Welcome, everyone, to the JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my squad: Priyanka Grover, Malcolm Kuno, and Rathi Pinhasi. Our next presenting company is IDEAYA, and presenting on behalf of the company, we have CEO Yujiro Hata. Yujiro?
Great, Anupam. Thank you so much for the kind introduction. And thank you so much to J.P. Morgan for the invitation to participate again this year at the J.P. Morgan Annual Healthcare Conference. Please note we'll be making some forward-looking statements today, and please refer to our SEC filings as appropriate. As we kick off 2025, we're delighted to give key guidance for this year. First, to start with darovasertib, here we have several key catalysts that we're guiding for in 2025, including our first potential readout, which is a median PFS readout, which is our primary endpoint for our first-line HLA-A2 negative metastatic uveal melanoma registration trial by year-end 2025.
Next, we're also guiding towards a darovasertib phase II, first-line metastatic uveal melanoma readout for overall survival also this year. Next third, as folks know, we have a phase II neoadjuvant uveal melanoma clinical trial ongoing. Here, we're guiding toward over 70 patient clinical data update, as well as a regulatory update in 2025. And then finally, last, for darovasertib, we're targeting to start our second registration trial program for this program in the first half of this year. Next, across MAT2A and MTAP deletion, we have several key catalysts that we're guiding towards, including ongoing phase I to II expansion.
Here, we're focused specifically on non-small cell lung cancers, as well as urothelial cancer. Next, we have two combination efforts ongoing with IDE397. First is with the TROP2 ADC Trodelvy with our partner Gilead. Here, we're guiding for clinical program updates in 2025, as well as our core objective to enable wholly owned clinical combination with MAT2A and PRMT5 with our recently announced development candidate IDE892. Next is our newly acquired clinical asset, IDE849. This is a potential first-in-class DLL3 topo ADC, which we anticipate having clinical program updates also in this calendar year. In addition, across our earlier clinical development portfolio with our partner GSK, we are guiding towards a medical conference update of our potential first-in-class Werner helicase inhibitor IDE275 in the first half of this year.
In addition, for PARG, we have phase I monotherapy expansion that's ongoing, and we also anticipate having a phase I expansion of endometrial cancer with our partner Merck for the Keytruda combination here in both microsatellite stable as well as high MSI. Next, as we mentioned earlier, our focus on the topo ADC area, which is another big focus, is key combinations with our potential first-in-class PARG inhibitor IDE161. Here, we anticipate enabling hopefully multiple clinical combinations in this area. Next, also with our partner GSK, we're guiding towards a phase II expansion, which would trigger a potential $10 million milestone payment.
And then lastly, although we have six potential first-in-class programs in the clinic, we have a rapidly expanding clinical pipeline with three targeted IND filings also in this calendar year, including, as noted earlier, IDE892, we believe is a potential best-in-class PRMT5 inhibitor, a potential first-in-class bispecific ADC, and B7-H3 PTK7. And then lastly, a potential first-in-class KAT6 dual inhibitor IDE251. To just quickly go through, since our founding almost 10 years ago, we've made significant investment in developing what we believe is a leading drug discovery platform that spans both target and biomarker discovery, drug discovery, as well as translational research.
This has driven several of our key programs, including the discovery of IDE397, our MAT2A inhibitor, IDE275, our Werner helicase inhibitor, IDE161, our PARG inhibitor, as well as IDE705, our Pol Theta helicase inhibitor. What drives a lot of our research and drug discovery engine is also a structurally enabled platform that includes several key components, which are described on the slide, including a full suite of capabilities, both in terms of structural biology. One of the areas that we have become known for is our achievement of generating several, what we believe are first-in-world cocrystal structures across several distinct targets, including Werner helicase, PARG, and Pol Theta helicase.
As shown to the right, we have also integrated key core capabilities in AI machine learning, which we have utilized across the pipeline, including assets that are currently in the clinic, as well as our next-generation targeted development candidates. As you can see here, we have, through the years, now built a very extensive clinical pipeline that spans, right now, as noted earlier, with darovasertib, a registrational trial, as well as multiple programs that are in phase II, as well as early phase I clinical development. And as noted earlier, three programs that are now in IND enabling studies.
Several of the key themes that really tie our pipeline together, which is, one, we believe each of these programs we have the opportunity to be first-in-class. Second, for all of these key programs, they are biomarker-enabled. And as you can see to the right, for several of these key both clinical as well as preclinical programs, we are working in partnership with several leading organizations. So for our lead program, darovasertib, this is a potential first-in-class protein kinase C inhibitor. Here, we're targeting a key activating mutation called GNAQ GNA11, which we believe is prevalent in the majority of patients with metastatic uveal melanoma.
As shown to the bottom left, this agent has shown significant single-agent monotherapy efficacy, including the ability to demonstrate tumor regressions in preclinical models. This program has been presented at several major medical conferences, including here as an oral presentation at ESMO back in 2023, and as you can see, based on this waterfall plot, we do see significant activity, including an overall response rate here, which has been reported roughly 45%. And here, just as context, historical response rate has been in this indication in that 0 to 10% range. Next, in terms of median progression-free survival, here we've reported a median PFS of approximately seven months.
Think it is also important to note, in the hepatic-only setting, we've seen a PFS that's been approaching a year. Historical PFS in this indication has been roughly two to three months. We think based on this benchmark, we feel good and have high confidence in the ongoing registrational trial, which was noted earlier, the primary endpoint of median progression-free survival. This is a two-year PFS Kaplan-Meier curve. I think several pieces to highlight here. Here we're showing some just historical studies that have been done, including an approved agent in the HLA-A2 positive setting, as well as some of the control arm data, which has been largely in the control arm checkpoint inhibitor.
As you can see, based on this two-year PFS Kaplan-Meier curve, you see a fairly significant shift to the right. Also importantly, as you can see, this fairly long tail of roughly about a quarter of patients that are shown to be here continue to be progression-free beyond two years. This is just a side-by-side comparison to just give you a sense of, again, some of the historical data relative to the darovasertib-crizotinib combination that's ongoing in the frontline registrational trial. As noted earlier and also at the bottom, historical PFS has been reported at roughly two to three months and historical response rates from 0% to roughly 10%.
By each of these measures, in terms of activity we've seen with darovasertib, both in terms of response rate and PFS, we do believe we have the opportunity to hopefully position this agent as an important therapy in metastatic uveal melanoma. This is the clinical trial design of our ongoing registrational trial. And here, as you can see, this is a randomized trial with a two-to-one randomization. We're targeting enrollment of roughly 200 to 250 patients in this first portion. And as we're now getting closer to hopefully reaching this first key primary endpoint of median PFS for potential accelerated approval.
The next piece I would note is that this is an integrated phase II/III design. So that basically means that we have the ability to not only achieve accelerated approval through this study, but also full approval. And here, the full approval endpoint would be median overall survival. Another major initiative beyond metastatic uveal melanoma we've been pursuing is in the neoadjuvant uveal melanoma setting. There was an early data set that was presented at ASCO last year as an oral presentation. As you can see on this slide, so these are now patients we're treating with primary ocular melanoma prior to the primary procedure.
And as highlighted here, in just over 60% of patients that we've treated that were enucleation eligible patients, we have been able to preserve their eye, and roughly 50% of patients we're seeing greater than 30% tumor shrinkage, so very robust activity, and this is all of this data is with darovasertib monotherapy, so we are in ongoing discussions with the FDA to finalize this clinical protocol, which we anticipate will happen in the first half with our objective to launch a registrational trial, and there's really two key cohorts of focus. First is the plaque therapy cohort, where we have a significant focus as a primary endpoint on vision preservation.
And then second is the enucleation cohort with a key primary endpoint around eye preservation rate. And for both cohorts, a secondary endpoint of no detriment to event-free survival. And as noted earlier, we anticipate finalizing the protocol this half, as well as launching this study in the first half of 2025. So in quick summary, we do believe the uveal melanoma population is significant. So as we're targeting the metastatic uveal melanoma population first, we believe annual incidence, which is predominantly in the US and Europe, is roughly 4,000 to 5,000 patients.
Here, just would emphasize in the HLA-A2 negative setting, which we believe is the majority of this population, there are no FDA-approved therapies. Next, for the neoadjuvant uveal melanoma setting, here there are no approved therapies. And here, we believe the annual incidence now jumps to roughly 12,000 patients. The next set of programs we'll focus on in a new tumor area is an MTAP deletion. This is believed to represent roughly 15% of all solid tumors. Our lead program here is IDE397, which is in an ongoing phase II trial. And the two key indications we're pursuing are non-small cell lung cancer as well as urothelial cancer.
As you can see on this slide, the US annual incidence we believe is significant, approximately 50,000 patients across our two key focus tumor types of lung cancers and urothelial cancer. And there's several other indications that we're also interested in, including head and neck cancer, gastric, as well as esophageal cancer. This waterfall was presented at the Triple Meeting last year in Barcelona. And here, we're demonstrating as IDE397 monotherapy an overall response rate of roughly 30%.
As you can see in this waterfall plot, a very high disease control rate of over 90%. On this one-arm plot, a lot of the data is not fully mature yet. As you can see, really the key takeaway message here is that the median duration of response in PFS is still too immature on this one-arm plot. The median duration of treatment is, at least at this time, at this snapshot, was over half a year. Here we have several radiographic images I'll show you. This was a confirmed cCR in a urothelial cancer patient. As you can see in the nodule to the left, and at week 18, we've shown an ability to have a maintained complete response at the week 18 scan.
This patient was on several prior therapies, including adjuvant PD-1 therapy. This slide highlights the combination work we're doing with Gilead and Trodelvy. So this was a patient, a urothelial cancer patient with both MTAP deletion as well as an FGFR fusion. Here we're showing a patient at week 12 with a partial response. This patient did confirm. We have also reported through posters this presentation that we have seen multiple responses as part of this dose escalation. As noted earlier in the presentation, one of our core focus areas in MTAP is to enable wholly-owned combinations in this pathway.
And through that effort, IDE892, which we believe is a potential best-in-class PRMT5 inhibitor, as you can see to the right, we see significant and very robust combination effect with our phase II MAT2 inhibitor IDE397. Here we just show the overview and schematic of the mechanistic rationale of the Trodelvy combination with IDE397. And here, really, our focus area is to leverage the biology around the purine and pyrimidine pathway, in particular the impact to the generation of nucleotide pools through the methionine cycle, in which you can see MAT2A is further upstream than PRMT5.
You see some preclinical mechanistic rationale data to the right. And as noted earlier, our objective with this is to enter into the expansion phase here in the next roughly a quarter or two. So here's a summary of our clinical development plan. So as you can see, a very significant focus on high-conviction rational combinations. We do have ongoing monotherapy work in both non-small cell lung cancers, urothelial cancer, as well as the two mechanistic combinations around the TROP2 ADC as well as PRMT5. The third program that we'll go through is the newly acquired DLL3 topoisomerase I ADC.
For those that are familiar with small cell lung cancer, we believe a very significant population of roughly 350,000 global annual incidence, of which roughly over 100,000 patients in the US and Europe. Here's some of the preclinical data that's just surrounding this new asset, IDE849. As you can see to the right, very significant activity as a monotherapy agent in various preclinical models. As you can see, both the CDX and PDX model. Also to the left, you can see very DLL3 specific binding in the DLL3 setting versus other DLL areas, including DLL1 and DLL4.
This is a CT scan waterfall plot on eight evaluable small cell lung cancer patients. These are all pretreated patients. As you can see, very robust monotherapy activity with eight partial responses out of 11 by RECIST. just would highlight here that not all of the patients have confirmed, but all of the unconfirmed responses remain confirmable. Here's some radiographic images of one of the small cell lung cancer patients. As you can see to the left, a very sizable tumor mass. You see over 70% reduction at week six. This is a very rapid and deep response that we're seeing in this patient.
This patient had prior platinum doublet and checkpoint therapy treatment. As shown to the right, we have several strategies here, including a focus in small cell lung cancer as well as neuroendocrine tumors. A significant focus for us will be around enabling the combination with our potential first-in-class PARG inhibitor IDE161. Next to the pipeline here is our potential first-in-class phase I Werner helicase inhibitor with GSK, IDE275. Here, as you can see to the right, the patient selection biomarker is high MSI. We see exquisite activity in this genetic setting and very little activity in the microsatellite stable setting.
We also demonstrate preclinically the activity across several tumor types, including endometrial, gastric cancer, and colorectal cancer, which we believe enables this asset to be applied in several solid tumor type settings. With our partner GSK, we're evaluating two clinical opportunities here, both as a monotherapy agent across MSI high and several of the solid tumors I just mentioned, as well as in combination with GSK's checkpoint inhibitor dostarlimab. This is a program that GSK is pushing forward in the clinic, and as you can see the financial economics of our partnership with GSK.
The next program is IDE161, which is a phase I PARG inhibitor, so this is in the HRD DNA damage repair arena. So this asset's currently in dose optimization. We did recently expand in our priority tumor type here of endometrial cancer. And that ongoing evaluation is ongoing as a monotherapy agent. A significant focus for IDE161 is around key combinations specifically with checkpoint inhibitors and, as noted earlier, with topo ADCs. Here, just to the bottom left, as we show somewhat what we think are quite interesting data in terms of the immune effect of PARG, which we believe will enable an opportunity with checkpoint inhibitors, which we're evaluating currently in endometrial cancer with our partner Merck.
As shown to the right is some mechanistic data in combination with the topo ADC class. And as you see here in this figure, combination data with Enhertu where we are enhancing the durability versus the single agent. So this is a schematic of the development plan for IDE161. As you can see here, we're both focused on monotherapy. And as noted at the top, a very significant focus on combination development. Our sixth clinical program in the clinic is IDE705, which is a potential first-in-class Pol Theta helicase inhibitor. Here, our focus is to address PARP-acquired resistance, specifically a mechanism called BRCA reversions.
And as here, as you can see to the left, in combination with GSK's PARP inhibitor, we see very dramatic complete responses in this model as well as in other various models. So this program is in escalation with the next phase being targeted phase II expansion. The next two programs I'll go through are both the IND-enabling studies. So this is a potential first-in-class B7-H3 PTK7 bispecific ADC. As you can see to the bottom right, we do believe this has significant application based on the double-positive expression of B7-H3 PTK7.
Here, we would have a significant focus on three areas. One is in tumor types such as lung and colorectal cancers as a monotherapy, and we also do plan to pursue combinations with our PARG inhibitor IDE161. The last program I'll highlight is IDE251. This is our potential first-in-class dual KAT6 inhibitor, which has high selectivity in the KAT family, and here, I'll just quickly go through this, but as you can see in the top right figure, we have interest in potential biomarker populations, including 8p11 application, and here, we believe we've demonstrated superior in vitro efficacy profile versus a KAT6 selective compound, so this is our last slide in summary, so as we highlighted through this presentation, then I think upon, we'll move into the Q&A portion with other members of management.
We've now advanced six programs in the clinic, all of which we believe have the opportunity to be first-in-class. And then we have three additional INDs that we're targeting for calendar year 2025. So with that, on that note, we'll move into the Q&A portion.
Good. Did you want to invite them to come?
Yeah. I think Darrin and Mike.
Hi. You're just thinking. I just want to remind folks, there are three ways to ask a question. Raise your hand, which is the old-school way. Submit a question through the question portal. It'll show up here. Or you can just email me. So maybe I'll kick off. Can you talk a little bit about the recently in-license DLL3 program? Why was that a strategic interest to you? Why you're excited about it? It's a hot therapeutic area. We've seen some activity in the space.
Yeah, so we're very excited about this asset. For us, we had several key criteria that we were looking to fulfill. First, we wanted an agent that had early clinical validation, but that we felt still had the opportunity to be first-in-class. Second, we wanted an agent that had a key application in lung cancer. And then finally, third was really our strategic focus to enable a combination with IDE161 PARG. So we believe that this mechanistic rationale between PARG and specifically topoisomerase-based payload is significant. We know that there's, at least based on the interactions we've had, we believe also high pharma interest on enabling this combination.
So we're thrilled about the asset. It's obviously seeing very robust activity. And as you said, it's definitely an area that's garnering more and more interest.
And I guess if I just think about the history of the company, the DLL3, and then the one that comes to mind is Dara, right? darovasertib you got through business development. And largely beyond that, the pipeline has been internally from the synthetic lethality pipeline. How do we think about your openness to business development versus focusing on your R&D engine internally?
Yeah. I mean, Anupam , as you said, our internal R&D engine has been highly productive, and so I think for us, we really look at business development as a way to accelerate our strategy, so we have the opportunity to identify an asset that we believe has the ability to accelerate our strategy. It's something that we're going to take a serious look at. In terms of the two beyond darovasertib assets, obviously, the next two transactions we did were both in the biologic space, so I think there inherently, we had not built internal capabilities there, so we felt that we needed to access those assets externally, and that was really with the mindset specifically to enable key rational combinations, as noted earlier, with one of our key internal assets, IDE161.
Anupam, as you very well know, one of our core focus areas over the last 10 years has been around identifying what we believe are high-conviction rational combinations and being very focused on enabling those and hopefully being, in many cases, the first to enable a lot of these key combinations.
So maybe just to summarize, you look at BD as a way to accelerate kind of what you have internally already, combinations or that type of thing.
Yes. Exactly. Yep.
Questions from the audience? Yeah.
Yeah. I mean, you may ask us for permission. I'm interested in the BD direction and BD interest in the future.
So I would say that we're always looking at different opportunities externally, including in China. We obviously have done our last two transactions there. For us, we're agnostic geographically where the technology comes from. But I think at this point, we also have a very full pipeline, but we're always looking externally.
Thank you very much. And I still have one question about the PARG program. Is there any efficacy and safety update about the single-dose clinical trial?
Yeah. Talking about PARG?
Yeah. So that program, we've presented data before. It's continuing to dose optimize the PARG program. And based on the data that we've previously seen with some level of activity in endometrial cancer, we're continuing to move out an arm in endometrial cancer to get a better understanding of the activity of the PARG inhibitor in that indication. But also, because we've seen activity in endometrial cancer and because of some of the data that you, Yujiro, presented today, we're interested in the combination with a checkpoint inhibitor for that indication.
And then beyond that, we're looking at the potential for a combination with topo II ADCs. And during the dose optimization phase, we're continuing to look at additional indications to see where that drug will have its greatest effect.
Additional questions from the audience? Maybe I can ask a broad question on darovasertib, which is kind of when you look at the totality of what you have in metastatic and you look at what you have in the neoadjuvant setting, what do you think are the most misunderstood points by the street on that program specifically?
Yeah. I mean, I'll maybe start, and Darren please jump in here. So I mean, I think in the metastatic uveal melanoma area overall, I think people feel pretty good about where we are. The enrollments have been going terrific and the registration trial, as we presented at ESMO in terms of the PFS data, I appreciate that single-arm data, but it was just much higher than anyone's ever seen before in this indication. I do think as we are planning to give a survival update on the combination, that's going to be important. I mean, we talked about it on the phone.
We'd never shared survival data before. Appreciating that single-arm data, but the historical survival here has been pretty consistent about a year. So I think that's one on the metastatic side. I think on the neoadjuvant uveal melanoma side, here, it's just about having more data. So we had a dataset that we shared. There wasn't a lot of data on specifically around vision and visual acuity. So I think that will help. Next is also just finalizing the protocol with the FDA, I think will be important as well. So Darren?
Yeah. The only thing I'd add to that is if you go back to our recent roundtable discussion we had with the ocular oncologists that we've worked with who have more insight into the data because they're actually treating the patients on a daily basis. Remember what Carol Shields said in that conference that we had? She said, "This drug, when we're talking in the neoadjuvant setting, this drug is a game changer." So it's not very often as a medical oncologist like myself where you're sitting and working with a program like the darovasertib in the neoadjuvant setting and the darovasertib crizotinib combination in the metastatic setting where at the end of the day, you're going to have the ability to really just upturn the apple cart on how you actually manage this disease.
The whole paradigm of how we approach uveal melanoma may change very soon because of the activity that's been seen. You've seen some of it with the data that we presented at ESMO in the metastatic setting. You've seen some of it, and you'll see more of it this year in the neoadjuvant setting. But suffice it to say, and again, we're having this kind of effect because we're on the driver of the disease, Protein Kinase C. And with that, you're seeing dramatic results. And in the case of the metastatic setting, you've seen data that shows that our response rate is superior to what's ever been presented before.
That's true for our progression-free survival based on the data that we've presented so far. We have the opportunity in the future to present some overall survival data in this patient setting. And then in addition, in the neoadjuvant setting, we've already presented some of this information. We're saving eyes. We're improving the potential for patients to preserve their vision. We're reducing radiation. And all of this is going to lead very likely to a large change in the management of the disease. And I think as more and more of this data becomes unveiled over the next quarter or two or this year, I think people are going to start recognizing that more and more. And it's going to become very, very obvious where we're headed.
Questions from the audience?
Given your extensive expertise and library compounds from the synthetic lethality space and then your recent transition into acquiring some ADCs, has there been the consideration of applying the two technologies on the same sort of dual payload synthetic lethality ADCs?
Thank you. Very good question.
Yeah. I think that's a great question. I think you're reading our minds there. We're running a lot of business in that space, and we're having a lot of conversations with people about exactly those opportunities.
Additional questions from the audience? Go ahead.
Yeah, you're talking about lots of combination with 161 with ADCs, but two ADCs you acquired from China is too early in terms of clinical implication, so I don't know which ADC you're going to combination with 101 at the beginning.
Yeah. So in terms of the IDE161, I think you said IDE161 combination PARG. So our perspective here is that we're going to pursue combinations with both of the ADCs. So obviously, the DLL3 ADC, which is more advanced, we anticipate we'll enable that first. But our plan here is to do combinations with both programs.
Questions from the audience? Maybe one from me. Just what are the final gating factors to getting alignment with the agency on the uveal melanoma study? I think the guidance is first half, right?
Right, so we're on the precipice of having a type B meeting with the FDA in the next few weeks to discuss the protocol design, and there, hopefully, you've heard from us before. We've kind of come to some agreement on what the primary endpoints are and obviously an important secondary endpoint of event-free survival, but now it's really just digging into the details. What's the sample size? How is the study going to be powered? What additional secondary endpoints make the most sense? Those are the things that we're going to work out, and with the completion of this meeting, our hope is that we can conclude on the design of the phase 3 trial.
And we're also, in parallel, in progress doing the mechanics behind what it's going to take to actually execute the study. So those are things that are happening in parallel, and we're trying to move as quickly as possible to get the first patient dose the first half of this year.
Any final questions?