Everyone, thanks for joining. I'm Matt Biegler, I'm an analyst covering oncology here at Oppenheimer. Super excited to be with our next presenting company, which is Erasca. I've got Jonathan and David here for a fun fireside chat. We're gonna be talking all things RAS. Welcome, guys.
Thanks.
You know, look, congrats on the recent data. I mean, you guys, as I said, you know, you guys kind of gone all in on RAS. I think existential question for the community now is: How do we expand upon G12C into other mutational types? There's two approaches out there. Revolution Medicines' got their molecular glue, Amgen, BBOT have, like, the more traditional pharmacologic intervention, effectively taking the acrylamide off of the covalent G12Cs and expanding that footprint into other mutations. As I said, you know, you've got both. Just kind of, like, walk us through your pipeline and how you're thinking strategically from a high level, and we can kind of dive into the more nuances.
Yeah, thanks, Matt. It's a really exciting time in RAS targeting, developmental therapeutics, for the reasons you suggested, that there's a lot of different modalities and tools in our toolkit as a cancer-fighting community to be able to use. As a company, Erasca is really committed to erasing cancer, as well as eradicating RAS-driven cancer, and we believe that we can hopefully live up to our name with our focus on RAS. The lead programs are ERAS-00 15 and ERAS 4,001. ERAS-00 15 is a cyclophilin A binding molecular glue that works by a similar mechanism as Revolution Medicines' RMC-6236.
You know, we have a lot of respect for the pioneering work that Warp Drive Bio and Revolution Medicines have done with RMC-6236. That really was eye-opening for all of us within industry and academia to see that when you go after RAS mutations as well as wild type, that it could be tolerated, and you can see pretty profound responses. I'd say that there's more improvements to be had there in terms of potency and PK, so we can get into that. We do think that based on the characteristics of ERAS-0015, we have a shot of being best in class for what is a very exciting field.
Switching gears to the switch II pocket inhibitors, ERAS-4001 is based on the thesis that if you go in with a highly KRAS-selective approach, you spare HRAS and NRAS, that maybe you can widen the therapeutic window. If so, that leads to a potentially more combinable type of profile. ERAS-4001 is a highly potent, with good PK, pan-KRAS molecule that hits all of the main KRAS mutants really hard. It is a reversible switch II pocket binder along the lines of what BBOT and Amgen and others are doing.
I'd say that's a little more crowded of a space, but we really like having the orthogonal mechanisms of the pan RAS molecular glue and the pan KRAS approach, because also you could potentially combine them in the future.
I mean, is it a zero-sum game, or do you think one approach might be better for certain tumor types than the other? I think I get what you're gonna answer based on your remarks about the combinability of particularly the switch II pocket binders.
Yeah. First of all, I don't think it's zero-sum. I've been in zero-sum areas before. I think TRK was really interesting because when you reduce it down, there really it literally, there was room for two players, and it was zero-sum. Any patient we got, you know, the LOXO didn't, and vice versa. That really was ultra rare in terms of the TRK fusions. I'd say with RAS, unfortunately, the unmet need is just so high that 25%-30% of all patients with solid tumors have a RAS driver mutation of some sort.
Yep
... it definitely is not zero-sum, and I'd say there's room for a pretty robust ecosystem, taking a diversity of approaches. It's still early days. I think we're in early innings still.
Yeah.
There's gonna be, I think, different swim lanes that emerge for each modality, and that's why we like having our, you know, toe in each of those waters.
What's kind of the pitch if we just dial into the molecular glue, 0015? That's the one that's a bit more advanced right now, at least in terms of clinical data. It's like, what's the pitch there? Is it just better binding the cyclophilin A gets better PK relative to daraxonrasib?
Those are somewhat related, actually separate concepts. The pitch is really, it stems from the CYPA binding. ERAS-0015 binds CYPA to form the binary complex that then goes hunting for RAS to form the ternary complex, that then causes the, you know, steric hindrance of the effector signaling, that then just shuts down the pathway. That relatively short-lived phenomenon, but it's a very powerful phenomenon in terms of switching off RAS, in terms of the growth and proliferation that happens, and ideally, it happens in a window where there's apoptosis of the cells. Our molecule binds CYPA with 8-21 fold higher binding affinity than does 6236 .
What you get is a lot more of those binary complexes going around to hunt for RAS, you just get a lot of interesting benefits from that. One is that it translates into much higher cell-based potency. It also results in having 1/10 to 1/5 of the dose that's needed to achieve the same degree of tumor regression across multiple solid tumor models in vivo. From a PK standpoint, this is where the nexus happens. Because you get CYPA overexpressed in multiple solid tumors, including lung, PDAC and CRC, you just get a lot more of ERAS-0015 lingering.
It's almost like a depot effect, where the biodistribution of 15 when measured at 4 hours and 24 hours, just lingers, I would say that you get much higher tumor concentration of 15 relative to the blood and peripheral tissues. Does that lead to a potentially widening of the therapeutic window and tolerability? It's theoretically possible, and if we see better tolerability in terms of rash and/or GI, that could be one explanation. The other is a somewhat independent phenomenon, which is from a PK standpoint, ERAS-00 15 just behaves better than 6236, at least in non-clinical models. It's TBD. We think that's the case in the clinic, but stay tuned for the first half update to really show the translatability there.
We do think that, from PK standpoint, ERAS-0015 has higher bioavailability orally, in terms of %F across multiple species tested. It also has a lower clearance of a longer half-life, it just has a flatter exposure curve, which then minimizes the peak to trough ratios that could also lead to a potential safety and tolerability benefit. It's really a composite of the potency and the PK, and biodistribution that stem from the CYPA binding affinity, as well as the overall PK optimization.
Yeah, it seems like the early data that you presented ahead of JPM would support that theory, right? I mean, you're getting activity at doses maybe a tenfold lower than what daraxonrasib/Revolution Medicines RMC-6236 are getting.
That's right. That was really... You know, we weren't sure if that tenfold sort of dosing advantage would hold true. You know, it, you know, when you do things in mice, they don't always translate in the clinic. In this case, we're pleasantly surprised. We weren't sure if it was gonna come in at one-tenth or one-fifth, or, you know, not even translate, and so it was a real upside surprise for us that we didn't just see one response, but we saw, to your point, multiple responses in patients at eight milligrams QD versus the first clinical response with RMC-6236 at 80. That 10 to 1 framework seems to hold so far.
That wasn't even predicted to be the, what's called the PAD, the pharmacologically active dose. We think the PADs could be higher than eight, and it's gonna be in a range that's higher than that. There's more upside in terms of efficacy. From a safety and tolerability perspective, we're pleasantly surprised that when you take a 10x more potent compound, you're actually not seeing, you know, meaningful changes in terms of safety and tolerability. These were mostly low grade, and we hadn't seen DLTs as of the time of the data cutoff in early January.
Yeah.
Finally, from a PK standpoint, we're actually seeing linear PK. One of the issues around RMC-6236 is there's sort of this exposure plateau. As of the data cutoff, we hadn't seen that. There was linearity of exposure at all doses tested south of 40 milligrams.
I wanted to ask about the GI tox. It doesn't seem like you're seeing as much as daraxonrasib. Any idea why, or you think it's just kind of the hypothesis playing out, you've got better binding, maybe you taking advantage of that depot effect that's there?
Yeah. There's that peak to trough lower peak to trough ratio. There's the better biodistribution. Those are two potential upsides for both rash and GI tolerability. The third for GI is just drug load. When you take hundreds of milligrams versus tens of milligrams, the GI tract just sees less drug that causes local effects, and so you get less of the nausea, and then potentially some of the other things like the diarrhea and vomiting.
What about rash? I mean, I think it's hypothesized that rash is maybe more of an HRAS or NRAS driven event. You obviously do hit those two isoforms with this drug versus the other drug that you're developing. I guess my bigger question is like, do you think that this drug might be able to be used in colon cancer, or is this more of like a pancreatic is probably the best indication for it initially?
Well, I think empirically, first of all, there's a theoretical benefit from biodistribution and lower peak to trough. Because RAS is an on target, you know, AE, as you would expect. The question, I think empirically, if we're able to take ERAS-0015 and successfully combine it with an anti-EGFR antibody, then that is sort of the definitive, objective, you know, action and outcome that you would want to show that your compound is better tolerated than the other pan-RAS inhibitor in development. I think, you know, stay tuned. Our goal is to be able to explore combinations like that in the second half of this year. We'll give a more full safety and tolerability update in the first half as monotherapy.
If we're able to successfully combine with an EGFR antibody, we'd be the first company in the world to be able to show that.
Yeah, 'cause RevMed has to dose down in colorectal, right?
Well, they've never shown combinability with an EGFR antibody, so that's just never been shown to be tolerated.
I see.
I think that's actually why there's such a big push for pan-KRAS, because if you are unable, due to the overlapping tox of skin tox, to combine a pan-RAS with an EGFR antibody, then it's no wonder you need to take a different approach with an H and N-sparing approach. If you can use pan-RAS and successfully combine with anti-EGFR, then why wouldn't you want to? 'Cause by shutting down H and N, we also know from the C. Lover et al. paper from Science earlier in January, that H and N RAS are potential escape mechanisms through PI3K.
You really wanna shut that door if you can, and if you can't, for tolerability, concerns, because, you know, because of the RAS concerns, then that's when you might need to take more of a pan-KRAS or K-selective approach.
Yeah. I like the idea. Didactic, right? We're gonna put them both in the clinic and see how they do.
Yeah. Right.
Biology is obviously complex. RAS has a lot of different levers to it. There's a lot of feedback amplifications. I personally think combinations are the way to go in the forward. I think, the way to go forward, I think in cancer in general, combinations are the way forward. Yeah, kudos to you for doing that.
Yeah.
Where are we now with the AURORAS-1 trial and dosing and, you know, the next kind of update that we'll get later this year, you know, how encompassing do you expect it to be?
Yeah, the AURORAS-1 trial, as we announced earlier this year at the JP Morgan conference, is going really well, better than anticipated. It's enrolling super fast, and that's really a testament, unfortunately, to the unmet need, but also really the enthusiasm of the investigators, as well as the patients for this, you know, potentially better approach to pan-RAS. It's progressing well. We're on track for a first half update. It'll be dozens of patients from a safety, tolerability, PK, as well as efficacy standpoint. We will be able to show, you know, what the monotherapy activity looks like at various doses within not just one tumor type, but probably multiple tumor types. I think David will talk a little bit about 4001.
That'll be an update in the second half, but as far as AURORAS-1, we're on track for a first half update.
Gotcha. This is like a typical phase I bucket trial, whenever if you have a RAS mutation, then you're eligible, or is it more, unified in terms of, like, what indicates CRC, panc, lung, etc.?
Yeah, it's all comers with RAS mutations in a dose escalation, which is typical because you want to be able to fill up those dose-level cohorts as quickly as you can, so that the name of the game is really assessing safety and tolerability primarily.
Yeah.
You really don't wanna put too many guardrails there. We do have in our protocol, the option to backfill, which we are doing. When you backfill at dose levels that have been cleared from a safety perspective, we are backfilling, and in that case, you can put your thumb on the scale in terms of what kinds of patients you want.
Gotcha. I do get questions about IP. Like, you're pretty sure you have freedom to operate here without infringing on any of Revolution Medicines'-
No IP issues, and then the fact that we have U.S. composition of matter that goes out to 2043 is really, you know, a tribute to the chemistry that was done at the time.
Have you released the structure yet? I mean, do we know kinda how different this one is from the others that are out there?
Well, we haven't released the structure, but I think, you know, it's, it is different from RMC-6236.
Right
it's been optimized for both potency and PK in a couple of key regions.
Gotcha. Yeah, let's get David involved here. With 4001, this is the pan-KRAS. It's interesting. I remember maybe 2 years ago at AACR when Amgen unveiled 410, and I just thought it was a really, really cool idea. Like I said, basically take the acrylamide off of LUMAKRAS and kind of optimize for the different mutants. Is this same idea here, or is it different enough from the others? I guess a better way to ask the question is, how different is it from Amgen 410 or BBOT's 11818?
Yeah. Thanks, Matt, thanks for having us here. Yeah, on the pan-KRAS side, unlike RMC-6236, where the structure is available there, you know, we did a lot of head-to-head comparisons pre-clinically that Jonathan described. In the pan-KRAS space, there just aren't as many structures that are available, it's harder to do those head-to-head comparisons. Now, specifically with our compound, there are similarities to some of the other pan-KRASs in terms of, for instance, it's a switch II pocket binder. You know, it's got good activity against the on and off state, single-digit nanomolar potency against both, albeit more potent against the GDP state, some other attributes as well from an in vitro potency and in vivo aspect as well, that we really like.
One key difference, with our molecule relative to some of the other pan-KRASs, many of those are actually built off the same initial scaffold.
Yeah
versus ours is on a different scaffold. If you think about some of the potential issues that might be lingering with some of the pan-KRASs, at least what we've heard anecdotally from some PIs, you know, having a different scaffold could be an advantage for us. Yeah, I think what we really like about this program is that it's got good, a good profile across several different preclinical parameters that I just outlined, plus it's also built off this different scaffold that could allow it to avoid some liabilities of the other compounds.
Assuming that, you know, as Jonathan mentioned earlier, you know, the Sealover paper with HRAS and NRAS kind of bypass, assuming that is an issue, I mean, I wouldn't say it's played out clinically yet, but we're still in the early innings here. Assuming it is, like, what do you think you would combine this with in order to override that bypass mechanism?
Yeah, well, I mean, this is a classic tension in oncology, right? About trying to balance safety and efficacy, right? You know, if you hit all three RAS isoforms, you know, maybe you get rash if you spare H and N. If you look at the BBOT data, for instance, from January, where they had less rash, you know, so it's that classic tension. Now, in terms of where we think it could play, you know, I think the field is still trying to answer that question. I think there could be different swim lanes for a pan RAS versus a pan KRAS. You know, for instance, if, as Jonathan was mentioning with regard to, you know, 6236, hasn't really shown any combination data with anti-EGFR.
you know, if a pan KRAS could play there-
Mm-hmm
... in terms of its ability to combine with anti-EGFR, that could be a real advantage. If it turns out, for instance, that there's a Goldilocks approach, and Jonathan was alluding to this in his comments as well, where you can actually hit all three RAS isoforms with 0015, but have, you know, maybe less of the RAS issue, you know, that could actually be a really big win.
Yeah. Yeah, as I said before, it's really just about getting it in the clinic and testing out the different theories, right?
Yeah.
Yeah. It's pretty cool. Where are you kind of right now with your phase 1 BOREALIS-1? I know it's enrolling. Just kind of what kind of data should we expect later this year from that one?
This study, we filed and cleared the INDs, actually for both molecules, 0015 and 4001 in Q2 of last year. The BOREALIS-1 study is ongoing. What we said at JP Morgan, AURORAS-1 is exceeding our expectations. We set high expectations for both of our trials, and AURORAS-1 is exceeding that, just for the reasons that Jonathan mentioned in his comments, and that BOREALIS-1 is on track. You know, that will have a second-half data update this year.
That will be similar to what Jonathan described in terms of the AURORAS-1 update, in terms of it being also dozens of patients, also focused on safety and tolerability, PK, and early signs of activity, and that will then set us up to be able to move into monotherapy, dose expansions, as well as combination dose escalation work, in 2027.
Is the eligibility similar to AURORAS, effectively?
Yeah
- tumor-
Yeah
with the RAS?
Basically, if you have the RAS mutation, you know, it's an all-comer study. With the ability for backfill and as Jonathan was describing, you know, putting our thumb on the scale at the appropriate time.
Just to go back to kind of differentiation from Amgen AMG-510 and dba, how kind of selective are you for the different mutant types, and are there any, as a class, that don't seem to work very well against? I don't know. I mean, does it even have any activity against, like, G13 and some of the other, maybe more rare, mutational forms?
Yes, that's a good question. I think a lot of the pan KRASs have that similar profile in terms of being good inhibitors of most of the G12X mutations. The exception there being G12R, which to your point, is not a highly frequent, you know, mutation. Q61 is another one as well that generally the pan KRASs don't hit as hard.
I see. Is there any ideal indications that you think for ERAS-4001? I mean, I gather from your comments earlier that if you can spare some of the skin tox from H and N, you know, maybe if you could combine it with, like, an EGFR, then colon cancer would be obviously a logical choice, but are there any other cancers that you think really make sense for this drug?
Yeah, I mean, I think so. I think, you know, CRC for sure, if it's, you know, combinable with anti-EGFR would, you know, make a lot of sense. Frankly, I think, you know, if we go back to the pan RAS space, you know, where RevMed has shown the most amount of data, is in pancreatic cancer, and specifically second-line pancreatic cancer. I think a lot of these other indications, you think about the big three of, you know, PDAC, CRC, and non-small cell. Non-small cell and CRC could also potentially be, you know, swim lanes where a pan KRAS could play. We'll see how our pan RAS plays in those areas as well. Also those long-tail opportunities beyond the big three are areas where either a pan RAS or a pan KRAS could play, will be data-driven.
The nice thing for us is that, you know, we are one of only a few, if maybe the only one, that has both a pan-RAS and a pan-KRAS. Regardless of how the field evolves, if it turns out that there's different swim lanes for both, if it turns out that one molecule is, you know, the one ring to rule them all, to use the Lord of the Rings analogy, that Jonathan likes, you know, we've got an answer for both.
It's interesting, I was just looking at your pipeline. You also have, at least in preclinical development, an EGFR antibody. I'm just wondering if how you're thinking about potential combinations in the future as you really round out this pipeline to Erasca, as the motto is?
Yeah, I mean, we as a company have been focused on the RAS/MAPK pathway since the beginning, and we focused on, you know, from the RTK level all the way down. ERAS-12, which is the program that you're referring to, is a bispecific, biparatopic antibody going after EGFR, both domain II and domain III. The approved EGFR antibodies, like cetuximab and panitumumab, hit domain III only, but this molecule, ERAS-12, hits domain II and domain III, which we think could actually lead to enhanced, you know, activity when the EGF ligand is present. You know, there's a lot of potential benefits of that ERAS-12 program.
It is still an early program, and so it's one of those ones that, you know, we'll as it progresses, we'll see where it best fits in.
Any preclinical data from that one that you're planning on presenting this year?
We haven't guided to anything specifically there. It's still an early program for us.
Yeah. Cool. Maybe just last question, anything else that you think the street is misunderstanding about the story? I personally think it's been resonating. Clearly, it's been resonating with investors, given the performance, and I think, you know, a lot of the read-through from daraxonrasib and some of the other novel assets that are coming out. Anything else that you think investors should be aware of?
Yeah. You know, I don't think that people are missing much right now. You know, I think that we are a pure play RAS company, which is really important, especially given what Jonathan mentioned about, you know, 25% to 30% of cancers have a RAS mutation. You know, we've got 2 really exciting assets in 0015 and 4001. I think, you know, if you think about our valuation and how it's ticked up over, you know, time, and especially even this calendar year, I think it just speaks to the unmet need, as well as, you know, people's enthusiasm about what we're doing, and especially that data that we shared at JP Morgan last month.
I think that if we're able to show good data on one or both of these assets, that's gonna be hugely valuable to patients. We're very excited about the upcoming, you know, H1 and H2 updates later this year.
Awesome. Jonathan and David, thank you so much. It's fun as always.
Thanks, Matt.
Congrats on the progress. Yep.
Thank you.
Thanks, everyone, for joining.
Bye.
Bye-bye.