IDEAYA Biosciences, Inc. (IDYA) Earnings Call Transcript & Summary

Hi. Thanks so much for joining us. I have to read some disclosures, and I don't have them printed so I'm going to grab them from my phone, sorry. But thanks so much for joining us here to discuss IDEAYA. We've got Yujiro Hata and Andres Briseno. I'll let you guys introduce yourself in a second. But before I get started, I do need to read some disclosures. We are required to make certain disclosures in public appearances about Goldman Sachs relationships with companies that we discuss. The disclosures relate to investment banking relationships, compensation received or 1% or more ownership. We are prepared to read a lot disclosures for any issuer upon request; however, these disclosures are available and most recent reports available to you as clients at our [ firm's ] portal. Okay, with that out of the way, welcome. Thanks so much.

Maybe we can just start kind of high level. I'd love to get a bit of an overview of IDEAYA, what you do in a focus kind of on the key value drivers over the next couple of months.

Sure. Well, thank you, Corinne, for the invitation. We very much look forward to participating again this year. So IDEAYA Biosciences, we were founded about 9 years ago. We're a leading precision medicine oncology company with a significant focus in an emerging area called synthetic lethality. Within that, we now have 4 first-in-class programs in the clinic. Darovasertib, which is a PKC inhibitor in a registrational trial for front-line metastatic uveal melanoma. We also recently just presented in an oral presentation at ASCO in the neoadjuvant uveal melanoma setting. Beyond that, we have IDE397, a Phase II MAT2A inhibitor targeting MTAP-deletion. Our third program is a PARG inhibitor, also targeting HRD solid tumors as well as Pol Theta. Our fourth program in the clinic, also targeting HRD solid tumors. We have a fifth program that we're targeting to get in the clinic with Werner Helicase before the end of the year. We have 2 more candidates; hopefully, we'll have time at the end that we're targeting to deliver by the end of the year. So we do anticipate hopefully seven plus possible first-in-class programs in the clinic in the next couple of quarters.

Maybe let's start with the most recent update because you did have data last weekend at ASCO in the neoadjuvant uveal melanoma space. I mean maybe I'll just start with a brief refresher on what exactly presented.

Yes. So the data that was presented was from our Australian investigator. It was 15 patients' worth of data. And within that, at least our feeling is that the data well exceeded our expectations. So in quick summary, I would say, we saw a significant tumor shrinkage. And I think that was great to see as monotherapy. Corinne, as you know, we're testing it as a combination of the metastatic setting, but it's pretty clear to us in the new adjuvant setting, monotherapy is sufficient. And then lastly was really around the eye preservation rate. So all of the patients that were enrolled into this study were basically on track to get their eye removed because their ocular tumor was of a certain size or location. And remarkably, within that group, 3/4 or 75%, we were able to get them off of the enucleation track. In addition, we did present an early snapshot of our data. We have noted, we've enrolled now, I believe, it's 43 patients. So enrollment is taking off. Within that, we shared 8 patients' worth of data. They've been on for more than 4 months, and we see very consistent results.

Great. Maybe you could contextualize for us how like the 75% preservation of the eye, like how is that clinically meaningful? Or how does that compare?

So I think it's really important to first start with the unmet need. So there are no approved therapy, systemic therapies for both neoadjuvant and adjuvant care. When we started this journey about 1 year, 1.5 years ago, at least in the clinic -- I mean our expectations when we got the feedback from the KOLs is that even a 10% eye preservation rate will be a game changer in this indication because the alternative is we're going to remove your eye for those patients. So that was our expectation going in. And obviously, based on the early data thus far, we're just well north of that type of target. So hopefully, that will bode well as we now are preparing for this Type C meeting with the FDA.

Great. And we do expect another dataset from the company-sponsored study that you referenced. Remind us the differences between those 2 studies and what we -- how we should think about what that trial will show.

Yes. So that's correct. We're guiding in the second half of this year, 2 key updates, including from our Phase II company-sponsored study. It is going to be a larger dataset. We anticipate it will be 30 patients or more. We do want to have ideally 4 to 6 months of follow-up for each of the patients, certainly see what we hope is really the full potential of the molecule. Probably the main difference between our company-sponsored study versus what we saw at ASCO is that not only will we have enucleation patients, but we'll have these smaller to medium-sized tumors as well. We are considering for our next update in the second half, do we combine that with the regulatory feedback or do we separate them? So that's still under discussion. But I think either way, we're really excited to give that update in the second half.

Yes. And how do these data and kind of the robustness of results inform your strategy as you think about neoadjuvant and adjuvant uveal melanoma on the forward? And what do you plan to request as you go into this Type C meeting with the FDA?

Yes. So first, our interest and intention is to evaluate this molecule both in the neoadjuvant and adjuvant setting. From a regulatory perspective, in this upcoming meeting in the second half, our primary focus will be to get endorsement for what we hope should be an accelerated approval study, specifically in the neoadjuvant setting. And as it relates to that, our plan is to bring forward both an accelerated approval study design as well as for full approval. So that's our objective for this upcoming Type C meeting. We would then -- at least our current plan is to then go back to discuss the adjuvant trial after that.

Okay. This approach obviously would be a pretty like paradigm-changing -- treatment paradigm -- treatment regimen in uveal melanoma. So I guess, what do you think you need to show to change behavior as you think about going to the physicians and convincing them to use this in neoadjuvant, adjuvant uveal melanoma?

Yes. So I think typically, in these kinds of situations, it's really driven by 3 things primarily. First is the unmet need. And the great news here is, at least personally, at least we think there's no greater unmet need than the neoadjuvant setting in uveal melanoma and oncology today as we just walked through. Second is, what's the risk-benefit profile. And here, Corinne, as you know, we have evaluated darovasertib as a monotherapy agent for years. We've been in now over 100 patients as monotherapy. And at least our perspective is that the AE profile is highly manageable. And we also know from the metastatic setting, we've been able to keep patients on the treatment for multiple years. So that's the second. And then finally, third is what is the effect size we're seeing. And at least right now, based on parameters tumor shrinkage, we'd like to use response criteria as potentially the primary endpoint for accelerated approval. And then second, as we talked about, at least in the enucleation patients, the preservation rate we're seeing is so well north of what we were hoping for when we started this process.

Yes. Maybe before we talk about the metastatic setting for a bit, how are you thinking about the market opportunity here in neoadjuvant uveal melanoma and adjuvant as well?

Yes. So I think a good place to start is, there is a competitive molecule that was approved in the frontline setting of HLA-A2+ metastatic uveal melanoma. And that patient population, we believe, is roughly about 1,000 patients. So if you start from there, we think the primary setting in uveal melanoma is at least 10x that size. And so I think the good news there, at least on this other example, we already have real sales numbers. And I think as you know, when you're trying to project into a new market, that becomes one of the key aspects. But here, we have real numbers to rely on. And how we get to that 10x number, one is purely annual incidents. We know in the pre-metastatic setting, the annual incidence jumps by 8,000 to 10,000 patients, which is almost double. The next is around duration treatment. So our CMO recently mentioned at ASCO that we are in the process of amending our protocol where we would treat up to 12 months in neoadjuvant, up 12 months in adjuvant in our existing Phase II study. So that's another multiple would just be duration. And then lastly is around total prevalence. So when you look at the metastatic setting, there's not a significant jump between annual incidents and prevalence because OS is so short. That's not the case in the pre-metastatic setting. So we know that there are a lot of patients that are sadly not doing anything. They're doing wait-and-see because there's no good therapies available for them. And so we should capture a portion of that. And that's why we think this is very much of a significant opportunity. And duration, frankly, we could really be at the start of this journey. And so there could be a subset of patients that want to stay on it as long as they can.

Okay. Maybe we'll take that as a segue to the metastatic setting. So maybe first, just you're enrolling patients in a registrational trial. What are the next expected updates?

Yes. So the primary focus right now in terms of updates in the metastatic front-line trial that we have started last year is where are we in enrollment relative to the target. So most of our analysts are projecting a late '26 launch. So we've been pegging our enrollment targets to hopefully enable that time frame. So what we can say right now is not only are we on schedule, we're slightly ahead of schedule. So that's great. And we're still in the process of activating sites, in particular, in Europe. As opposed to the readout here, the primary endpoint is progression-free survival, which is -- would be the primary endpoint for accelerated approval. There all that really matters is the hazard ratio. So this will be a blinded study. So that will come once enrollment is complete and a sufficient follow-up has occurred.

And remind us what the prior study showed and what the study is powered to demonstrate with respect to PFS?

Yes. So we haven't gone into the specifics of the powering assumptions, but really the quick summary is historical PFS and the indication that's across half a dozen trials has been in that 2- to 3-month range. In the front-line setting, data that we presented in an oral presentation at ESMO last year, we had a PFS that was higher than 7 months. And the subgroup of patients with hepatic-only disease, we saw a PFS that was approaching a year. So by every standard, we're just -- we're significantly above what we've seen before. And that's what gives us the confidence. And so I think the powering assumptions we placed is that we're going to hit that type of objective.

Okay. And as you mentioned, there is a competitive agent in the space. So talk to us about how you think about the market opportunity in metastatic uveal melanoma.

Yes. So in terms of metastatic uveal melanoma, here I would start with annual incidents. This is predominantly in the U.S. and Europe. We believe it's about 4,000 to 5,000 patients annual incidents. Total prevalence is probably in that 10,000 to 12,000 patient range. Right now, there's only an agent approved an HLA-A2 positive. We believe that represents about 1/3 of that population. And the remainder is HLA-A2 negative, where there's nothing approved. And that's the significance that we're running a front-line trial in that setting. But I would say, important to highlight that our drug works irrespective of HLA-A2 status. So we are not giving up on the A2 positive. So they're assuming approval in A2 negatives. We will continue to publish data in a peer-reviewed setting in positive and target to get on compendia for pricing and reimbursement.

Okay. Great. And are there any other indications where you see a role for daro or the combination? And maybe you can just expand on what those look like?

Yes. So I would say our primary focus is to have this agent penetrate the patient journey in uveal melanoma because we think the opportunity is so significant in neoadjuvant and adjuvant beyond the metastatic that we just walked through. I would say beyond that, our probably next biggest focus is in cutaneous melanoma. So we know that GNAQ/11 is present and about 4% of skin melanoma. We've already shared some data publicly. And really the quick summary is the data looks very similar to what we see in uveal. We're seeing responses there, and we're seeing quite significant durability, which is encouraging. So there, the primary focus is really around finding these patients and enrolling them.

Okay. Great. Maybe we'll switch gears here and go to IDE397. Maybe first, MAT2A inhibitor being developed in patients with MTAP-deletion. Maybe if you could just briefly remind us of the mechanistic rationale for this molecule and how it differs from the PRMT5 inhibitors that are also in development here?

Yes. So here, the patient selection biomarker in question is called MTAP-deletion, Corinne, as you know, is a very large biomarker, represents about 15% of all solid tumors. There are probably 2 primary targets that have been pursued today in this pathway. One is PRMT5, as you mentioned. There are these second-generation molecules, which are called MTA cooperative PRMT5. And the second is MAT2A. So the similarity is that both of these molecules, the patient selection biomarkers, MTAP, the way they do it is different. So I'll focus on MAT2A primarily because that's our asset in Phase II, which we're clearly first-in-class or have the opportunity to be first-in-class there. And here, this is all around depleting SAM levels. So MAT2A is involved in the conversion of methionine to SAM. And if you inhibit MAT2A, you deplete SAM levels. And we know the role and importance of SAM has several key important factors, including being the key substrate for protein methylation of PRMT5. And that's where, if you look at all the various CRISPR screens, MAT2A comes out as one of the top hits for synthetic lethality with MTAP. The second, which I won't get into too many specifics, but is around the combination rationale with PRMT5. And here, we know for those second-generation PRMT5 inhibitors to work, a critical aspect is to be MTA to be bound to the binding pocket of PRMT5. MTA and SAM compete at that same binding pocket and have a similar KD. So it's not just about having elevated MTA, it's also about what are your levels of SAM. So if you can deplete SAM levels, you really influence the stoichiometry of these 2 key co-factors. So beyond that, we have a lot of data that we've been generating independently. We've now looked at over 20 models. We've been doing great work with Amgen. We just actually ran into Jay Bradner in the hallway. And we believe the mechanistic rationale of this combination is significant. And Corinne, I know you've been hearing us over and over on this one, out of all the various combinations one can pursue an MTAP deletion, we continue to believe this is the high conviction. This really is the critical experiment being run clinically. And at least from our vantage point, the primary reason why is there's a lot of various bypass and resistant mechanisms that we've identified specifically related to PRMT5, including around this change of MTA levels. And so a lot of that data we now have, and we are planning to publish that work to really hopefully educate the public on why this is the combination people should focus on.

Okay. That's helpful. We did see a number of the monotherapy updates around the PRMT5 inhibitors last fall. I guess, how do you think about the differentiation potential of a combination approach?

Yes. So I would say, first and foremost, I would say, 2 observations there. One is when you look at precision oncology in general, and I'm going to generalize here, but obviously, it's not just about seeing responses. Ultimately, you need to drive durability. We saw that very much front and center in the KRAS space. And now the question is what is the combination that makes significant mechanistic rationale that might have the opportunity to drive that durability, in particular, if you want to get into the earlier line settings of tumor types that we're interested in, including lung cancer, bladder cancer. So right out of the gates, the assumption, at least, I think, should be you're going to need to go in combination if you want to really penetrate that front-line setting and hopefully address durability. So I think if I were to put at the top of that list, Corinne, what we're trying to really achieve through this combination is to deliver that durability, which personally, if you look at the swim lane plots that have already been published by the second-generation PRMT5 inhibitors, as you know, one was presented at the triple meeting at least personally, I just don't believe that durability is there right now. So I think that's going to need to be delivered through this type of combination.

Yes. You did also report some that you'd hit [ RPDT ] for the monotherapy a couple of weeks ago at a high level, obviously. You didn't share the data, but what are you seeing in those monotherapy cohorts? And how does that kind of inform your expectations for the combination?

Yes. I would say here, Corinne, I think you're probably seeing some of our messaging communication of all this on this one. I would say we're becoming -- excited about what we're seeing. I appreciate that it's taken a bit of time to really -- for us to identify what the right tumor types are, including squamous lung in particular. And then second, to really identify the right dose. So as you know, we had started the expansion phase, probably about 1.5 years ago. And through that, we are looking at roughly about 4 or 5 different doses. And within that, we narrowed it down to this one because this is where we are seeing, a, the most responses, including confirmed responses by RECIST and also where we feel like we can treat these patients long as from an AE perspective. And it was really finding that sweet spot. So we are becoming more and more confident on what we're seeing on the monotherapy side. But with all of that said, our continued central strategy in this pathway will continue to be rational combinations. And hopefully, what you'll see by the time we end the year, is that IDEAYA will be viewed as one of the leaders in MTAP-deletion with one key category, which is the breadth of our portfolio in MTAP. We're not just investing in MAT2A, we've invested very broadly across this pathway. And you're going to start hearing more of that as our candidates start getting delivered.

Okay. I think I've got a question on that later. But for now, I'm going to establish the Amgen combination. And just remind us the specifics of the collaboration and kind of where you are in that clinical study, when we could get next data?