Good afternoon, everyone, and welcome to the last session of day two of the Cantor Global Healthcare Conference. I think you'll be rewarded with a great last fireside chat of the day, and of course, we'll start up early tomorrow morning with another great set of presentations. But be sure not to miss the topical panels, which we'll kick off after this session. My pleasure, my name is Eric Schmidt. I'm one of the Cantor research analysts, and my pleasure to be hosting this next fireside chat with Erasca and their Chief Financial Officer and Chief Business Officer, David Chacko. So David Chacko, thank you for being here today.
Thank you.
Maybe for those a little bit less familiar, why don't you give us the bird's-eye view of the company and where things stand?
Yeah, absolutely, so Erasca is a portmanteau of our mission to erase cancer. We were founded back in 2018 by our CEO, Jonathan Lim, who's a serial entrepreneur, as well as Kevan Shokat at UCSF, and they came together after the successful exit of Ignyta, where Jonathan was previously CEO, really going after the RAS/ MAPK kinase pathway and trying to shut this down as comprehensively as possible. We do that through three complementary approaches, where we target key upstream and downstream nodes, like for instance, with naporafenib, our pan-RAF inhibitor. We target RAS directly, like with the two new assets that we in-licensed in May of this year, a pan-RAS molecular glue that we call ERAS-0015, as well as a pan-KRAS inhibitor that we call ERAS-4001.
And then the third approach is to target key escape routes that cooperate with the RAS MAP kinase pathway. And using that approach, our goal is to hopefully comprehensively shut down the pathway, in particular, in these tumor types where, you know, the RAS/ MAPK kinase pathway is highly implicated.
So since your founding a few years back now, you've been pretty active in the in-licensing side. What are you looking for? What kind of special differentiation do you bring to that business development activity? I know you're very involved with this sort of thing yourself. So, what is the special sauce behind Erasca?
Yeah, I would say, you know, the special sauce behind Erasca has to start with our team. I mean, we've got an exceptional team at Erasca, very skilled drug developers, you know, who have been through the ups and downs, have been at successful companies, either, you know, by whatever metric you wanna look at, including acquisitions like, you know, Turning Point or Ignyta. And so I think the secret sauce definitely comes down to that. I think we also have a tremendous knowledge of the RAS/ MAPK kinase pathway, the biology and the clinical aspects of it, including the translation. Now, with regard to the first part of your question around the BD aspects, we have built the pipeline through a lot of external innovation.
We've done eight deals in the last four years, including the two most recent ones that we brought in. I would say there, where we've been successful is a combination of people recognizing the track record. I think we've also been very speedy in our deal execution, where we've actually been able to get deals that other parties were already further ahead than us. I also think that we've been very creative in our deal-making, where, for instance, we've used our equity as currency to get licensors not only interested in what we can do with their asset, but the broader vision of Erasca and what we're trying to do in terms of erasing cancer, not just again, with their one asset, but the entire portfolio.
And you know, frankly, I think a fair amount of luck will also play into it from time to time.
So how do you choose this pathway? What's special about RAS? Why Erasca? What, what made you orient all the company's activities toward RAS/ MAPK kinase?
Yeah, so the RAS/ MAPK kinase pathway is implicated in anywhere from a third to half of all solid tumors, so it's a super important pathway. Historically, it's been a really difficult pathway to go after. You often need combinations to successfully address it. And so it was the challenge of taking on a really, you know, difficult target, and you know, set of targets that got us very excited about it. Kevan Shokat had published a paper. Everybody's familiar with his 2013 paper about targeting KRAS that led to the likes of Amgen's and Mirati's molecules in the KRAS G12C space. But he published a subsequent paper in 2018 about going after the active state of RAS, which was, in many ways, the genesis of Erasca.
And since then, like I mentioned, we've built a what we believe to be the industry's leading portfolio going after this pipeline. So we've got naporafenib, which is our pan-RAF inhibitor, that's in our SEACRAFT-1 study in RAS Q61X solid tumors, as well as NRAS melanoma that we call our SEACRAFT-2 study, and that's a pivotal study that just initiated a few months ago. We've got the two new RAS molecules, ERAS-0015, the pan-RAS molecular glue, as well as ERAS-4001, the pan-KRAS molecule. And then we've got ERAS-0012, which is our bispecific biparatopic antibody going after EGFR.
Right now, a very active pipeline. How are you planning to allocate resources across those assets that you just mentioned?
It is a very active pipeline. I would say that our top priority is actually ERAS-0015 that we just brought in in May. Our second priority is ERAS-4001, which is the pan-RAF, pan-KRAS molecule, and then our third priority is naporafenib, and as I mentioned, naporafenib is now in its pivotal study. We think that that actually provides a nice floor to the Erasca opportunity in terms of it being a high probability of success opportunity, just given the data that has already been generated in phase one and two, but a smaller commercial opportunity, especially compared to the pan-RAS and pan-KRAS, that has the potential to address, you know, maybe millions of patients.
Okay, maybe start at the top then with ERAS-0015 and ERAS-4001. I mean, one's pan-RAS and the other's pan-KRAS. Just educate us on, you know, why both and what the difference is here.
... Sure. So I'll start off with maybe the differences. So ERAS-0015 is a pan-RAS molecular glue. For those in the audience that are familiar with RevMed's molecule, RMC-6236, this molecule works through the same mechanism of action in terms of forming that tripartite complex with ERAS-0015, with cyclophilin A, and then with the RAS protein itself. So it actually works through a similar MOA, and we think for various reasons that we have superior properties with our molecule. ERAS-4001 is a pan-KRAS small molecule inhibitor that targets the switch II pocket, so this is more of a traditional small molecule inhibitor.
As far as why both molecules, I think it gives us a nice hedge in terms of, you know, being able to play the RAS space with two different molecules, and understanding, as more and more data comes out, to be able to evolve our strategy. Right now, you know, RevMed, to their credit, has done an exceptional job of de-risking the pan-RAS target. We think, as I alluded to earlier, that we have a potentially better molecule there. On the pan-KRAS side, there is no clinical data to date yet. That is obviously a space that we're watching very closely as others in the field disclose their clinical data to see, you know, what are the best places for these molecules to play.
But I think having both gives us the flexibility to see if there are certain indications where one may be more applicable than the other, and it also gives us the opportunity to combine both assets. So if you wanna have, you know, almost like a RAS clamp, where you can have both the pan-RAS and the pan-KRAS to be able to shut down both the on state and off state of the RAS protein, that could be a nice combination.
Okay, so, RevMed, they call their 6236 a RAS(ON), a pan-RAS(ON) inhibitor or multi-RAS(ON) inhibitor. Same as what you're saying is a RAS(ON) inhibitor, I assume-
Mm-hmm.
... active and on being-
Yeah.
Interchangeable. Just you prefer active, they prefer on?
We use probably interchangeable language-
Okay.
But yes.
So I just wanna clarify. So this is obviously, you know, hot pathway and hot targets and hot molecules. You're able to bring them in back in June timeframe?
Yeah, it was in May of this year. That's right.
May of this year.
Uh-huh.
How'd you find these things? How'd you come about, you know, this deal?
Yeah, so as I alluded to earlier, there's a little bit of luck that plays into all of this. So we actually had our own internal pan-KRAS program that we called ERAS-4. In the process of advancing that program internally, we came across some external IP, and as we dug further into that IP, we realized that it came from this company called MedShine, and so we reached out to them. They were actually interested in exploring us taking it on in terms of a global licensing deal, and so we did that. In that same process, they also introduced us to one of their other Chinese partners, a company by the name of Joyo Pharmatech, that had the pan-RAS molecular glue, ERAS-0015.
They've got very good capabilities within China, but we were looking for an ex-China partner to continue to advance that molecule. So we spent a lot of time on the ground, and then we worked closely with both of these parties to be able to execute these transactions rather fast in, again, in May of this year. In addition to that, we were able to raise nearly $250 million, in fact, more than $250 million in Q2 of this year, largely on the back of these two assets.
Maybe, David, just summarize the financial terms that you have with Joyo.
Yeah, so we were able to get both of these deals at attractive terms. In terms of the Joyo asset, the pan-RAS molecular glue, it was a $12.5 million upfront payment. We also have various development and regulatory milestones that total up to, I believe, about $189 million or so. And then we have a single-digit royalty on that product. In terms of the other molecule, the pan-KRAS molecule, we were able to get that for a $10 million upfront. I believe it was about $120 million or so of total deal value, including the development and regulatory milestones, and then single-digit royalty on that one as well.
Okay. So, you mentioned the ERAS-0015 pan-RAS inhibitor, very similar in mechanism of action to RevMed's tri-complex inhibitors. Any IP concerns or considerations that you ran into there?
No, we've diligenced this really closely during our own diligence process. We ran it to the ground with our own in-house counsel, with third-party outside counsel, and then as part of the financings that I alluded to, underwriters' counsel did their own diligence as well, and so we feel pretty strong about the IP position. The IP on the ERAS-0015 compound actually does go out to twenty forty-three, so that gives us a nice patent life on this. The other thing I'll mention, too, is that the IP space, especially in the pan-RAS molecular glue arena, is pretty competitive or pretty crowded, and not only that, but the chemistry that is involved in making a pan-RAS molecular glue is quite difficult.
And so those two factors combined, I think the likelihood of there being, you know, many, many more pan-RAS molecular glues, like the dynamic that played out, for instance, in the KRAS G12C space, I don't see that playing out as likely in the pan-RAS molecular glue space.
Okay, so you did allude to some potential for differentiation for ERAS-0015 versus the RevMed RMC-6236 compound? What would, what might that be?
Yeah. So, the licensor had actually done a lot of head-to-head comparisons of, their molecule versus, RMC-6236. And in those head-to-head comparisons, they showed that this molecule had better binding to cyclophilin A. As I mentioned, this is a tripartite complex that, you know, does bind cyclophilin A. So about 4X-5 X greater KD relative to, the comparator compound. What that translates to is, better in vitro potency, where we looked at multiple cell lines, that showed, you know, really across the board, just better potency in vitro for our molecule versus, the comparator.
That then translates as well into better in vivo potency, where with about one-tenth the dose, we're able to achieve comparable levels of tumor growth inhibition across multiple, cell lines that represent G12V, G12R, G12X more broadly. In addition, we also have a longer tumor residence time with our molecule, such that we think that we should be able to drive anti-tumor activity more strongly, given that the molecule persist in the tumor. In addition, we have better ADME and PK properties, so in a side-by-side comparison, we saw better oral bioavailability, better clearance, and better half-life, and from an ADME perspective, our kinetic solubility also looks really good.
So it sounds like you have a very well-behaved molecule. As I understand the RevMed compound, you know, one of the considerations is that you're not trying to dose up to full target potency or coverage. You're trying to kind of provide a bit of a window effect where you're not susceptible to some of the GI and other issues that they have seen at full inhibition of the target, and just be below that. Do you think your therapeutic window will also be potentially differentiated, or are you just gonna hit maybe maximum tolerability at a lower gram dosage?
I think one aspect is that we anticipate being at a lower gram dosage. You know, I think that is one thing that will help us. I think, you know, if you look at their AE profile, the number one AE that they're seeing is rash. And to their credit, that is a ... It seems to be more of a high frequency, but low severity type of event. And that is likely on target, and so we anticipate that we should also most likely have rash. If you look at GI, that does tend to often be associated with drug load in the GI tract. And so to the extent that we have a lower dose, we anticipate that the AEs related to GI should actually be, you know, could actually be better with our compound.
What's the path to testing this hypothesis, not just in terms of differentiation, but first, just in terms of tolerability, safety, activity?
Yeah, so we're gonna follow, in some ways, a standard phase 1. In other ways, we are, you know, trying to do things differently so that we can move as quickly as possible. But, you know, the phase 1 will be a dose escalation study, where we're gonna be studying ERAS-0015 to be able to identify, you know, its go-forward dose, to be able to identify, you know, if there are signs of efficacy that are particularly attractive. We'll also, of course, look at the PK properties of the molecule.
And then I think one other thing that's worth pointing out is that if you look at an analog in the G12C space, where compounds like divarasib from Roche and Genentech have greater preclinical potency compared to the first-generation adagrasib and sotorasib, and that preclinical potency differentiation is translating into higher response rates, better PFS. You know, we think potency matters, and so we think that that's another thing that we'll wanna test out in our clinical studies to see if we're seeing, you know, better efficacy as well as a result of the previous properties that I mentioned.
Okay, and what is the timeline to an IND or to the start of a phase 1?
Yeah, so, what we've guided to publicly is that we'll have an IND filing in H1 of next year for ERAS-0015, and then Q1 of next year for ERAS-4001, and that both molecules will have their phase 1 monotherapy dose escalation data in calendar year 2026.
Okay, maybe let's transition a little bit back to ERAS-4001, and this is obviously a molecule that doesn't have the benefit for... I don't. Well, you alluded to some other preclinical compounds. I'm not aware of any preclinical proof of concept here with pan-KRAS.
In the field-
Yes
... as a whole? Yeah, there's limited data, especially on the clinical side. Even on the preclinical side, there's just limited data in terms of what others have put out here.
Okay, so what does the landscape look like preclinically? Will you be the first in class?
There are other compounds. So, for instance, Pfizer just initiated in their their clinical study in July of this year, and there's others that are in this space as well. The nice thing here is that I think we are on the leading edge of, you know, this first wave of compounds that are coming through. And we've got a molecule that, you know, generally looks pretty good from a potency standpoint. It's in vivo activity, its ADME and PK properties generally look pretty good as well. So, you know, we're excited to be able to advance this one as well.
Okay. But, too early to say if differentiation is apparent yet. You have a good-looking molecule. We'll see if the others have something similar.
Correct. And I you know I think just the absence of clinical data right now from anybody in the space just makes it hard to-
Sure
... make any comparisons right now.
That's obviously a much more risky proposition clinically without that proof of concept.
Yeah.
Maybe just, coming back to ERAS-0015 , remind us what you think the market opportunity is. We've obviously seen some very promising data from RevMed in pancreatic and increasingly in lung cancer as well.
Yeah. Yeah, I think the market opportunity here is quite large. You know, I think it's unfortunate that there are, you know, 2.7 million patients diagnosed annually with RAS mutant tumors. So, you know, the opportunity is gigantic here. You know, if you look at the epidemiology, the big three are CRC, pancreatic, and non-small cell lung, and then there's a long tail of other opportunities as well. And so we are looking at, especially those big three in particular, in terms of our clinical development plan, as well as some of the other opportunities as well. So I think that, you know, the size of the opportunity suggests that it is a space that should be able to support multiple players. This is not a zero-sum game.
We've always said that, our success is theirs and vice versa. And so we, you know, strongly believe that, there is, room for multiple players in this space.
How does pan-KRAS play on top of pan-RAS? Are we likely to see activity in the same histologies?
Yeah. So again, here I'm speculating again in the absence of clinical data, but, you know, there, there is reason to suggest that, there may be certain histologies where pan-KRAS may be more amenable. So for instance, you know, the, rash that is often seen, in, you know, with a pan-RAS inhibitor, if that's going to be compounded with the combination agent that you're giving. So for instance, like cetuximab in CRC, could you actually get a better rash profile and therefore a better AE profile with a pan-KRAS that spares, particularly NRAS, which may be what's mediating the rash? So there may be certain opportunities for, pan-RAS versus for pan-KRAS. Again, we're gonna have to see what the clinical data ultimately look like in terms of where those opportunities are.
Okay, maybe transition over to naporafenib.
Sure.
This is your BRAF, CRAF, pan-RAF inhibitor. I think it was in-licensed from Novartis.
That's right.
Why did the company choose to pursue this asset?
Yeah, so naporafenib, as a reminder, is, as you said, the asset that we brought in from Novartis in December of 2022. It is the most advanced pan-RAF inhibitor in development. It's been dosed in over 500 patients to date, which really establishes just a wealth of data around safety and tolerability, as well as proof of concept data. And we were really excited about its profile, in terms of, you know, being first in class, which I think is particularly important in melanoma. Right now, the treatment options in melanoma are abysmal, in the post-IO setting. The approved standard of care is chemotherapy. It has only one and a half months of PFS, and you know, even single-agent MEK is only slightly better at about 2.5 months- 2.8 months of PFS.
With the Novartis combination of naporafenib plus trametinib, we, you know, we're seeing about five months of PFS, 13 months- 14 months of OS. So we're seeing a nice improvement between PFS and OS relative to the standard of care. And so, you know, that was what got us really excited about it, plus the opportunity to look at it in other tumor types like RAS Q61X solid tumors, which is the focus of our SEACRAFT-1 study. So to have a pivotal asset in naporafenib with the potential to expand it elsewhere with its breadth of data, you know, these were all of the factors that got us excited.
Why is pan-RAF better than BRAF?
So it depends what tumor types you're talking about. I assume you're talking about, like, the BRAF class one inhibitors in particular. So, you know, the BRAF class one, you know, goes specifically after the BRAF V600E mutation. So for BRAF melanoma, which is that V600 mutation, or BRAF CRC, then yes, you're gonna want a BRAF inhibitor. But other mutations like, you know, for instance, this RAS Q61 are gonna work much better with a compound like naporafenib. And the reason for that is that Napo has a profile that shows very good potency against BRAF and CRAF, which we think are the two isoforms that you wanna hit from an efficacy standpoint, with relative sparing of ARAF, which we think will help from a tolerability standpoint.
RAS Q61, as an example, tends to signal predominantly through BRAF and CRAF, so having a molecule that potently inhibits that is great, and then because of the potential for some escape to happen via ARAF, we have a MEK inhibitor, trametinib, one notch below, to mop up anything that gets through.
That's the SEACRAFT-1 study, the SEACRAFT-1 trial?
SEACRAFT-1 is the RAS Q61 study.
Just tell us about that design a little bit.
Novartis had demonstrated data in melanoma as well as in non-small cell lung, albeit a small data set, where they saw two out of three responses in RAS Q61 non-small cell lung. The focus of our SEACRAFT-1 study has been to enroll patients that have the RAS Q61 mutation, that tends to be congregated in about a half a dozen tumor types, to see if we can potentially see a signal across these different tumor types. We've got a few different paths that we can take for this, depending on what the data look like, which we're gonna be sharing in Q4 of this year. You know, as we think about it, you know, there's sort of three options.
On one end, you can see a situation where we're seeing activity against multiple tumor types, where we may then potentially wanna pursue a tissue-agnostic path. Now, that's great from a commercial perspective. Now, the clinical and regulatory bar in the last few years has actually increased there, so in some ways, it's actually more challenging to pursue a tissue-agnostic path. On the other extreme, you have a situation where maybe the data show that the signal is really only in melanoma. That's fine, because that gives us further conviction around our SEACRAFT-2 pivotal study in NRAS melanoma that we can then double down in. And then you can imagine a third opportunity in the middle where we're seeing activity in some, but not all tumor types. And so really, across that range of different outcomes, we're relatively agnostic about which one we see.
And these data will come out, I think you've now said, at the Triple Meeting?
That's right.
Is that right?
Yeah.
Ballpark, how many patients are we gonna see?
Yeah, so what we've been guiding to here is, you know, call it dozens of patients across those different tumor types.
Across a variety of tumor types.
It will be across a variety of tumor types, but dozens-
Many
... of patients total, not dozens of patients per tumor type.
Dozens of patients is an open-ended figure.
It is an open-ended figure.
Two dozen, three dozen, four dozen?
We're gonna have to see.
Low to single-digit dozens?
We're gonna have to see.
Okay.
Yeah.
... So you said kind of relatively agnostic to whether you do tumor agnostic or stick with melanoma or do something in between. Why are you so relatively agnostic? I mean, I would think the more, the better.
The more, the better, in some ways, but in other ways, as I mentioned, that because that clinical and regulatory path is more difficult,
Mm-hmm.
You know, not that we're afraid of a challenge by any means, but especially just given the wealth of other opportunities that we have around ERAS-0015 and ERAS-4001 , you know, it just. Again, as I mentioned earlier, Napo provides a nice floor to our opportunity, and then the world just grows larger and larger with the RAS assets.
You've already committed to SEACRAFT-2, the melanoma-specific study. Is there any world in which you decommit to SEACRAFT-2?
You know, I think the data that we have shown already, which is from the Novartis' phase I and II, that showed, you know, a doubling to tripling of the PFS relative to standard of care, a doubling of the OS relative to standard of care, you know, that gives us really strong conviction around, naporafenib's potential in NRAS melanoma. And we've got a pivotal stage asset, so I think, you know, we're moving forward with that. I suppose if we see negative data, that's a different story, of course. But assuming that we see data that's comparable to what we've seen before, you know, we're still very excited about NAPO.
What ballpark size is the opportunity in Q61X, melanoma?
So it varies by tumor type. You know, you'll see it anywhere from about 20% of melanoma, 10% of thyroid, 2% of non-small cell lung. You know, if you look at analyst forecasts, they estimate peak sales of around $1 billion.
Just in melanoma or...
Uh, PAN.
PAN. Okay.
Yeah.
Melanoma being a good chunk of that?
Melanoma is probably-
Yeah
... a few hundred million dollars in terms of its peak sales. Yeah.
Where are we with the SEACRAFT-2 trial execution?
The SEACRAFT-2 study is our pivotal study, which we initiated in Q2 of this year. That's got a two-stage design, so stage one is a dose optimization, where we're exploring two different doses of naporafenib plus trametinib.
.. No, you're not, you're... I think you're early. You're about 10 minutes early. Come on back.
Stage one is where we're exploring two different doses of Napo plus trametinib versus single-agent MEK. That's an open-label study with anywhere from 60 patients- 120 patients. With as few as 60 patients, we may be able to say that we like dose X the best, be able to talk to FDA and get their buy-in on that, and then move into the stage two portion, which is for the registrational portion. The other advantage of this two-stage design is that from stage one, we'll be able to report in 2025 the results of that stage one portion. Wall Street will get a randomized readout versus single-agent MEK in 2025.
You haven't said first or second half of twenty twenty-five?
We haven't said yet.
Okay.
Correct.
And that will trigger the phase III portion of the study?
The whole thing is phase III, but it'll trigger that stage two-
Two, six-
... portion. Yes
Stage two portion.
Yes.
phase III. Okay, so a nice near-term readout to look forward to in addition to the 2026 readouts for the newly acquired compounds.
That's right.
And you had another program. We haven't talked about it. I'm not sure how active it is, the ERAS-0012, the EGFR bispecific. Are you still engaged there?
We are. That is a program that is moving forward nicely internally. This is a bispecific, biparitopic antibody going after EGFR. It goes after both domain 2 and domain 3. All of the approved EGFR antibodies, like cetuximab and panitumumab, go after domain 3, which is the inactive conformation. This molecule has the ability to go after that, but also D2, which is the active conformation, which we think will help when EGF is overexpressed.
David, you've done an awesome job answering all my clinical and development questions.
Thank you.
Now I'll turn it to a CFO question. Which is actually the one day job you're supposed to be doing. Tell us about your cash, your runway, and any expectations you have for partnerships.
Sure.
Out-licensings, in this case, yeah.
Sure. So we ended Q2 with $460 million of cash, which allows us to guide to runway into the first half of 2027. As I mentioned in Q2, we were able to pull in about $250 million of cash, which was nice, and then in terms of your final question around, you know, partnerships, you know, right now we're really excited about these assets that we brought in around ERAS-0015 and ERAS-4001. They're new in our hands, and so we wanna continue to advance those. Now that said, we're always, as a company, looking for the best way to bring therapies to patients as quickly as possible.
And so, you know, if there's, you know, interest as we talk to other parties, we're always gonna see what's the best thing to do in light of patients' need.
Thank you so much for sharing the Erasca story with us. Appreciate it.
Thank you.