Welcome everyone to the 42nd annual J.P. Morgan Healthcare conference. My name is Anupam Rama. I am one of the senior biotech analysts here at J.P. Morgan. I'm joined by my squad, Malcolm Kuno, Lorea Hall, Priyanka Grover. Our next presenting company is IDEAYA, and presenting on behalf of the company, we have CEO, Yujiro Hata. Yujiro?
Well, great. Well, thank you so much, everyone, for attending today's presentation. And thank you also for J.P. Morgan for the opportunity to present today. So earlier on Sunday, we provided several key program updates, which I'll highlight today. In addition, we did give our 2024 corporate guidance. In 2024, we believe there's gonna be a big opportunity for darovasertib, in particular, a significant focus on Phase 3 company-sponsored neoadjuvant uveal melanoma trial. In addition, we've given specific guidance of our target to Phase 3 clinical efficacy data in the middle of this year. Next, providing regulatory guidance also in 2024 for the neoadjuvant uveal melanoma indication. The darovasertib first-line metastatic uveal melanoma potential registrational trial enrollment is going as planned.
We noted on Sunday that we have achieved double-digit enrollment and international site activation has been achieved. Next, for MTAP deletion, we have several key updates, including continued Phase 1/2 expansion in MTAP deletion, specifically targeting non-small cell lung cancer and bladder cancer. In addition, with our partner Amgen, for the IDE397 and AMG 193 combination, that we have ongoing Phase 1 enrollment in the dose escalation and the development of a joint Amgen and IDEAYA public initiative strategy in 2024. Next, a few weeks ago, we did announce a new partnership with Gilead for the combination of IDE397 with Trodelvy, specifically in the indication of MTAP deletion bladder cancer, and we are guiding towards a target FPI on that trial, in the middle of this year.
Next, further down our portfolio is IDE161, which is a first-in-class PARP inhibitor, targeting HRD solid tumors, where we will be targeting program updates in 2024, as well as enabling specific combinations in 2024. Our fourth first-in-class program in the clinic, GSK101, which is against Pol Theta helicase, is ongoing in terms of Phase 1 dose escalation. Next, for Werner helicase, we continue to be on track for IND submission in 2024. Here we can say, high level, we feel good about where we are on the GLP toxicology studies, and everything continues to be on track for what we believe has the opportunity to be a best-in-class molecule for Werner helicase.
And then lastly, we have multiple next-generation programs where we're targeting a development candidate nomination in 2024. We're in a strong financial position, and we're guiding towards a cash runway into 2028. So over the last 8.5 years, IDEAYA has built a leading functional genomics synthetic lethality platform, and through that, we pursued several key patient selection biomarkers, including MTAP deletion, HRD, and high microsatellite instability, which has generated several of our key first-in-class programs into the clinic. What underpins this pipeline is a very vast and integrated drug discovery platform, including target and biomarker discovery, drug discovery, as well as translational research.
We built our s ynthetic lethality target and biomarker discovery platform through several key molecular biology platforms, including dual CRISPR, as well as a paralog gene platform as well, where we integrate both public and proprietary datasets to help us both prioritize our targets, as well as validate our potential biomarkers for the clinic. Since the company's founding, one of the key focus areas for us has been to pursue and unlock chemical opportunities where we have the ability to be first in class. And we've done this in several examples, including MAT2A, which is now Phase 3, PARP, which is in Phase 1 expansion, Pol Theta, which also recently entered Phase 1, and as we noted earlier, Werner helicase, where we recently selected a development candidate.
An area where we're continuing to invest in building our capabilities is around AI machine learning, enable computational drug discovery, where we integrate these capabilities, where our capabilities in structural biology to specifically advance our timelines to IND for, challenging first-in-class targets. Since our founding, we have now built a highly diversified, first-in-class portfolio that includes four first-in-class clinical programs in darovasertib, where we initiated a registrational trial on first-line metastatic uveal melanoma. Next, IDE397-MAT2A, targeting MTAP deletion, which is now Phase 3 expansion. We're in two key combinations, including with Amgen and Gilead. And then third, IDE161, which is noted earlier, in phase 1 expansion, targeting several key HRD solid tumors, including CRC, endometrial cancer, as well as others. And then, as noted, earlier as well, Pol Theta helicase, which is in phase 1 with our partner GSK.
And then Werner helicase, where importantly, we're targeting IND submission this year, and we have retained significant rights, including a 50/50 U.S. profit share. In terms of darovasertib, here, this is targeting specifically a target called PKC, and we're targeting a specific activating mutation of GNA11. What makes this mutation unique is the predominance of uveal melanoma patients harbor this activating mutation of either GNAQ or GNA11. Darovasertib has shown, as shown to the bottom left, a significant single-agent activity, in addition to the ability to demonstrate, single-agent regressions here in a specific GNAQ mutant model. The clinical data that we've observed to date in terms of a tolerability profile, we believe, darovasertib, has an overall, favorable tolerability profile.
Here, what we're highlighting within the trial data that we've generated, and we'll go through the efficacy data here shortly, which is when you compare our Phase 3 data, which we'll walk through shortly, versus tebentafusp's randomized Phase 3 data, we have been treating patients that have had a much higher disease burden, including based on LDH status, size of the metastatic lesion, as well as when you look at single versus multi-site metastasis. Here's a really quick summary of the data that we've shared to date in terms of a waterfall. And as you can see in the first line setting, we see a very robust, confirmed overall response rate of 45%. Historical response rate in this indication has been from 0%-5%. Importantly, we do see activity irrespective of HLA-A2 status.
As shown to the left in HLA-A2 negative population, where we are running our frontline registrational trial, and to the right in the HLA-A2 positive setting, as we can see, we see clinical efficacy irrespective of HLA-A2 status. We've also looked at ctDNA molecular response. There has been data published in the indication of metastatic uveal melanoma, which demonstrates that ctDNA can be a valuable efficacy tool, in particular for being predictive of survival, and that data was published in the New England Journal of Medicine. As we can see, we see quite a significant response rate as it relates to molecular response of 94%. In addition to the various response rate data that we've shared, we also believe we have a very favorable median progression-free survival.
Historical PFS in metastatic uveal melanoma has been 2-3 months. Here in the frontline setting, we're seeing a PFS exceeding seven months, and importantly, in the hepatic-only setting, a PFS that's approaching a year. Here I would highlight in Teva's pivotal Phase 3 study, over half of the patients that they treated in the frontline setting had hepatic-only disease. Here we highlight further data that supports the durability that we're observing with this combination in the metastatic uveal melanoma setting. This is a two-year PFS Kaplan-Meier curve, and as you can see, as shown clearly here in the figure, this combination in the any line mUM setting shows a very favorable Kaplan-Meier curve versus Teva's frontline trial as well as versus their control arm.
We would anticipate, if, in our registrational trial, only looking at the frontline setting, that we would have the opportunity to further enrich this two-year Kaplan-Meier curve. So in summary, when you look at overall response rate and progression-free survival and any additional metric that we looked at in our Phase 3 company sponsor trial, our data does compare very favorably versus the historical data as shown on this table. So as we now noted in the beginning of the presentation, we've launched into a frontline registrational trial. That study is well underway, and the key aspects of the design of the trial is that it's a randomized trial against investigator's choice at a 2:1 randomization. The primary endpoint for accelerated approval is median progression-free survival.
This is an integrated Phase 2, Phase 3 design that would enable us to get both accelerator approval and full approval in the same study, and the full approval endpoint is overall survival. We have also received fast track designation for this combination in mUM, and we've also achieved orphan drug designation for uveal melanoma. A key aspect of darovasertib for 2024 will be the neoadjuvant uveal melanoma opportunity, where we're seeing a clear signal of efficacy as a monotherapy agent, and as noted earlier, we're committing to give a Phase 3 clinical efficacy update middle of this year. There's two cohorts that we're focusing on in the neoadjuvant application. First is the enucleation cohort. Here, we believe one of the key endpoints has the opportunity to be around eye preservation, and the second cohort being plaque therapy.
Here, looking at decrease in radiation dose as well preservation of vision. In addition to mUM, we've also looked at cutaneous melanoma, and to the right, we have some early data where we're clearly seeing a durable signal. In this case, two patients that have responded as confirmed PRs, patients that have been treated out to almost 600 days. And as you can see here, three out of four patients, we see tumor shrinkage. Overall, darovasertib, we believe, is a blockbuster potential opportunity with the ability to potentially get approval in the frontline setting across this entire patient journey, including neoadjuvant, adjuvant, and metastatic uveal melanoma. Our next program that we'll highlight is MAT2A in the MTAP deletion space. This program is targeting a patient selection biomarker called MTAP deletion, which does represent roughly 15% of all solid tumors.
IDE397 pre-clinically has demonstrated robust, single agent activity, including tumor regressions in models, and tumor indications, including lung cancer as well as bladder cancer. One of the key aspects of the program is the clinical combination that we are advancing with Amgen, with their MTA-cooperative PRMT5 inhibitor, AMG 193. In 2023, we presented, with Amgen in a peer-reviewed setting, the combination data, which is reflected to the right, where we see tremendous synergy with these two molecules together, importantly, at a fraction of the monotherapy dose, where we see in this model, in this MTAP lung cancer model to the right, complete responses in all animals in both cohorts.
In terms of our experience of IDE397 in the clinic and our Phase 3 monotherapy expansion, we're specifically focused in lung cancer as well as bladder cancer, and as we can see, we both see molecular responses as well as tumor shrinkage greater than 30%, based on CT assessment. A month or so ago, we also announced a new collaboration with Gilead to do a combination with Trodelvy, which is a Trop-2 ADC, with IDE397, specifically targeting MTAP deletion bladder cancer. Several pieces to highlight here. First, we believe this potential combination from a mechanistic standpoint is unique to MAT2A versus PRMT5. Second point I would highlight is that MTAP deletion prevalence in bladder cancer is over 30%.
We have seen monotherapy efficacy in the clinic with IDE397 in the MTAP deletion bladder cancer setting, including confirmed complete response as well as robust tumor shrinkage across multiple patients, and as you can see to the right, a very significant activity from a ctDNA molecular response rate perspective. There are three key activities for this program, including our monotherapy expansion, our combination work with Amgen, with their MTA-cooperative PRMT5, and then lastly with Gilead, with their Trop-2 ADC inhibitor. The next program that we'll go through is PARG, IDE161. Several key highlights here. PARG is a target in the PARP pathway, often been referred to as the counter opposing mechanism to PARP inhibitors.
Here, we are targeting HRD solid tumors, and we also have interest in tumor indications where PARP is not approved, including CRC and endometrial cancer. Here, we just highlight that IDE161 is a first-in-class inhibitor, very active cellularly as well as in vivo, and we'll show more data on that, here in the next slide. One of the key aspects of PARG, which got us excited about this target versus PARP, is that we do see differential activity in the HRD setting with a PARG inhibitor versus a PARP inhibitor. In addition, we do see activity, specifically in the ER-positive, HER2- negative breast cancer setting, and more favorable efficacy pre-clinically, relative to commercially approved PARP inhibitors, as shown to the right. We have observed early RECIST responses, in the clinic.
As noted here, we have two patients where we observed a RECIST response out of five. We are still early in our dose evaluation as well. We have not confirmed a move forward dose at this point yet. In addition, new data that we did share Sunday morning is that we also have now have a prostate cancer patient with a greater than 50% PSA reduction, and at this point, we've only treated two prostate cancer patients. So this highlights our current focus. So for monotherapy, as noted earlier, we'll be focused on several key tumor types, including endometrial cancer, colorectal, ER-positive, HER2-negative breast, as well as prostate cancer.
In addition, the team is hard at work for enabling several opportunities on the combination front, which we believe are gonna be, one in particular, a potential near-term opportunity, that hopefully we'll be share more about in 2024. Our fourth program in the clinic is GSK101. This is the first Pol Theta helicase inhibitor to enter the clinic.
Here, we're very focused on HRD solid tumors, and here we believe the primary utility of Pol Theta helicase is gonna be in combination with PARP inhibitors, specifically to address, what's been a key challenge for PARP inhibitors around, PARP-acquired resistance, specifically around the mechanism of BRCA reversions, of which we believe the backup repair mechanism of microhomology-mediated end joining plays a key role, of which we know Pol Theta is a key Achilles' heel of microhomology-mediated end joining. Beyond our four clinical programs that we just walked through, the next key asset that we're targeting to get into the clinic is Werner helicase. Here, we're targeting IND submission, this year, and as noted earlier, we believe we have the opportunity to be first in class.
Next, we have multiple development candidates that we're targeting for 2024, including in the MTAP deletion space, and look for us to continue to bolster our drug discovery platform to our future pipeline. Quickly, on Werner helicase, as noted earlier, a key opportunity, we believe, one of the most exciting targets in precision medicine oncology today. Here, the patient selection biomarker is high microsatellite instability, and as you can see to the right, we show exquisite activity in a high MSI setting, and we see no effect on the microsatellite stable setting. We believe here, there should be an opportunity in the clinic, both in terms of as a monotherapy, as well as in combination with GSK's PD-1, dostarlimab.
As noted earlier, we do believe we have the opportunity to be best in class based on very specific features of our Werner helicase inhibitor versus the current competition. So this is just a quick summary of what's to come next in our pipeline that we're now targeting to advance for development candidate nomination in 2024. As you can see to the middle, we're showing data where we see eight out of 10 complete responses in the MTAP setting. This target is not in the PRMT5 pathway, and we also believe has the potential to be combinable both with MAT2A and MTA-cooperative PRMT5. So as you can see, 2024, we believe, is set up to be a truly transformational year for IDEAYA, with four first-in-class programs in the clinic, soon to be five.
In addition, we believe we have line-of-sight opportunities to have seven or more first-in-class opportunities, all within our cash runway. As noted to the bottom, we have over $650 million of cash on the balance sheet and an extensive runway into 2028. So with that, Anupam, we're done with our presentation, and excited to.
Yeah. Do you want to introduce who's coming up?
Sure. We have Michael White, our Chief Scientific Officer, and Darrin Beaupre, our Chief Medical Officer.
Many of you have been in sessions with me. So just to review, there are three ways to ask a question, right? Old school, raise your hand, I'll call on you. There's, like, a new school way, which, you know, if you have access to the Q&A portal, you can submit it, and I'll get it on this iPad, and I'll ask anonymously on your behalf. I guess there's an intermediate strategy where you can just email me, and I'll still ask it, anonymously on your behalf. So, with that, Yujiro, I kind of wanted to talk a little bit about, m aybe first we'll start with DARO. And, the language for DARO, in terms of the metastatic setting, said clinical, I mean, it said a clinical update, right?
Now, t hat could be data, that could be enrollment progress, you talked about the site activation, like, what does that, what does that encompass?
Yeah, so the reason why we use that language is for the first line registrational trial. We do think, for that trial, for that program specifically, it is gonna be more about where we are, as it relates to the progress of that registrational trial. It's obviously a randomized study. We think there are several key aspects in terms of milestone, in terms of, for example, where we are with enrollment, have we selected one of the two doses, as part of the design of the study? So we think there are several opportunities for inflection points. And Anupam, as you're aware, a lot of our analysts have been projecting a late 2026 launch, so we have been pegging our enrollment targets to enable that type of outcome.
So in terms of the actual clinical efficacy data, there, at least our anticipation right now, is the predominant focus for this program will be in our Phase 3 neoadjuvant uveal melanoma study. And that's where we've provided the specific guidance for an update middle of this year, as well as the target to have regulatory guidance update this year as well.
So two questions there, right, on the neoadjuvant side. So for your corporate update, what's gonna be the size and scope of that neoadjuvant update? And you know, what have you learned from some of the IST stuff that might inform how you think about a win scenario?
Sure. I'll have Darrin, our CMO, answer that.
Yeah. So many of you have probably seen some of the data that we have accumulated through our investigator-sponsored trial in Australia. It's actually quite striking in the neoadjuvant setting, where we've seen a significant amount of patients have tumor shrinkage and a large number of patients, in fact, of a small sample size, had their eyes saved. And so as part of an extension to that, we're obviously going into the O09 trial, where we will be evaluating two populations of patients. One population of patients is those folks with that have a large tumor that are likely to have enucleation, and another set of folks that have mid to small-sized tumors that will likely go on to plaque brachytherapy.
The idea here is to accumulate the data necessary to show that we can, in the case of a large tumor, shrink the tumor, but also allow eye preservation and hopefully vision preservation. And then on the brachytherapy side, the idea would be, if a patient's destined to get plaque brachytherapy, and then ultimately have a high likelihood of being blind thereafter, so saving the eye is nice, but going blind isn't, isn't so nice. The idea would be to give neoadjuvant therapy, so you could shrink the tumor enough, less radiation. T herefore allowing eye preservation.
So, you know, the idea is to produce a data package based on what we've seen in the IST, and based on what we've seen in our currently running O09 study, which we believe by midyear will have a significant amount of evidence to have a discussion with the FDA of how we plan to proceed into a registration opportunity that would allow us to achieve an accelerated approval type approach for those folks with large tumors, and to get full approval based on a randomized approach, likely with the brachytherapy group. That's sort of where we're sort of heading at the moment, and the data looks outstanding at the moment. Our O09 study is performing as expected, and we're really building on a story that we've already seen preliminarily in the IST trial.
Questions from the audience? Yeah.
Old school. Old school way of asking questions.
Just raise my hand.
Yeah.
Thank you.
Oh, yeah.
Peter Tummino from Nimbus Therapeutics. You said, with your Werner helicase agent, that there's an opportunity for you guys to be best in class. Can you say a word about what you think the attributes are that are gonna distinguish the various Werner inhibitor agents progressing? What's gonna be most important?
Yeah, thank you very much for the question. I'll let Mike answer that. And I would just sort of highlight, you know, we obviously have more information than we can publicly disclose. You know, I think we've been given some pretty specific direction from our partner to keep some of this information confidential, but I think we can high level try to capture some of the key themes there.
Yeah, and I think some of the key points there is, obviously, you're gonna want a molecule that is going to deliver the synthetic lethality that is CRs in the MSI-H setting, not MSS, so that's really key, where we have a really nice efficacy package on the table showing that. Especially showing that in very stringent models that represent patient populations downstream of many lines of treatment, including immunotherapy, which is obviously where we're gonna be running our phase one. So that's quite exciting. That's quite important. You need to have a molecule that is able to stay on this target in the context of MSI-H, which is obviously mutagenic, and so we're very excited. We think we have a molecule that can do that, that can withstand that environment with respect to intrinsic and re-acquired resistance.
Also, the genetics is telling you that this should have. This target in this setting should have a therapeutic window that you can sail an aircraft carrier through. So you should have a molecule that's very, very safe. And we're winding down our preclinical activities to get the IND out, and the in-life is behind us for the GLP studies in both species, and we continue to have high conviction in that thesis.
And then just would add to that is, you know, I think we do believe there's substantial opportunity for differentiation, and I think that's great news for everyone that might be working on this target. Thank you.
Questions from the audience? So maybe just going back to DARO and neoadjuvant. You mentioned the regulatory. Like, what is the kind of push-pull levers that are, you think, that need to be discussed with the regulators as you think about that path forward?
Well, obviously, we're very interested in getting this molecule to patients as quickly as we can, especially, you know, since we're saving eyes, and you can imagine, number one, on any patient's list of things when they have a large tumor and someone walks in the door, who's their physician, and says to them, "Your eye has to go." they're willing to listen to anything possible that can save the eye. The ocular oncologists recognize how important that is, and with the activity that we're seeing, it's critical then to have those discussions with the FDA to talk about what's the most rapid path in order to get this available to patients.
So I guess, you know, to answer your question, you know, lining up to the middle of this year, we really want to lay out a package based on data and based on what's known about the field, which, by the way, we're gonna be cutting new ground here. You know, this. There hasn't been a drug in the past that actually shrank tumors like we're doing. So they haven't really talked about this in the past, either at the FDA or even with some of the investigators that we work with in the Clinical Ocular Oncology Cooperative Group, which we're working with.
Long and short of it is, what we wanna do is create a package that allows us very rapidly to get this drug to patients in that large tumor case, so talk about what an accelerated approval type design would look like. But in addition, as you know, for full approval, the FDA will require a randomized trial, and so we have to come up with a design and a plan on how to do that. At the moment, it seems to make the most sense in the plaque brachytherapy group, where patients can be randomized. I would argue that, you know, in those folks with large tumors, you can't do randomization. It's not ethical. Why would you randomize someone to have their eye removed when they have a 50% or more chance of having it saved? That would be crazy.
But those are the kind of discussions that we need to have, not only with the critical people who are the key opinion leaders in this field that we're working with very closely, but once we formulate a plan that makes really great scientific sense, to take it to the FDA, and actually, to be quite honest, help educate them on the field, on what we've learned and what the direction we're heading, and with their feedback, come up with a plan that allows us to bring benefit to patients as rapidly as we can.
Okay. Questions from the audience? Maybe switching gears to IDE161. So you, you've shown us some early responses, early activity. You know, correct me if I'm wrong, you've seen responses in a lot of variable indications, but the focus here is on HRD breast and ovarian, right? So how do we read through what we know from some of the single-agent activity to the focus indications?
Yeah. So thank, thanks for that, asking that question, Anupam. So I think the ovarian and breast, I would just mention, are two indications where we received fast-track designation. With that said, we are still in the evaluation process of how to prioritize the solid tumor types. And, you know, some of this has been empirical, some of this is, based on our clinical experience as well as our preclinical data. You know, some of the additional guidance we gave on Sunday specifically highlighted, in terms of priority, endometrial cancer, colorectal cancer, ER-positive, HER2-negative breast, as well as prostate cancer. And so in terms of endometrial cancer and CRC, there, we know PARP inhibitors are not approved in those indications in HRD, so that's a clear point of differentiation.
We know in ovarian cancer, you know, there's just more therapies there, of course, you know, multiple PARP inhibitors approved there. We think that's a higher bar. So at least our current thinking right now is that we would focus on some of these other tumor types. The prostate focus is, I would say, has been a new addition based on this PSA reduction we saw recently in one out of two patients.
When do you think we will get some of that? We know when the next update is, but a better understanding of kind of indication selection and focus?
Yeah, I think a lot of that, we'll know a lot more in 2024. You know, we're still doing dose evaluation. We have expanded at a dose, but we're still continuing to do dose, dose evaluation. You know, ideally, it's a situation where the data is a good portion around our move Phase 3 dose, as well as once we have a better understanding of the refinement of the tumor types. So, right now, we've noted several, and then build, obviously, a denominator that we hope is really meaningful from an update perspective. So we did provide guidance that we'd be giving updates in 2024, but we were not exactly specific on what that would entail. So, you know, we just want a bit more flexibility on that, on that. But Darrin, any other here?
Yeah, the only thing I'd add is, obviously, when you're in an early phase trial, you have patients on different doses. You have a heterogeneous patient population. When you start to see activity like we've seen in three tumors, you wanna start heading down that path. So even though we haven't lost interest in some of these others, but obviously, when the trail is right there in front of you, well, you wanna start heading down it. So that's kinda what we're doing, as we continue to learn more about the dosing.
Questions from the audience? Maybe I'll squeeze just one last one in here in terms of the gating factors to the IDE397 Trodelvy combination, study in bladder.
Sure. Darrin, you wanna take that?
Yeah, really, it's just a matter of putting a protocol amendment in and getting that executed. So we're well on the path of moving that forward. And, you know, the plan is by, you know, the middle of this year to be executing on that study. But really, you know, our collaboration with Gilead and discussions have been great. I think the path there is fairly obvious. We have a drug that's approved in bladder cancer, typically used in a later line, where people would love to see it be used earlier in the appropriate patient population. We have a drug like IDE397, which is in our clinical trial, where we've seen, in a significant number of patients, either tumor shrinkage or a response, and molecular response in a handful of patients, which suggests that we do have an active drug.
We have the biology that supports it. It's really a great opportunity to test. And knowing that other standard of care agents tend to do more poorly in an MTAP-deficient setting, like checkpoint inhibitors, like N42- mab, it just seems like the seas have parted in terms of allowing Trodelvy to get the opportunity to move up, and we think IDE397's the perfect partner to help it do that.
Any final questions? All right. Thanks, Yujiro and team.
Great. Thanks so much, Anupam.