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

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, [indiscernible], Malcolm Kuno and Rati Pinge. 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 JPMorgan for the invitation to participate again this year at the JPMorgan 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-lin HLA-A2-negative metastatic uveal melanoma registrational trial by year-end 2025. Next, we're also guiding towards a daro-crizo Phase II first-line metastatic uveal melanoma readout for overall survival also this year. Next [indiscernible], as folks know, we have a Phase II neoadjuvant uveal melanoma clinical trial ongoing. Here, we're guiding toward over a 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 registrational 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/II expansion. Here, we're focused specifically in non-small cell lung cancer as well as urothelial cancer. Next, we have 2 combination efforts ongoing with IDE397. First is with the TROP-2 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 TOP1i 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 a Phase I monotherapy expansion that's ongoing. And we also anticipate having an Phase I expansion in 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 PARP 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 6 potential first-in-class programs in the clinic, we have a rapidly expanding clinical pipeline with 3 targeted IND filings also in this calendar year, including, as noted earlier, IDE892, what we believe is a potential best-in-class PRMT5 inhibitor, a potential first-in-class bispecific ADC in B7H3/PTK7, and then lastly, a potential first-in-class KAT6/7 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. And this has driven several of our key programs, including the discovery of IDE397, our MAT2A inhibitor, IDE275, or 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've utilized across the pipeline, including assets that are currently in the clinic as well as our next-generation targeted development candidates. So 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, 3 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 7 months. And I think 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 2 to 3 months. So we think based on this benchmark, we have feel good and have high confidence in the ongoing registrational trial, which as noted earlier, the primary endpoint of median progression free survival. This is a 2-year PFS Kaplan-Meier curve, and 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. And as you can see, based on this 2-year PFS Kaplan-Meier curve, you see a fairly significant shift to the right. And also importantly, as you can see, this fairly long tail of roughly about 1/4 of patients that are shown to be here continue to be progression free beyond 2 years. So 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 and as noted earlier and also at the bottom, historical PFS has been reported at roughly 2 to 3 months and historical response rates from 0 to roughly 10%. By each of these measures, in terms of activity we have 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. So this is the clinical trial design of our ongoing registrational trial. And here, as you can see, this is a randomized trial with a 2:1 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 and beating 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 2 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 U.S. and Europe is roughly 4,000 to 5,000 patients. Here, I 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 2 key indications we're pursuing is non-small cell lung cancer as well as urothelial cancer. As you can see on this slide, the U.S. annual incidence, we believe, is significant, approximately 50,000 patients across our 2 key focused tumor types of lung cancer, urothelial cancer. 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%. And as you can see in this waterfall plot, a very high disease control rate of over 90%. On the swim lane plot, a lot of the data is not fully mature yet. But as you can see, really the key takeaway message here is that the median duration of response in PFS is still too mature on the swim lane plot, but the median duration of treatment is, at least at this time at the snapshot was over half a year. Here, we have several radiographic images I'll show you. So this was a confirmed CR in a urothelial cancer patient. And as you can see in the nodule to the left and at week 18, we've shown an ability to have 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 -- post 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 MAT2A 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 pyrimidine pathway, in particular, the impact to the generation of nucleotide pools through the methionine cycle, which you can see [indiscernible] 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 2. 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 cancer, urothelial cancer as well as the 2 mechanistic combinations around the TROP2-ADC as well as PRMT5. The third program that we'll go through is the newly acquired DLL3 topoisomerase 1 ADC. So for those that are familiar small cell lung cancer, we believe a very significant population of roughly 350,000 global annual incidents, of which roughly over 100,000 patients in the U.S. and Europe. So here are some of the preclinical data that just surrounding this new asset, IDE849. As you can see to the right, very significant activity as a monotherapy agent in various preclinical models, which 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 DLL3 areas, including DLL1 and DLL4. So this is a CT scan waterfall plot on 8 evaluable small cell lung cancer patients. These are all pretreated patients. As you can see, very robust monotherapy activity with 8 partial responses out of 11 by RECIST. I just would highlight here that not all of the patients have confirmed, but all of the unconfirmed responses remain confirmable. So here's a radiographic -- some radiographic images of one of the small cell lung cancer patients. And as you can see to the left, a very sizable tumor mass, and you see over a 70% reduction at week 6. So 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 on small cell lung cancer as well as neuroendocrine tumors. Also 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 demonstrated 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 2 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 is 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 Trop ADCs. Here, just to the bottom left, as we show some -- what we think is 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 TOP 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 PARG-161. 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 program -- 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 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 an escalation with the next phase being targeted Phase II expansion. The next 2 programs I'll go through are both an IND-enabling study. So this is a potential first-in-class B7H3/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 B7H3/PTK7. Here, we would have a significant focus on 3 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 PARP inhibitor, IDE161. The last program I'll highlight is IDE251. This is our potential first-in-class dual KAT6/7 inhibitor, which has high selectivity in the KAT family. And here, I'll just quickly go through this. But as you can see on the top right figure, we have interest in potential biomarker [indiscernible], including 8p11 amplification. And here, we believe we've demonstrated superior in vivo 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 Anupam will move into the Q&A portion with other members of management. We've now advanced 6 programs in the clinic, all of which we believe have the opportunity to be first-in-class. And then we have 3 additional INDs that we're targeting for calendar year 2025. So with that, Anupam, we'll move into the Q&A portion.

Good. Do you want to invite Darrin to come?

Yes.

I just want to remind folks, there are 3 ways to ask a question. Raise your hand, which is the old school way. Submit a question to the question portal, will show up here or you can just e-mail me. So -- maybe I'll kick off. Yujiro, can you talk a little bit about the recently in-licensed DLL3 program? Why was that a strategic interest to you? Why you're excited about it? It's a hot therapeutic area and we've seen some activity in the space.

Yes. 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 of 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 Daro, 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 and versus focusing on your R&D engine internally?

Yes. 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 asset that we believe has the ability to accelerate our strategy. That's something that we're going to take a serious look at. In terms of the 2 beyond darovasertib, obviously, the next 2 transactions we did were both in the biologics 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. So Anupam, as you very well know, one of our core focus areas over the last 10 years has been around identifying the -- 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...

Yes, exactly.

Questions from the audience?

[indiscernible]

So I would say that we're always looking at different opportunities externally, including in China. We obviously have done our last 2 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.

And I still have one question about the PARG program. Is there any efficacy and safety update about the single-dose clinical trial?

Talking about PARG.