's pretty large. It's a big overall pie of unmet need. And you can take slices of the pie with mutant selective approaches. But I will say, if you're successful at a pan-RAS and/or pan-KRAS approach, and you can address the entire population, then that would be preferable.
So it's really a matter of can you hit the target hard enough to be able to get the efficacy you want with the right therapeutic index. And safety and tolerability then become a key. So then let's talk about the data and the science. Right now, the only data in the world on either pan-RAS or pan-KRAS that we're aware of is what's been generated with RMC-6236, which truly is pioneering and very exciting. When we first saw that data, I got to say, I was personally surprised that you could actually hit pan-wild type in terms of K, H, and N and still have a therapeutic index. So kudos to it. It was really exciting for the entire field.
And so the fact that you can do that with, I think, very reasonable safety tolerability. There is frequent rash, rash is the most frequent TRAE, but otherwise, there's a very exciting path forward there from a safety tolerability as well as efficacy standpoint. And so within the pan-RAS space, I'd say as 6236 garners further success, it's good for ERAS 15 and vice versa. I think being the second company in that space, as we enter into the clinic next year and as we generate clinical data in 2026, it basically allows us to, I think they'll benefit from that as well. So it's just such a huge unmet need that there's more than enough room for two players. I'd say pan-KRAS is an exciting theoretical mechanism from a scientific standpoint because of that HRAS and NRAS sparing. So do you get less rash than what's seen with the pan-RAS?
Don't know. Jury's still out. We'll need to see clinical data from other companies or ourselves in that space. And then mutant selective data, we haven't seen mutant selective data yet, but it's really going to be all about safety tolerability and efficacy. And again, that's going to be smaller patient subsets. And so just from a total unmet need, it's a smaller opportunity than the pans.
The looming chapter that's out there as well for all of us to measure based upon precedent is also this question of durability of the kind of penetrative results that we're going to see.
That's exactly right. Yeah. Second half of this year, I think there'll be some durability information, at least for the pan-RAS molecule.
Right. Exactly. And so you articulated quite well, but I want to reiterate, it's that quest for finding that therapeutic index that could work with hypothetically the risk of hitting the RAS pathway too broadly. Talk to us a little bit about how it is informing your own Erasca's clinical development strategy, approaching about thinking about what are the toggles and the dials. Is it about dosing regimens, dose? Where are you with that?
Yeah. The interesting thing about ERAS-0015 is that we think that because of the five- to tenfold higher potency, the predicted active dose in the clinic is likely to be sort of about one-tenth or so of the RP2D of the reference compound. And so if we can get by with a lower dose, there might be potentially better GI tolerability. There's no reason to believe that RAS will be any better. And then there could be fewer, if there are any off-target consequences of the pan approach, you might see less of that in terms of a higher potency molecule. We have seen sort of in other from history as well as from other mechanisms, including G12C, for instance, that more highly potent molecules tend to perform better from an efficacy standpoint. So jury's out on that as well. That'll be data-driven.
But we've seen whether it's osimertinib versus erlotinib in the EGFR space, or whether it's alectinib, lorlatinib versus crizotinib in the ALK space, or even more recently, whether it's divarasib or olomorasib versus adagrasib and sotorasib in the G12C space. Better preclinical potency does seem to translate into higher ORR. So do we have the therapeutic index with our molecule to be able to show that? Don't know, but we hope so.
Yeah. I know that foundational premise is always what kind of girds us for that gulf of translating preclinical data into the clinic. And potency does seem to be the right barometer. And it would be fascinating to see that data there in terms of, especially when you think about on-target versus broadly wild-type RAS interactions there, perhaps generating the total complexion. And you're thinking about a therapy for a patient and their ability to tolerate it that.
Yeah. And Chris, the other point worth noting about ERAS-0015 is because it's about a fourfold higher binding affinity to cyclophilin A versus the reference compound, it seems to have better tumor tissue distribution. So it just lingers in the tumor tissue longer. So that from 4-24 hours in vivo models, it actually the levels don't really taper off. So it just lingers around the tumor tissue, which could be a better biodistribution pattern in terms of anti-tumor activity.
.
Touch upon ERAS-4001 a little bit. Tell us a little bit about what the early personality is like here?
Yeah. So this molecule loves KRAS and doesn't love H and NRAS. So it's a little finicky in that way. And that's what you want. So the thesis is all about H and NRAS sparing. Now, we've heard from pathway suppression from David with pan-RAF and MEK. You see RAS. I talked about the pan-RAS approach. You see RAS. It's really just emblematic of RAS map kinase. It's really just par for the course. So the question is, is the RAS that you're seeing with pan-RAS, is that mostly from KRAS wild type or is it coming from H and/or N as well? We don't know. But if you dial out H and N and are really picky for K only, does that translate into a better therapeutic index? So that's the personality of that molecule is to really be particularly focused on pan.
The good thing is that there's not an insignificant amount of KRAS wild type activation that happens when you put KRAS under pressure. That will help differentiate it from, say, the mutant selective KRAS inhibitors, like the G12C selectives that don't hit KRAS wild type. You could have KRAS amplification-mediated resistance that would not be addressed by those mutant selective approaches, but would be addressed by 4001.
Biology is complex. It's almost impossible for there to be a single bullet. Combination strategies are de rigueur. Therefore, talk about your RAS clamp strategy where you're coupling your assets together. Talk a little bit about what motivates this strategy and how you're thinking about developing this approach.
Yeah. So this is really interesting. And actually, members of our SAB that we've talked to about this concept love this idea because I think we're uniquely situated, as I mentioned, to be able to sort of prosecute both the pan-RAS molecular glue along with a traditional switch to pocket binder and putting them together. So the idea here would be if you have a wider therapeutic index for the pan-KRAS, you hit the KRAS mutation really hard with that. And then if you have RAS in the inactive GDP toggling into the active GTP state, or what people also know as the off and on state, you get just enough pan-RAS molecular glue on board.
You may not even have to go full dose, but you get enough on board to target that GTP-GDP state so that you truly leave and you touch HRAS and NRAS to prevent isotype switching, which is another mechanism of acquired resistance so that you really clamp RAS with no place to go. I think of that as horizontal versus vertical inhibition. We've tried vertical inhibition, including most recently with ERAS-007 ERK, along with a BRAF as well as an EGFR inhibitor with encorafenib/cetuximab, for instance. We've tried vertical, but we've never tried horizontal inhibition. This could be really interesting to just, as you mentioned, clamp RAS with a RAS clamp.
Exactly. Combinations with other modalities. Naturally, you just have to think about harnessing everything that the body brings to bear, immune modalities, combinations with PD-1. Always seems like a good idea. You actually have, I believe, some preclinical data points there to help inform thinking about this. So remind us of what that preclinical data in combination with PD-1 is and where you're at with thinking about using some of the money that you've raised to advance programs there.
Yeah. I mean, look, that's a really important ability for the molecules to be able to combine with PD-1 for non-small cell lung cancer. PD-1 is just such a mainstay of therapy. So if you can combine, that'll be amazing. Preclinical models in the KPC PDX model with both 15 and 4001 showed in all seven, 7 out of 7 mice had complete responses. So just flatlining of the tumor. And then on KPC rechallenge, which means you reinject the tumor cells into the other side of the mouse without giving any more therapy. So you discontinue the combo regimen. And what you see is a small blip in KPC, but then it completely disappears, showing that you've already primed the immune system to fight off the KPC rechallenge. So we saw that with both molecules.
I would say we'll learn more about the combinability of pan-RAS as a class with PD-1. We're optimistic that that can occur. And then I think importantly with 4001, this is a reversible inhibitor. So unlike the G12C covalent modification or covalent binding mode, which leads to haptenization, which might be responsible for some of the liver tox that's been reported with that class of molecules, 4001 is a reversible binder. So you are less likely to get that haptenization and liver findings. So we're cautiously optimistic there as well.
I've really enjoyed this conversation. I feel like I've been alert, awake throughout a wonderful postdoctoral and yet kind of at the grad student level dissertation and explanation of really this alphabet soup of complicated pathways. Help us with the final page of the PowerPoint that investment group analysts are going to need to put cash, cash runway, and punctuate for us what the measuring milestones will be that you'll be looking to achieve by the time we get to that point. Where's the cash?
Sure. Yeah. So we ended Q1, which was the last quarter that we reported on, with $334 million of cash. That includes the proceeds from our March financing, but does not include the additional $184 million that we raised in March of this year, sorry, in May of this year. That actually has allowed us to extend our runway to the first half of 2027. And in that timeframe, we'll have readouts from SEACRAFT-1, which is the RAS Q61X solid tumor study, which will be in Q4 of this year. We'll have a readout from SEACRAFT-2, stage one in calendar year 2025. We'll have a readout from the two new assets that Jonathan talked about, ERAS-001 and 005. We'll have its phase I monotherapy readout in 2026. And ERAS-4001, the pan-KRAS, will have its readout also in 2026 from its phase I monotherapy.
Terrific. That was very clear and helpful. It's always great to have the path and the financing to light the way. So Jonathan and David, thank you so much for joining us. Appreciate the update and all the best going forward'
Thanks a lot, Chris.
Thank you.