IDEAYA Biosciences, Inc. (IDYA) Earnings Call Transcript

Good afternoon, everyone. I'm Judah Frommer, one of the SMID biotech analysts here at Morgan Stanley. Welcome to the 22nd Annual Global Healthcare Conference. We're very pleased to have Yujiro Hata, the CEO of IDEAYA with us today. I'm just going to read a quick disclosure before we jump into questions. Please see the Morgan Stanley Research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley representatives. So with that, Yujiro, maybe we could start with a quick overview of the company, for those that are less familiar with IDEAYA.

Great. First, Judah, thanks so much for the kind introduction, and great to be part of the Morgan Stanley conference event this year. So IDEAYA Biosciences, we were founded just about 9 years ago. We have a core focus in emerging area of precision medicine oncology called synthetic lethality. Today we have advanced 4, what we believe, are potential first-in-class programs in the clinic. Our most advanced asset is darovasertib. This is in that registrational trial for potential frontline approval in metastatic uveal melanoma. We also have a key update, we're guiding for in the second half of this year, including a Type C meeting with the FDA that's scheduled for the third quarter, to hopefully get endorsement and support around a registrational trial in the new adjuvant uveal melanoma medication. In addition, we've guided towards the second half Phase II clinical efficacy update as well in this indication. Next is we have a Phase II program called IDE397. This is a -- what we believe is a potential first-in-class MAT2A inhibitor, targeting a very large patient selection biomarker called MTAP deletion. We also have our third program in the clinic in PARG, IDE161, in Phase I dose escalation. We also have a fourth program in the clinic, in Pol Theta Helicase with our partner, GSK. We're targeting to have our fifth program in the clinic with Werner Helicase case by the end of the year. And we're also guiding towards our sixth, seventh and eighth development candidate by the end of the year.

That's a great overview. We're going to try to unpack as much as possible in the time allotted. And I should mention, if there are questions from the audience, please do raise your hand and we'll try to wrap those questions in.

So starting with darovasertib. You had an impressive data updated at ASCO in neoadjuvant uveal melanoma from your IST and separately with the company-sponsored Phase II study. Can you provide a recap of the data and what's deemed clinically relevant in this setting?

Yes. No, great way to start. So yes, Judah, as you mentioned, we had an oral presentation at ASCO a few months ago. This was 15 patients that were enucleation patients. And really, the high-level summary is, in the predominance of these patients, we saw a very robust ocular tumor shrinkage of greater than 30%. In addition, we saw the vast majority of these patients that were going to get enucleated where we were able to deliver a result where we were to preserve their eye. So we think both of these are really important, clinically meaningful outputs on these patients on the IST. And obviously, that's going to be a big part of our discussion with the FDA in terms of what are the relevant endpoints, both in terms of potential primary endpoints as well as secondary endpoints. Lastly, I should have mentioned, at that ASCO update, we believe we've continued to demonstrate a reasonable manageable AE profile, that we believe further provide support around the risk-benefit profile, specifically in the neoadjuvant setting, which, as you know, becomes even more critical in the premetastatic setting.

Okay. Great. So we are expecting a second half update from the company-sponsored neoadjuvant study. How many more patients and how much more follow-up can investors expect versus the June update?

Yes. So we're anticipating a fairly robust data set for our second half clinical data readout. Here in aggregate, we anticipate it will be over 50 patients. Will be a combination of our Phase II company-sponsored study as well as our IST data that was shared at ASCO. I would say primarily, we're going to combine that data set because that's the data that we did provide to the FDA. And what we've promised the public is that we'll share a data set that's largely similar to what the FDA reviewed, to provide that feedback as part of the Type C meeting. Here what people should anticipate is a very full data set as it relates to adverse event profile and in terms of clinical efficacy. So people will see a waterfall, very clear visibility around what kind of ocular tumor shrinkage we're seeing, what is the eye preservation rate we're seeing. We also anticipate being able to share a spider-plot type data set as well. So I think, hopefully, it should very much round out in terms of what we're seeing overall for this program in the neoadjuvant setting. And obviously, now we're in that range of over 50 patients. We would hope it's a fairly definitive data set at least as it relates to preliminary Phase II data.

Okay. Great. And you recently noted as part of your earnings that you have scheduled a Type C meeting with FDA for Q3. Can you remind us of what you hope to gain alignment with FDA on as part of the meeting and how will you provide the update on the feedback? Could this update come with the Phase II company-sponsored data update?

Yes. So I would say the primary objective for the Type C meeting with the FDA will be largely around what are the clinical endpoints, because we are attempting a study here, obviously, hopefully, with endorsement from the FDA, which is a trial that's not been attempted before, right? So I think we've been saying for quite a long time that some of these key -- what we think are clearly areas of clinical benefit, like eye preservation, can we positively impact endpoints such as visual acuity, we think are relevant. However, Judah, as you know, when you look at historical neoadjuvant regulatory approvals, typically, you've seen, as primary endpoints in a randomized fashion, endpoints such as effect-free survival as well as relapse-free survival. So I think for us, some of the key points of clarification we would like to provide is what is the FDA's perspective on some of these additional novel endpoints such as eye preservation and visual acuity. So that's first. And in addition to that, what will be their perspective of the use of some of those endpoints either as a primary endpoint or a secondary endpoint? And this will, I think, be important as it relates to the next topic I'll bring up, which is around effect-free survival, relapse-free survival. Because when you look at historical neoadjuvant trials, typically what you've seen is EFS and RFS used as the primary endpoints. And when they're utilized as the primary endpoints, oftentimes needing to show superiority versus the control arm, right? So now here, will it be required as a primary or will it be required as a secondary? And in that context, could impact sort of the various gradients of what one might need to achieve as it relates to EFS and RFS. And I think to quickly to go through the kind of menu of possibilities there, right, on the far right or most stringent or highest bar for us would be we would have to demonstrate superiority. The next one over would be either equivalence or non-inferiority. And then I would say the least stringent for us would be around no detriments to EFS, RFS. And we think that will largely be based on what is the perspective of the FDA on some of these more novel endpoints. Do they view those as clinically important? So hopefully, we can get clarity, uncircle these items. The last piece I should have mentioned would be around what is the population we evaluate. So we will look at ideally 2 cohorts. One will be enucleation; the other, plaque therapy. If randomized, enucleation would be drug versus obviously getting enucleated. The plaque therapy cohort would be daro followed by plaque versus plaque alone. And here our also view that, ideally, could we focus on the high metastatic risk population? Because if we can, we should be able to get the readout such as visual acuity as well as EFS, RFS faster, right? But then obviously, we wouldn't want to be limited in the label to just the high-risk group. So what is -- obviously, we appreciate this will all be a review issue, but we can obviously get that feedback from the FDA as well. So I know I put out a lot there, but obviously somewhat of a complex equation, but a lot of key pieces we hope to get, hopefully, endorsement and resolution on.

Okay. No, that's great color. So if we move on to the Phase II/III registrational study you're running in frontline metastatic UM, can you elaborate on the study design and next updates for this study?

Yes. So the high level, which we felt was a really great outcome with the FDA, is this is an integrated Phase II/III trial where we in the same trial could get accelerated approval. Here the primary endpoint is progression-free survival. There our targeted objective is to enroll roughly 230 patients. As we've mentioned publicly recently, we have already enrolled triple-digit enrollments. So we're almost halfway there or largely halfway there. And then for full approval is OS. And so we would add additional 120 patients for that. Here it's randomized against standard of care, which we anticipate will be PD-1, PD-1 plus CTLA-4, as well as DTIC. Here, in terms of historical PFS, obviously, these are time-to-event endpoints, but for whatever it's worth, historical PFS has been reported at roughly 2 to 3 months based on some of those benchmarks. And historical PFS has been reported in that 10- to 12-month range.

Got it. And if we move on to the adjuvant uveal melanoma setting, that's another large market, do you have plans for that setting?

Yes. So great question. I would say we are seriously evaluating the adjuvant portion. I think some of it is going to depend on the outcome of the FDA on the neoadjuvant piece and what exactly study design will we need to implement. So for example, if it is a randomized study, we're obviously -- we do have the ability to look at some of these clinical benefit endpoints. And obviously, if we're evaluating endpoints such as EFS and RFS, I think the bigger question for us is, because in the neoadjuvant setting, you're getting in front of the adjuvant setting, do we need -- is it worth it for us to run a full randomized adjuvant study and trial? Because obviously, that will be a larger trial, these endpoints will likely take longer to read out. So I think once we have that endorsement on the neoadjuvant piece, we provide that update, we'll make that evaluation for the adjuvant portion.

Okay. That makes sense. And you touched on pieces of this in your answers, but just to wrap up the daro section, can you discuss the unmet need that remains in uveal melanoma and the market opportunity for daro in general?

Yes. Look, I've been working on oncology since the 1990s, and I think, frankly, I'd have to say, out of many tumor types that are out there, uveal melanoma continues to be one of the highest unmet medical needs. So sadly for patients, there are no systemic approved therapies for either neoadjuvant setting, there are no systemic approved therapies for the adjuvant setting. We believe for the predominance of these patients with metastatic uveal melanoma, which we believe the majority are HLA-A2 negative, there are no approved therapies, right? So we're seeking frontline approval in the metastatic setting for HLA-A2 negative. Obviously, by default, if you're the first approval in neoadjuvant, and if we pursue the adjuvant, that would also be in the frontline setting. And sadly for these patients, for survival, right, I mean, these are -- it's a really tough situation, right? I mean, historically, it has been viewed as a 10- to 12-month survival.

That makes sense. Okay. So moving on to IDE397, your MAT2A inhibitor. You recently showed impressive monotherapy data in bladder and non-small cell lung cancer. How are you thinking about a monotherapy strategy given you have combination studies with AMG193 and Trodelvy?

Yes. So I think for us, that's going to be a question we're going to continue to generate data on to really think about what our registrational path forward is. And what we've publicly guided is our objective to do that next year in 2025. So here, we're continuing to generate monotherapy data in lung cancer as well as urothelial cancer. Really for us, the quick summary is we do believe we've demonstrated preliminary clinical proof of concept. We do believe we have an active agent as a single agent, as well as an acceptable AE profile based on the expansion dose we've selected. In parallel, as you mentioned, we have 2 key combinations ongoing, one with Amgen with PRMT5. I know they have an upcoming presentation coming up here at ESMO. There we've publicly noted, as part of our last earnings release, that we've recently now financially budgeted to prepare for that expansion phase with Amgen. Here the priority tumor type focus will be non-small cell lung cancer. The next, now shifting to Trodelvy with Gilead, so that combination is focused specifically in MTAP deletion urothelial cancer. Here what we can say is the dose escalation is going well. I believe we just recently cleared the first cohort. We don't think this is going to be a very long dose escalation because we're -- our initial dose cohort is starting up that approved Trodelvy dose. So it's likely that we won't need to dose-escalate beyond the second cohort. Hopefully, we'll be in a position to also expand in that combination, perhaps maybe even as soon as the end of the year, obviously, pending the results and the cadence of enrollment. And then lastly, Judah, I think as you know, one of our broader objectives is hopefully to build one of the broadest industry portfolios in MTAP. So we have 2 additional internal programs in MTAP deletion, including a targeted goal to have a second development candidate in the MTAP arena by the end of the year. So we would hope that should be positioned for the clinic by middle of next year. And so that is a very important strategic imperative for us.

Okay. Got it. So maybe just a couple of more pointed questions on the combos. So if we start with PRMT5, can you just walk us through briefly the mechanistic rationale for pairing a MAT2A inhibitor with a PRMT5 inhibitor? And just again, remind us what the next updates are for that combo.

Yes. So here we've generated a lot of data with Amgen on the mechanistic rationale, and I know our plan is to publish preclinical data with them in a peer-reviewed setting around the mechanistic rationale. And this will include, I would say, a substantial amount of preclinical data and also further support around the mechanistic rationale, some of that we can cover right now. So first, I would just highlight that the objective around the combination with MAT2A and PRMT5 is not about hitting the PRMT5 pathway harder. These are 2 distinct targets that we believe have complementary mechanisms to fully suppress the MTAP deletion pathway. In particular, we believe that by inhibiting both MAT2A and PRMT5, we can also help address certain very key [ bypass ] resistant mechanisms that we've identified with PRMT5. Essentially, every preclinical model that we've tested to date, we see greater efficacy in combination than either maximal efficacious dose as independent agents. So I think that gives us high conviction. The 2 pieces to be aware of in terms of the mechanism, one is around this interplay between 2 key co-factors. One is elevated MTA, which is what's often people view drives the synthetic lethal with MTAP deletion. And that the other is the presence of another key enzyme called SAM. And we know that MTA and SAM compete for the same binding pocket of PRMT5. So what we're trying to do is to influence the stoichiometry between MTA and SAM levels. As we know with MAT2A inhibition, you deplete SAM levels. And if SAM and MTA compete for that same binding pocket, it's not just about elevated MTA, it's about can you deplete the levels of SAM to sort of tip it in the favor of greater PRMT5 suppression. We also know in different tumor types, you do see variability of MTA. So this could become critical as you also expand the horizon of tumor types. Lastly, as I mentioned earlier, is around certain compensatory resistant mechanisms. One of the observations we've also seen is around, in the presence of PRMT5 resistance, is around this over-expression of MAT2A, which would mean you're putting more SAM into the system. And so there are several, I would say, key factors involved in terms of the mechanistic rationale. So we think this is going to be a critical combination, in particular, if you want to have a viable approach clinically to hopefully target the frontline setting, especially in tumor type like lung cancer, which, Judah, as you know, is a very high bar, right? Here you're going to be competing likely with KEYTRUDA chemo doublet or triplet, which is going to require quite a result to be able to displace.