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

In the room and on the webcast. I'm Yigal Nochomovitz, one of the biotech analysts here at Citi. We're starting our health care conference this morning in Miami. Our first company is IDEAYA Biosciences. We're privileged to have Yujiro Hata, the CEO of the company, with us this morning. Welcome, Yujiro. Thank you very much. It's been a busy time.

Yes. Thank you, Yigal, and thanks to Citi for their invitation this year, and we very much look forward to the conversation today.

Awesome. So just as a reminder, for those in the audience, if you have a question, we have microphones, you can ask and I'll relay that. So maybe just to start out, I know a lot of people are obviously very familiar with the company, but just give us a broad brush strokes, what is synthetic lethality? Why is the company focused on that particular therapeutic hypothesis? And then from there, we can dive into each of the many programs you have.

Yes. So IDEAYA Biosciences, we were founded just about 10 years ago, as you mentioned, Yigal, with a significant focus in the area of synthetic lethality. And the reason why we focused in this area at our earliest days of inception was the perspective that the area of synthetic lethality would open up new targets and therefore, the ability to go after new patient selection biomarkers, many of which there are not treatments for today, including areas such as MTAP deletion. I would say one of the key challenges as you delve into synthetic lethality, a lot of the targets are extremely challenging to drug. So good examples are targets such as Werner Helicase, Pal Theta Helicase. I think we'll talk more about that today. So as part of that, not only do you have to build significant capabilities in the area of cancer biology, translational research, you also have to build an enterprise around world-class drug discovery. And I would say that's been a significant focus for us since the earliest days of the company.

Tell us a little bit more about that because I think that's a little bit underappreciated just the incredible strength of the MedChem effort. I mean I was in your offices a few months ago and you were talking about it. So I would love to hear a little bit more about the strength there.

Yes. We believe over the last 9-plus years, we've built fully integrated capabilities. We have the ability, we believe, to drive, get or pursue our targets versus pharma. And really, it's soup to nuts capabilities we've built, and they span several key areas, including structural biology, computational chemistry. We've built significant capabilities around, obviously, medicinal chemistry, but we've also integrated new tools and capabilities around AI and machine learning. And this also, we believe, helps us accelerate the SAR lead optimization process. I think ultimately, at the end, what does differentiate us from, I would say, a lot of our peers, in many cases, we are venturing into targets that no one has drugged before. So in many cases, we are leading that charge across various different targets. And that's why when you look across our portfolio, many of them are positioned to be first-in-class, pretty much most of the programs we've taken novel chemistry approaches. And ultimately, what that requires, and I think this has been a journey for us as an organization, you have to have a very deep understanding of the biology to guide what exactly you're doing from a lead optimization chemistry perspective. And we have several great examples of that through the portfolio. Hopefully, that we'll talk about more today.

Okay. So that's a perfect segue into the first relatively mid-stage program, IDE397. So talk about MAT2A. MAT2A has been a tough nut to crack, shall we say. Many have tried and a few have succeeded. So tell us why it's so difficult? And what were you able to understand there to produce a very good inhibitor that has strong potential?

Yes. So maybe just to take a quick step back. For MAT2A, I think commonly, when you look at synthetic lethality and synthetic lethal with here, the patient selection biomarker in question is MTAP deletion, which Yigal, as you know, has been reported to represent approximately 15% of all solid tumors. Within that, I would say the 2 targets that have surfaced to the top are MAT2A and PRMT5. I would say MAT2A is less crowded than the PRMT5 space, and we believe some of it is because of the challenges around chemistry. Here, we did multiple years of chemistry. As you know, there have been first-generation molecules that had selectivity issues that created certain AEs that there were not a path forward. Second, they also had, which I would describe as ADME, DMPK properties, highly insoluble molecules. And these are really core challenges to solve. And then finally, last, we have not revealed all the specifics, mainly from a competitive enablement perspective. But one of the things I would highlight about IDE397, it is a very unique compound when it comes to sort of its PK properties. And we were very focused on trying to achieve a very specific type of profile for this molecule that we felt was critical and was a true standout. And ultimately, that translated to enhanced preclinical efficacy in models relative to other compounds that have been out there. And obviously, that's hopefully now also shown to translate in the clinic as well.

Okay. So maybe just give just a quick 20, 30 seconds on the efficacy that you've seen as monotherapy. And then, of course, the big question or one of the big questions is combo with PRMT5. Obviously, you're doing the work with Amgen. You recently disclosed that you have your own asset in that -- with that target. So I'd love to understand how you're thinking about the interplay between those?

Yes. No, thanks for asking that question, Yigal. So Yigal, as you know, we fairly recently in Barcelona had a late-breaker oral presentation at the triple meeting. Here, we presented just under 30 patients worth of data, specifically in MTAP deletion patients with a focus on both non-small cell lung cancer and urothelial cancer. And really, the quick summary here is we reported a confirmed overall response rate of roughly 30%. We also saw a very significant disease control rate over 90%. We had not, at that point, yet reached median duration of response, median PFS or median duration of treatment. But thus far, it's north of 6 months, which I think is encouraging when you look at the various chemo likely comparators like docetaxel, which we've seen have been reported with a PFS around 3 to 4 months. So I think relatively speaking, we think we're well positioned with the data that's been presented so far to date. So in terms of the combination efforts here, Yigal, as you know, we've been really communicating this for several years. In this pathway, our perspective are several things. First, we believe tumor type absolutely matters, and that's why we have our key priorities, including lung cancer, urothelial beyond that, I would say we have interest in gastric and esophageal cancer. And then finally last, I would say, head and neck cancer, probably in that order. And a lot of that is based on the basic research we've done as it relates to elevated MTA in either the deleted setting of MTAP or the wild-type setting. The second piece, as you know, we've consistently said in terms of strategy is we believe in this pathway, the central focus will be around combinations and specifically rational combinations. So we have 2 strategies we're taking right now, one, which is within the pathway of PRMT5 and MTAP and that's our work with Amgen. We believe we have fully suppressed this pathway to help prevent certain resistance and bypass mechanisms that we've identified that we published with Amgen also at the triple meeting. We believe the way we're going to drive the greatest number of responses as well as durability is going to be through a key rational combination, which is why we felt the imperative -- strategic imperative to have a wholly owned combination here. The second work with Gilead on Trodelvy, this is in urothelial cancer. This is trying to leverage a lot of the chemo MOA. As you know, we were earlier looking at chemo such as pemetrexed we believe the topisomerase payload can mimic that MOA to hopefully drive synergy with IDE397. We've seen early activity there, including responses. And here I'll note that they're plural now responses, which is encouraging. So we are seeing an early signal here on the Trodelvy combo. And I would say a lot more to come on that in 2025. We're controlling that trial. We'll obviously have more control over both the speed and the cadence of that data disclosure.

So obviously, with the Gilead announcement around the demarketing of Trodelvy in urothelial, I mean, you could look at that in many ways. It could be a good thing for you in the sense that the combo is the way to go, right? So tell us more about how you're thinking about that aspect.

Yes. No, Yigal, thank you for the question and definitely on-point question. And for the listeners here, as you know, that Trodelvy was recently changed as it relates to the approval in urothelial cancer. And here, what I would just highlight is several things. First is the experiment in MTAP deletion has not yet been run. And we do believe we should see enhanced activity, specifically in the MTAP deletion setting with the topoisomerase payload. So that's the first. Second is really the thesis that in combination, we believe we should be able to enhance the efficacy of what Trodelvy observed in urothelial cancer alone. And just to be clear here, we believe the core backbone in this setting is going to be around IDE397. And what we're trying to do is enhance that activity through a targeted delivery of the topisomerase chemo through the ADC format through differentiated pharmacology. That's the objective here. And then finally, last, what I would just emphasize with Trodelvy, our view is we should be able to pursue this with any TROP2 topo-ADC. So there are additional conversations going on there, not surprising, there are other companies that we know that are interested in enabling this combination. So from our vantage point, we're really looking at this as clinical proof of concept. Can we -- basically, our main question is, can we deliver this chemo payload of topisomerase with the mechanism of ID397 and deliver it safely. We believe if we answer that question from a POC perspective, our perspective is we should see -- hypothetically, we should see more efficacy. And once we've established that, then we should have a lot of different options because as you know, there's quite a few TROP-2 ADCs out there.

Right, right. Makes sense. And then just to come back to the combo with PRMT5. I know you may be limited in what you can say given your relationship with Amgen. But to the extent you can comment, obviously, a lot of people are very interested in the combo data when we may see that. As we know, the preclinical synergy was really, really strong, just flatlining tumors. So anything you can say there about the data disclosure pathway? And as far as your work with your proprietary PRMT5, when might we see that go into the clinic?

Yes. No, definitely. So here you go what I could tell you, the dose escalation evaluation is ongoing. There are multiple cohorts that are being evaluated. From our perspective, we believe there's the potential to have several potential cohorts we can move forward into the expansion phase. Here, what I would emphasize is several key points. First, as I mentioned in the very beginning part of the fireside, we do believe tumor type absolutely matters. So from our perspective, this combination evaluation, in particular, needs to be evaluated in the setting of non-small cell lung cancer. And obviously, here, ideally, you have 20, 30 patients at the right dose or doses. And we believe here, there are several multiple opportunities to evaluate in combination with the PRMT5 mechanism. And hopefully, this really establishes why we also decided to press ahead with our own MTA-cooperative PRMT5 inhibitor, which we do believe has a potential best-in-class profile. I'm happy to go through what our target product profile was for that. We're doubling down on this combination, and we continue to have conviction that this will be one of the key combinations that will hopefully deliver greater efficacy in this patient population.

Yes. I mean if you could -- to the extent you can give us a teaser or a preview of what you're engineering into yours that maybe even better than some of the others?

Yes. So first, what we would say is that we've studied this target for quite a long time. So we've been doing chemistry for well over 5 years. We've been working towards trying to develop a best-in-class profile. For quite some time, we've had a perspective and view on what the ideal target product profile is. So first, and I'll quickly go through them, is around the question of brain penetrants, yes or no. From our perspective, based on what we know of the target, the toxicology and various input from our clinical team as well, we believe brain penetrants is more a liability than a benefit. So really, our objective here was not to specifically have a brain-penetrant molecule. That's our team's perspective. And we believe some of that has already manifested in the clinic with other MTA-cooperative PRMT5 inhibitors that have been noted as brain penetrant, and you've seen some of that clinical manifestation already. The second is really around the balance between selectivity and potency. So we published some of this work in Barcelona, if you've seen that, which is there is a point at which you continue to drive potency, you start breaking the selectivity barrier. And without getting into too many specifics, we believe this is really the fine balance between not just MT-cooperativity, but cooperativity with other things such as SAM cooperativity, et cetera. We published that work in Barcelona. So we feel we've achieved that very fine balance of driving potency as far as we could, but maintaining sufficient selectivity profile. So I would say on that front, our molecule looks the closest to the BMS compound. The next is around ADME DMPK properties. And I think this is without calling out specific compounds, we do think there's quite a broad range in terms of the various molecules that are out there. Obviously, ideally, we're not having to dose at 1 gram or higher for monotherapy studies. We've obviously shown with IDE397 has really great ADME AMPK properties. And so that's what we have delivered here as well. Also lastly is around pure selectivity, just sort of broader target screening selectivity. This molecule, we think, is a true standout. And sorry, the last piece I should mention, this molecule has been handpicked to be combined with IDE397. Sometimes this is an empirical experiment. We have had about a half a dozen molecules at the very end we looked at. This molecule was the true standout in terms of combination potential with ID397. So we're excited about it. We anticipate we'll be able to file the IND approximately middle of next year. So hopefully, we'll be one of the first companies that could enable a wholly owned combination in this pathway.

For those that are a little bit less familiar, just explain the reason why the brain penetrants may be a downside?

I think this is purely around the biology of the PRMT5 target. So without getting into too many specifics. And as I mentioned earlier, there's already been data presented on MT-cooperative PRMT5, some of which have noted are some level of brain penetrants. And if you just look at the AE table, at least our team's view is that some of that has already manifested. So we appreciate the benefit of having brain penetrants, but ultimately, you have to evaluate target by target. Yigal, as you know, in this business on oncology, typically, the AEs that stop programs, one is liver, one is cardiovascular and CNS tox is another. So I think you have to definitely go in eyes wide open, understanding the biology. Ultimately, that was our call on this target, and that's exactly the profile we pursued.

Okay. All right. Let's shift gears a little bit here. Another important focus for the company, of course, is uveal melanoma and metastatic uveal melanoma and neoadjuvant as well. So maybe let's start with the -- working backwards from the recent neoadjuvant uveal melanoma data. So just share your overall synopsis of that. What are the key takeaways? How does that inform your Phase III strategy?

Yes. So Yigal, as you know, we had an oral presentation at ASCO in June, where we shared one of the first data sets around neoadjuvant uveal melanoma for darovasertib as monotherapy. Really here, the key takeaway is we're seeing over 50% of the patients, the majority of patients that were planned to get enucleated. We were able to preserve their eye. We also saw in a very large proportion of patients, very robust monotherapy tumor shrinkage, well over half that had over 20% reduction, which is where we believe we start seeing clinical benefit. So overall, it met all of our expectations from a clinical efficacy perspective. And importantly, the AE profile continued to be consistent with what we've seen in the metastatic setting with monotherapy. We believe this asset is unique and that it does have an AE profile that we believe does have a path forward in the pre-metastatic setting, which, as you know, the bar is higher. We also know patients from the metastatic setting, this is as monotherapy, patients have been able to stay on treatment for years. So we know patients can tolerate it for long periods of time as well, which is also important. A few months later, we presented more data, roughly 50 patients with the IST data and our own data. That number has now grown to over 75 patients of our own data, which we hope to be able to present sometime around middle of next year, hopefully at a medical conference. Beyond sort of the enucleation cohort, the second group of note here is the plaque therapy group. We had a small data set of about 10 patients around vision preservation type data, and that data set is only growing. So now we have over 20 patients worth of data that have been followed up for more than 6 months. We have over 30 patients with at least 4 months of follow-up. And that data set is only going to be growing. And we've been sharing that data with the FDA as part of our various regulatory conversations. So we're getting ready to hopefully launch the Phase III registrational trial for that in the first half of next year.

Okay. So let's dig in a little bit on the endpoints there, the vision preservation and the event-free survival. So explain a little bit as to how you have confidence in those endpoints and the data that support picking those for the Phase III.

Yes. And then I would say here, our discussions have continued to evolve as we continue to have discussions with the FDA. So and I've noted this in some other firesides recently. So I'll highlight it here. So in terms of the enucleation cohort, I think that's fairly straightforward. The FDA agreed around the primary endpoint for full approval will be around eye preservation. In our FDA briefing book, we noted an eye preservation rate of 10%. We're obviously well north of that. We've already reported over 50%. So we feel quite good about that. The second cohort is around plaque therapy. And here, we noted in our update in the summer around visual preservation. The second piece we've now included, these are as composite or co-primary endpoints to get full approval in that plaque therapy cohort is also around prevention of macular edema. And this is actually quite important because we believe about half of the patients in the high-risk population because of the amount of radiation they're getting, over roughly half of these patients are getting macular edema. So this is vasculature of the macula, which often causes blindness due to inflammation due to the radiation. We've already seen observations that patients were able to prevent macular edema from occurring. And that's been from input from our KOLs with feedback from the FDA. So that's also now being included as part of the final protocol submission for the registrational trial. So I think that's important. So if we hit either, that's what we're proposing, vision or the macular edema, we would hit our endpoint. The final, third, as you mentioned. So those will be...

Those are for -- and macular edema and the vision, is there not some sort of relation?