In the room and on the webcast, I'm Yigal Nochomovitz, one of the biotech analysts here at Citi. We're starting our healthcare 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. Yeah, no, thank you, Yigal, and thanks to C iti for the 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. Yep. 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, Pol Theta helicase. I think we'll talk more about that today. 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. 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. Yeah, we believe over the last 9+ years, we've built fully integrated capabilities. We have the ability, we believe, to drug or pursue 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 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, they'll be able to 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 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, a strong potential? Yeah. So maybe just to take a quick step back from 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 two 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 were not path forward. Second, they also had, I would describe as ADME DMPK properties, highly insoluble molecules. And these are really core challenges to solve. 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 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 with that target. So I'd love to understand how you're thinking about the interplay between those. Yeah, 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 six months, which I think is encouraging. When you look at the various chemo-like comparators like docetaxel, which we've seen have been reported with a PFS around three to four 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 two strategies we're taking right now, one which is within the pathway of PRMT5 at MTAP. And that's our work with Amgen. We believe to fully suppress 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 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 topoisomerase payload can mimic that MOA to hopefully drive synergy with IDE397. We've seen early activity there, including responses. And 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 marketing of Trodelvy and 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. Yeah, no, Yigal, thank you for the question. And definitely on point question. And for the listeners here, as you know, the 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 at 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 topoisomerase chemo through the ADC format through differentiated pharmacology. That's the objective here. Then finally, last, what I would just emphasize with Trodelvy, our view is we should be able to pursue this with any Trop-2 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. Basically, our main question is, can we deliver this chemo payload of topoisomerase with the mechanism of IDE397 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. 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. I mean, 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 again to the clinic? Yep, no, definitely. So here, Yigal, I know 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 MTAP-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. I'd love to hear it. Yeah, pushes what 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. Yeah, 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 would be maybe even better than some of the others. Yeah, 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 five 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 penetrance, 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 penetrance 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 MTAP-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, as 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 to too many specifics, we believe this is really the fine balance between not just MTAP-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 a gram or higher for monotherapy studies. We've obviously shown that IDE397 has really great ADME and PK properties, and so that's what we've 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 IDE397, so we're excited about it. We anticipate we'll be able to file the IND approximately middle of next year. 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 penetrance 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 MTAP-cooperative PRMT5, some of which I've noted are somewhat below brain penetrance. 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 penetrance, but ultimately, you have to evaluate target by target. Yigal, as you know, in this business, I'm 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 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 three strategy? Yeah, 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, a 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 started 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 in 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 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's only growing. So now we have over 20 patients worth of data that have been followed up for more than six months. We have over 30 patients with at least four months of follow-up. And that data set's 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 three registration 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 three. Yeah, and I would say here our discussions have continued to evolve as we've continued to have discussions with the FDA. 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%, or 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 registration 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 would be. But those are co-occurring, the macular edema and the vision. There's not some sort of relationship. There should be a relationship, correct, correct, right, but if it's a situation where you have prevented macular edema, that's a clear sort of yes or no. S o it just gives you another shot on goal, and this was actually based on feedback and input from the FDA. We incorporated that into the protocol, so that's why we're continuing to finalize that. Hopefully, that should be submitted here very shortly. The third one, which is a secondary endpoint, which is relevant for both the enucleation cohort and the plaque therapy cohort, is around EFS, also known as event-free survival, and I think what's really critical to note here, typically in neoadjuvant full approval trials, you need to show superiority in EFS. Here, the FDA has required what we believe is a much lower bar around no detriment to EFS. So there, you think about a hazard ratio, something like a 0.7 versus a 1 or 1.1 hazard ratio next. We believe we don't need all of the events to get that readout. At least our regulatory team feels about 35%-40% of the events. We should be able to get that first interim readout on EFS. Why we have confidence on that? Here, I would just highlight two pieces. One is there is a key published paper. Dr. Shields was part of that, who was one of our presenters in the past, which notes that with every millimeter that your ocular tumor shrinks, your risk of metastatic disease goes down by 5%. So here, as we said in the very early part, we're consistently shrinking these ocular tumors. So we don't believe that the risk of EFS is going to go up. We actually believe there's a possibility that we could actually improve EFS. Second, as you know, our drug has been utilized and shown to be effective, including as a monotherapy in the metastatic setting. We reported OS. We've reported waterfall response rate type data, and here, ultimately, in that setting, as you know, Yigal, you're treating micrometastasis, right, so being able to demonstrate you have activity in the metastatic setting is important, so now we'll have to just run this study. It's obviously going to be randomized, but that is why we feel good about all these various endpoints. Okay, that's all very helpful. Let's talk a little bit about the ongoing metastatic phase III. We don't spend as much time on that because it's sort of going in the background a little bit. But just get everyone up to speed. Where are you with that study? What are the objectives? What are the timelines? How do you see the data evolving relative to our competitor? Yeah. No, that trial is going great. And so what Yigal here is referring to is a frontline registration trial that we launched to get approval in the HLA-A2 negative metastatic uveal melanoma setting. And as we publicly noted, we've enrolled over 150 patients. We noted the last earnings. We're now approaching 200 patients. We are ahead of schedule by several months now. And that's why we feel comfortable, at least based on those timelines. We do believe we have at least the potential to hopefully have that accelerated approval readout towards the end of next year. This obviously assumes around the cadence of enrollment will continue in that fashion. But based on the fact that sites are continuing to get activated, including in Europe, at least right now, we feel good about that potential timeline. Here, just at a high level, as you know, Yigal, in the past and last year, we had an oral presentation at ESMO, where we noted a confirmed response rate of roughly 30%. We reported a PFS of roughly about seven months. And just as a reminder, the primary endpoint for accelerated approval is median progression-free survival. Here, we believe the control arm will likely land in that two to three-month range. So here, we would hope that we could at least double historical median progression-free survival. And then lastly, for full approval, so this is an integrated phase II/III study, we would be seeking full approval as well as accelerated approval in the same study. Here, we have not given the specifics around the powering assumptions. But as you know, historical OS has been about a year. And we've put in assumptions that we could at least exceed OS by roughly six months. The other recent communication that we've made is that we have been tracking OS. As you know, Yigal, we haven't presented OS anywhere yet on the combination of darovasertib and crizotinib. We have been tracking that data. This is from our phase II study, not the registration trial. So that data is now getting to the point of greater maturity that we're getting a better sense of where median OS is landing. So here, don't be surprised if we present that data sometime likely in the middle of next year. And we think that should obviously be helpful to be able to have some more insight of what's also OS looking like since we've already presented median PFS. Is there a scenario where if the OS look is looking really good in the phase III, that you could jump ahead and skip the accelerated and just go for the full, or that's not a realistic scenario? You know, it all, I suppose, will just depend on the powering assumption. So here, Yigal, maybe I should have said in the beginning, the first portion to get the median PFS readout, we've assumed roughly about 230 patients. And we've powered it with the assumptions I just mentioned to you. We should be able to hopefully double PFS. And then we would add an additional 120 patients with the powering assumptions of +6 months. So it would be an aggregate of roughly 350+ patients to be sufficiently powered for the OS readout. So that's why I think it depends on how large the effect size is. But at least our expectation, it should be the order of accelerated approval first through PFS and then OS. And sorry, the last part, Yigal, I should have mentioned, we have not provided an update on this. But as you know, there was a lead-in to the registration trial, which is around dose optimization, project optimization. We had two cohorts running. We hopefully will be able to report an update on that here fairly soon about what the move forward dose is. And hopefully, we'll be able to provide an update on that here somewhat in the very near term. Okay. We want to get to the earlier pipeline. But just one thing, HLA positives, is there something that you're going to do there for that population? Yeah. So yeah, so briefly on that, we have additional patients we're enrolling in the phase II study. So we're going to try to enroll 50+ patients. Really, the quick level summary is the drug is active irrespective of HLA-A2 status. We've shown that in the pre-metastatic setting as well. We see basically the same level of activity. We presented that at ESMO. We're going to continue to publish that data. So assuming we get approval in the HLA-A2 negative setting and frontline, at least the feedback we've gotten from our regulatory experts is that we have a very good shot to publish that data and to get on compendia for pricing reimbursement for the NCCN guidelines. And that would be exactly our plan. Got it. Okay, perfect. So a lot to talk about in the early development. Let's start with, I guess, one of the ones that I've been watching closely, the Werner helicase. First of all, just explain the target. What is its function? Why is it so interesting? How prevalent is that target in terms of addressing the span of solid tumors out there? And where are you in the process as far as the development? Yeah. So yeah, Yigal, as you know, Werner helicase is one of our favorite precision medicine oncology targets. And really, the quick summary here is we do believe it's been the crown jewel of synthetic lethality for quite a long time, for the last decade. And the reason why I make that comment is that if you look at all the various large cancer genome screens that have been done in synthetic lethality, this includes by the Sanger Institute, the Broad Institute, Project Drive, basically the top synthetic lethal target that drops out in pretty much all of these screens that we're aware of is Werner helicase. So it's a truly robust and unique synthetic lethal interaction. Here, the biomarker pair is with high microsatellite instability, which is prevalent in roughly about a third of endometrial cancer and about 20% of colorectal cancer and 20% of gastric cancer. It's a very significant market. We believe this is a true bona fide blockbuster opportunity. The second part around your question around Werner helicase, yeah, this is a very interesting target. The yeast homolog is a gene called SGS1. In humans, there's four human orthologs of SGS1, of which Werner helicase is one. That's in the RECQ helicase family. Without getting into all of the specifics, but helicase play a very critical role and have various roles in terms of its basic biology. Really, in a nutshell, helicases are involved in the process of DNA unwinding, which is important for processes such as transcription and as part of self-replication and DNA replication. Helicase has also been implicated around areas such as DNA repair and genome stability. I would say in a broader classification of DNA repair. What gets me personally excited about Werner helicase in particular is it's a genetic alteration that's actually found in the human population and has been associated with a clinical phenotype called progeria or aging. And what's really interesting about this target is it's a non-essential gene. And I think, Yigal, I think we've been talking about this for quite a few years, which I thought hope this is sort of the next wave of cancer targets that emerge, which is you can knock out this gene and the normal cell survives. And so therefore, based on that, as long as you have a selective molecule, we should hopefully see exquisite activity in the high microsatellite instability setting, but also have a very wide therapeutic window. As you know, I think a lot of what we're trying to do as an industry is to have a wider range of clinical benefit versus risk profile. I think Werner helicase is a great target. The last piece I'll mention, we don't believe the existing molecules in the clinic, the way they bind in their MOA against Werner helicase, is necessarily the perfect molecule. So we publicly stated with the OK from GSK, we do believe we have a truly differentiated molecule against this target. We did present in Barcelona recently about the existing Werner inhibitors having acquired resistance to those first-generation inhibitors. All I can tell you is that we were aware of this as we were picking our candidate. We believe we have a truly differentiated molecule from that perspective. We will have also guided that our plan to present this differentiation profile of this phase I molecule at an upcoming medical conference, so stay tuned from that front. All we can say is that we're excited to share that publicly, and I think there should be a lot of activity on Werner, hopefully in 2025 for us, as well as the broader space. As you know, Novartis and Roche are in early phase I trials. Okay. Let's jump over. We can keep going on Werner, but I want to make sure we hit the other topics. So the next one, the PARG inhibitor. So there's obviously some understandable, perhaps, confusion between PARG and PARP. So let's just clear that up as far as how PARG is different from PARP. You're combining not with the PARP inhibitor, but with immunotherapy. So talk about that strategy. Yeah. So yeah, so as you mentioned, Yigal, PARP and PARG, there are several key differences and similarities. One is they are in the same pathway. Second is that they have what have been described as sort of inverse or converse mechanism as it relates to PAR chain synthesis. One is involved in the formation of PAR chain. One is involved in the disruption. Third is that the primary, we think, biological difference also between PARP and PARG is that PARG also has, we think, an important role specifically in the area of replication stress. So here, I would say we have three sort of core focus areas with this program. First is continued monotherapy expansion work. We're hoping to start that expansion phase here very shortly in a very specific tumor type, solid tumor type. We likely won't disclose what that tumor type is because we believe we understand that there's competition that's trailing us now. The second, as you just mentioned, is around what we believe the opportunity to combine this mechanism around DNA damage repair with IO therapy and PD1 in particular. We'll be sharing that data. We anticipate at this upcoming R&D Day that they share that, and here we're collaborating with Merck. We're thrilled to do that. You may know that some of the data that's actually been interesting in terms of PARP-PD1 combo has been in endometrial cancer. Here, we'll be studying not HRD, but we'll be studying MSI high and microsatellite stable. Here, we do believe the higher end is a microsatellite stable, which is in the majority of that population. The final third, which I would say is probably our biggest focus right now for this target, which is the view that PARG mechanism specifically can enhance the activity of topo ADCs. You may know that there's been a lot of focus to try to enhance the activity of topo ADCs. We've seen high response rates there, but perhaps not, we want to see better activity as it relates to PFS and OS. When you think about combination opportunities with that class of agents, there's not a lot of great options. One obvious place to look is in the DNA damage repair arena. Here, I would say probably the biggest focus we've seen has been on PARP1. We think the other target that we think is a significant opportunity is around PARG-PARG. And this is really around the role of the PARG biology as it relates to the repair of the DNA damage elicited by topoisomerase payload. So we think this could be potentially a platform that can enhance that topo ADC class. Obviously, we can demonstrate that clinically. As you could imagine, Yigal, that would be an extremely exciting opportunity and probably one of the biggest things we're working on. And from a market perspective, that would be larger than MTAP. And so that's why we brought in this bispecific ADC to be able to wholly own that combination. And all we can tell you is that there's multiple conversations ongoing right now to enable that specific combination clinically. Inhibiting the PARG can help offset that in terms of the repair process of the ADC. Yeah. We can share that paper with you, but there was a great paper published a few years ago by Dr. Pommier of NCI that was one of the first places where this was published. We've been doing basic biology research on this for quite some time, and our reason to bring in the ADC ourselves was because of our conviction around this combination. Okay. The other one, the Pol Theta helicase, just explain the difference there in terms of the function versus the Werner. And here you are combining with PARPs in the HR phenotype. So talk about that strategy. Yeah. Yeah. So I would say the quick summary with Werner helicase, Yigal, and this is actually going to be one of the core themes at our upcoming R&D Day, which when you kind of take a step back and say, what is one of the biggest challenges we face in cancer. I think this is a consistent theme you're going to see through our entire pipeline and what we've been trying to do as an organization. Because people ask us, well, you have so many programs and targets, and how do they all fit together. This is really to answer your question on why we think Werner helicase is such an important target. One of our core objectives as a company for a long, long time has been about how do you address the challenge of tumor heterogeneity. And we believe that's really one of the core issues of why we can't drive greater durability in these patients. And so Pol Theta helicase and PARP is really a great example of that. So let's kind of jump into that quickly here. We know that one of the primary mechanisms of resistance to PARP inhibitors was an OlympiAD study that was published by AstraZeneca. Over half of these patients, BRCA2 breast cancer, was shown that resistance was driven by a process called BRCA reversions. So we know the core process in BRCA reversions is around a backup DNA repair mechanism called microhomology end joining, which we know Pol Theta specifically is the Achilles heel. So this is really a fit-for-purpose combination. We don't believe it's as much of a monotherapy path to help address what we think is one of the main mechanisms to resistance of PARP inhibitors. The preclinical data looks great. Another just tremendously wide therapeutic window molecule that GSK has. But here, yeah, we have very high conviction on it. The science is very sound and strong. Here, ultimately, if you sort of fast forward, what trial would you like to see? I personally would hope to see a head-to-head randomized phase III study of Pol theta PARP versus randomized against PARP and see if you can really deliver that great OS result we always hope for from PARP inhibitors. I think if you can do that, we have the opportunity to really change significantly for these patients, which, as you know, just such a high unmet need in this area. Okay. We're running out of time. Let's quickly hit some of the other you mentioned the topo one bispecific, so we'll skip that. You also have a KAT6 that's becoming more of an interesting target. There are a few other notable companies in that space. What's the quick pitch there? How's yours differentiated? Yeah. And so Yigal, we're really excited about this program. And I know our CSO, just kind of call out to our CSOs, this is a program he's really just absolutely excited about. And what I wanted to emphasize is several things. This really kind of gets into the core we talked about around addressing tumor heterogeneity. So I just want to make sure this is clear. Our molecule is not just a KAT6 molecule. It's a truly differentiated profile that addresses specific variants in this pathway around this KAT6 area. So there are different variants of KAT6, including KAT7s. I'm giving an early preview. We'll do a deep dive on R&D Day, not only revealing our development candidate here, which would be first in class with this profile, but also why this question around variance is critical as it relates to helping address what we talked about earlier around addressing the challenges of tumor heterogeneity. We would hope with this unique differentiated profile, this is going to open up several things. One is at least the potential to see efficacy without having to combine with fulvestrant. Second, we believe this will open up certain biomarker hypothesis that's not open to KAT6 selective only. And then finally, third, not only being applicable in tumor types like breast cancer, but we also believe we'll have application in areas such as lung cancer as well. So we've done a significant deep dive on this biology. We will definitely do an unveiling here shortly at the R&D Day. Another really exciting program, this would be our eighth development candidate. We're going to be targeting and push forward eight programs in the clinic, hopefully, in next calendar year. Just got to run, but remind everyone, when is the R&D Day? Yeah. So the R&D Day would be on Monday, December 16th. We'll be putting out the official agenda and all the various speakers. We'll have a pharma partner that will participate with us. We'll have a fairly long list of KOLs as well. So it should be great. I think it should be a really great opportunity to really showcase our science, our innovation. We're continuing to push the envelope. And as I mentioned, one of the key themes you'll hear as part of that R&D Day is our perspective on what we think is one of the greatest challenges of cancer, which is addressing tumor heterogeneity. And that's exactly what we're doing across our pipeline. And that's really the direct link that connects all our various programs together.