We'll get started. Welcome to this next session. Our next presenting company is Erasca. My name is Paul Jeng. I am one of the biotech analysts with Guggenheim, and I am very pleased to be joined today by Jonathan Lim, Chairman and CEO, and David Chacko, CFO and CBO from Erasca. Thanks for joining, guys.
Thanks, Paul. Great to be here.
Maybe a good place to start is just to provide a quick intro to the company and your pipeline for those who might be newer to the story.
Yeah. Erasca was formed in 2018 around the premise of erasing cancer and eradicating RAS-driven cancer. In fact, that mission is in our name, and we since then have built a pipeline. We have gone after the MAP kinase pathway broadly, but we have really settled on focusing entirely on RAS with a pipeline that we are very excited about. We have ERAS-0015, a pan-RAS molecular glue that is focused on really targeting RAS broadly in terms of all the key mutations, including also RAS wild-type in terms of KRAS, HRAS, and NRAS. Then we also have ERAS-4001, which is a pan-KRAS small molecule inhibitor. It is a switch II pocket binder that spares H and N-RAS, but hits K-RAS really hard. We are also excited about the prospect of putting those two molecules together, which I know we will talk about later.
Okay, great. ERAS-0015, your pan-RAS inhibitor, had a couple updates this year, April and July, which were really interesting. I was hoping you could first start by perhaps recapping the data that you showed, efficacy and safety profile. Then looking forward, you will have some updates for the program at the upcoming Triple Meeting in November, so maybe set some expectations with that in the context of what you already shown.
Yeah. We're really excited about ERAS-0015 pan-RAS program. Basically, what we've shown in April and July corporate disclosures is very compelling single-agent activity in both pancreatic cancer as well as non-small cell lung cancer, as well as safety and tolerability. As we look towards the Triple Meeting, we have an oral plenary presentation, and this is really geared towards the more the scientific audience. For most clinicians, they're aware of our data, but I think there's some clinicians where, when we've given corporate updates, those data may not be as visible as they would be in a scientific conference. So this is really a coming out, so to speak, for the scientific data.
Now, what we've shown in the April and July disclosures is in pancreatic cancer, monotherapy activity that's somewhere in the 40%-57% response rate, and that really depends on line of treatment, as well as dose. So what we're hoping with the upcoming data disclosure is, first of all, more patients enrolled, especially at what we call RDE, which are the recommended doses for expansion at 24 mg and 32 mg. So I think that's something to pay attention to, because in that July dataset, we did see a pretty striking dose response. So we had higher response rates at the highest response rates were at 32 mg, and the lowest response rates were at 16 mg, and then 24 mg was somewhere in between.
So I think we're going to want to pay attention to sort of the 32 mg dose especially, and then also 24 mg, and then just see whether that response rate lands within that 40%-57% range. I think we're going to want to see the line of treatment. We're also going to want to see the mutation breakout. I think there's an opportunity, especially for G12D, to show an opportunity for improvement over what's been reported for the comparator, where in FDA documents, it looked like the response rate was 24% against G12D. So I think in the July dataset, when you look at sort of what's been publicly disclosed, I think people have come to the conclusion that G12D along a dose range was somewhere in the 50% zip code.
As we show more data at the 24 mg and 32 mg doses, are we sort of landing in that 50 range? Then in an all-comers, if we're able to land somewhere in the, call it, mid-40% or so, that still would be about 10 points - 20 points differentiated versus what's been reported in the past with response rates in the 25%-32% range. I think that's how we look at pancreatic is, it's really exciting what's been achieved by daraxonrasib in the second-line setting, but I think there's an opportunity for better efficacy, as well as when you look at the safety and tolerability side of the equation, I think interruptions and dose reductions have reported in the New England Journal paper have been quite high in that 36%-56% range.
I think ultimately, we hope to be able to show improvements in the frequency and severity of rash, GI, and stomatitis, but ultimately, how do those translate into maintaining dose for patients to deliver the optimal dose to patients in a really aggressive tumor type like pancreatic. If we're able to show meaningfully lower dose interruptions and reductions, we think that's the other side of the equation that's really important. Then finally, for lung cancer, what we've reported previously was response rates in the 60-plus-percent range. If you look at the best targeted therapies in KRAS G12X, divarasib is sort of an example of a very potent G12C molecule that has achieved response rates in the 56%-59% range.
I think if we hold at or above that threshold in a non-G12C space, which actually is less sensitive to target inhibition than G12C tumors, which tend to be a little more sensitive to targeted therapy, then we'll be feeling very good going into the pivotal trials next year in second- line plus, as well as first line, that we have a very promising lung cancer drug. I think the totality of efficacy and safety in terms of what we've reported, we hope to have longer follow-up for these patients, hopefully more confirmed response rates than unconfirmed. Then I think if we sort of hold within those target ranges, then we'll really have a differentiated drug.
Okay. Yeah, super helpful. Any sense of, I guess, the scope of the data in terms of patient numbers we should expect?
Yeah, I think meaningfully higher. I think especially because we've been putting our thumb on the scale. Just to back up, the PAD, or pharmacologically active dose, for ERAS-0015 is 16 milligrams on the low end and then 32 milligrams on the high end. It really has differed by indication. I think in pancreatic cancer, which tends to be a little less sensitive to targeted therapy than lung cancer, we've seen more responses more in that 24 to 32 milligram range, and that's why I think especially at 32 milligrams, you just want to put as much drug and get as much exposure as you can. Because from a PK standpoint, we do have dose proportional, we've reported dose proportional increases in exposure from 16 to 24 to 32. We don't have that exposure plateau that's been observed with other molecules within this class.
I think for pancreatic, that really matters. I think we should have, in the July dataset, if we had 15 patients at 24 to 32, hopefully we have maybe more than twice that. With lung cancer, 16 to 32, because it's a more sensitive tumor type, we actually had quite a lot of responses at 16 milligrams in the April dataset. I think now with more patients at 32, at that time, we only had one patient at 32 milligrams responding. I think now with more patients at 32, we'll see if there's more meaningful activity at those higher end of the range.
Okay, super. You talked a little bit about the focus indications in lung as well as PDAC, and thinking about a pivotal study at this point. I guess, what does the sort of pathway look like in terms of getting that first study launched? How are you prioritizing lung versus PDAC, and anything about possible timing for getting a study launched?
Yeah, so we're moving as fast as we can. I think based on the data that we've disclosed, we already had the conviction that going into that, we weren't sure if there would be trade-offs of either better safety or better efficacy. But the fact that from April to July, we saw data that convinced ourselves that we were meaningfully better on both sides of that equation, we unlocked and were able to do a pretty significant financing, so that we have the balance sheet to really unlock three pivotal trials, two of which are phase IIIs. On pancreatic cancer, we have high conviction that first-line pancreatic, if we're able to see a difference in second- line plus and even third line plus, so heavily pre-treated population, then we think line of treatment does matter, and we should see even better activity in the first-line setting.
We basically are doing all of the blocking and tackling in terms of all the operational activities that one would need to do to move into a phase III trial. We are on track. Our guidance has been 2027 in terms of starting that, and we are on track for that. You can imagine, we are moving as fast as we can. In non-small cell lung cancer, we are taking a dual approach of going after second- line plus, RAS mutant non-small cell lung cancer with monotherapy, and that potentially registration-enabling trial will start in the first half of next year. We are also looking at first-line combinations for first-line RAS mutant lung. We have disclosed that we are combining with pembrolizumab. We have a clinical trial collaboration with Merck, and so we are in dose escalation with pembrolizumab.
I would say that if we go with a pembrolizumab-only combo, we could start that phase III as early as the second half of next year. If we want to layer on chemo on top of that, then we would start that in the first half of 2028. That is why we have broad-banded the guidance for that first-line trial for phase III, but between second half of 2027 and first half of 2028.
Okay. You mentioned that the successes as well as possible liabilities of daraxonrasib are really important in the way you think about the opportunity. I just wanted to get your thoughts on how you are tracking the launch, the commercial opportunity that is being shown by the asset, and how that informs how you think about your bar for success for 15.
First of all, daraxonrasib is just a great pioneer molecule, and we are super excited that patients now have access to that. I think the first quarter of sales for five weeks was really phenomenal. I think that is great that patients, it is a very high unmet need. As I said, I think there is, especially when you think about just monotherapy tolerability, and then when you combine it with chemo in that frontline setting, I just think that there is room for improvement, and there is room for more than one molecule. We are excited to build on that success of this class of molecules and really make sure that other treatment options are available for patients.
If you look at tolerability with chemo, down-dosing has been necessary on both the pan-RAS side as well as on the chemo side, somewhere around 36%-58%, depending on what side of the equation you're talking about. I think we won't know until we actually have our chemo data, but as we dose escalate, can we reach 24 mg-32 mg, and can we be able to sort of combine successfully with chemo with less down-dosing? I think if we can, then that would also, I think, convert into potential patient benefit in terms of response rates, tolerability, durability, all of that good stuff.
Okay. On the mutant-selective side, there's also a number of RAS G12D selective agents that are now in phase III, including in frontline PDAC. How does this impact, if at all, your evaluation on the landscape and opportunity in PDAC for ERAS-0015?
We have a hypothesis on that, and I think if our hypothesis is true, then I think pan-RAS is going to be an essential element of a frontline strategy for pancreatic cancer. The hypothesis is this. If you look at the allele-specific D inhibitors, whether they're pan-RAS, or sorry, whether they are a molecular glue or sort of a switch II pocket binder, the response rates that have been disclosed for the, or reported for those are anywhere from 30%-41%, with zoldonrasib at 30% response rate, Verastem's molecule is about 41%, and then Incyte's is in between at 37%. We'll know more next week, but let's say that based on the publicly available data, which shows that at a dose range, our molecule achieved about 50% + G12D response rate.
Why is it that there seems to be a range-bound nature of these allele specifics, but you're getting higher response rates with a pan-RAS? It probably has to do with wild-type signaling. If you take an allele-specific approach, by definition, you're sparing wild-type. Beyond that, you're actually sparing not just KRAS, but also HRAS and NRAS wild-type signaling, and you will need a pan-RAS to address that, both for primary and acquired resistance. We think that that hopefully translates into an ORR benefit, but more importantly, a durability benefit. Time will tell. This is just a hypothesis at this point, but based on our early read of the data that are available by ourselves as well as others, we just think there's potentially something there.
Okay. This question might segue into a conversation about ERAS-4001, but you are also going to be presenting some data at Triple Meeting for preclinical data with the 15 combo with ERAS-4001. Can you just speak about the rationale for combining pan-RAS with pan-KRAS and what we might expect from that data and any future development that would come out of it?
Yeah. Pan-RAS works by two mechanisms. One is the steric clash to basically inhibit MAP kinase signaling. The second is increased hydrolysis of RAS from the GTP state to the RAS GDP or off state. When you take ERAS-0015 to induce that off state, and you take ERAS-4001, which is an off-state preferring molecule, then you basically affect this one-two punch on tumors. Our poster presentation next week is really going to show the totality of data that we have for in vitro and in vivo, showing the possible synergy of that one-two punch. We are excited about that, and if that can translate in the clinic, then that could be really interesting as well.
Okay. Speaking of clinic, you are going to have a clinical readout for ERAS-4001 from the BOREALIS-1 study in the near term. What do we expect from that upcoming update?
The BOREALIS-1 study is our pan-KRAS inhibitor study. We have guided to the fact that we will have a phase I dose escalation update in the second half of this year. It is what you would expect for a phase I dose escalation. Its focus will be on safety, tolerability, PK, initial signs of activity, and with a focus on dozens of patients, and that will be the nature of that update.
Okay. How do you think about, I guess, the pan-KRAS opportunity in light of the other pan-RAS and mutant-selective inhibitors in development? How do you differentiate development of this asset compared to even ERAS-0015?
Yeah, there haven't been much in the way of data disclosures from other pan-KRAS inhibitors, just a couple of companies. How we think about it goes back to what Jonathan mentioned about the combination potential, for instance, with ERAS-0015. Because a pan-RAS inhibitor works through those two mechanisms that Jonathan was describing, including causing hydrolysis of RAS to the GDP state, this is where you have that potential for ERAS-4001 being more off-state preferring to be able to effect this one-two punch in combination with ERAS-0015. We are thinking about this in terms of its combination potential. If it shows good results out of the dose escalation study, then that allows it to potentially be a combination partner for ERAS-0015 with that one-two punch against the RAS protein.
Okay, great. Speaking of combos, there's a couple other interesting ones that I wanted to talk about. One is the PRMT5 combination. I think you recently initiated the combo with Tango's inhibitor. First, can you talk a little bit about the scientific rationale for combining pan-RAS with PRMT5, the way you see it, and what you would expect for this combo in light of the landscape out there?
Yeah, the rationale for it is what you would expect. I mean, these tumors are RAS-driven, and also with an MTAP deletion that leads to dependence on PRMT5. If you are able to hit it with both a RAS inhibitor as well as a PRMT5 inhibitor, then you should see this dual inhibition of the tumor. You see that in terms of the data that were presented a couple weeks ago at ESMO with an 82% response rate in the combination with pan-RAS plus PRMT5. We think that in our case, we could potentially show differentiated results, especially if you end up combining with a differentiated pan-RAS molecule like ERAS-0015. We're very excited about this combination.
We just issued a joint press release with Tango that we initiated the study of our molecule with vopimetostat, so that is an exciting combination for us.
Okay, great. On a different combination front, you also have a collaboration with Merck to evaluate ERAS-0015 with pembrolizumab in solid tumors. Can you speak about what the focus of this may be on? Is it going to be lung or some other tumor types, and when might we expect some data from the cohort?
Yeah. We do have a supply agreement with Merck, where, as Jonathan mentioned, they are supplying us with pembrolizumab for our combination study with ERAS-0015. That is also another exciting combination. When you think about a pan-RAS inhibitor, it has so many different ways that you could think about combining, and it goes back to Jonathan's earlier point as well about the safety and tolerability being very important as you think about different combinations. In terms of where it could play, I mean, one of the most obvious areas is in lung cancer. As Jonathan mentioned, we are looking at that combination of ERAS-0015 plus pembrolizumab, with or without chemotherapy, which would allow us to be, if we were able to do that, allow us to play in that first-line lung setting as the only pan-RAS that would be able to play there or is playing there.
That is an area that has been met with a lot of enthusiasm from the KOLs that we have spoken to as a potential mutation-agnostic opportunity in the first-line setting.
All right, fantastic. I think with that, maybe to close, can you talk about your cash runway and sort of what inflection points it gets you through?
Yeah, so we will be reporting earnings later this week, so I will give you our Q2 number, which was that we ended Q2 with $384 million of cash. That does not include the $632 million that we subsequently raised in July. So call it about $1 billion on the balance sheet, plus or minus. In terms of the milestones, it covers all of the corporate milestones that we talked about, including initiating those three potential registration-enabling studies, two in lung, one in PDAC.
Okay, great. Thanks for the heads-up on earnings, and I think with that, we will close. I thank you guys so much for joining us.
Thank you.
Thank you.