Okay, great. Welcome back, everyone to day one of Citi's Virtual Oncology Summit. This has been running for several years now. So we're pleased to have you back. This is the lunch session, at least on the East Coast, breakfast for Yujiro out west. It's my pleasure to have Yujiro Hata, who's the Chief Executive Officer of IDEAYA. Welcome, Yujiro. Thank you so much for taking the time out of an immensely busy. A busy time for you. As a reminder, if anyone has questions for Yujiro, please just email me, and I can relay and hopefully see those and relay them over. So obviously a big year coming up for you. A lot of programs, a lot of studies, both early as well as mid as well as late stage. So there's a lot to absorb. So maybe just at a first blush, you know, first question, just set the scene for everyone in terms of what to expect. What are the key readouts for 2025? You know, how to think about the company and how to think about the mission and the thesis. Great. Well, thanks so much, Yigal, for the kind introduction, and thank you to Citi for hosting us again this year at your oncology event. Today I'm dialing in from our San Diego office, so not my typical office background here. 2025, Yigal, we believe is set up to be perhaps our most transformational year, and I do think front and center. As part of that, as you know, is darovasertib, our lead program, which is in a potential registrational trial in the first-line metastatic uveal melanoma setting, and we have guided towards our first potential approval readout before the end of the year, and that endpoint is specifically median progression-free survival. As you know, we presented at ESMO a year or so ago, where we reported a median PFS of just about seven months. H istorical, PFS in the indication is roughly two to three months. The second, I would say key catalyst for darovasertib, and for the company, is, we're also guiding towards what we think will be a significant clinical data update in the neoadjuvant uveal melanoma setting. Here, we've enrolled roughly 95 patients, so a fairly large data set. We are also planning to provide a key regulatory update in the first half as well as it relates to locking down the final protocol for the registrational study. And then finally last for darovasertib, we've also got a third readout which is in the metastatic setting, frontline for the combination with crizotinib where the focus on median overall survival. And Yigal, as you know, we've never reported survival for this program yet. In terms of our powering assumptions for the full approval study, we're assuming ability to at least exceed OS by plus six months from the comparator arm. I would say beyond that, I would focus on several additional areas, and I think for here, Yigal, really our focus is to build a leading precision medicine oncology company with a truly diversified pipeline going after several key biomarkers. Now, what's next is in the area of MTAP deletion. Here we have ongoing studies both as monotherapy for IDE397, which is a phase I/II MAT2A inhibitor currently positioned as a first- in- class agent, where we're studying both lung and urothelial cancer. As you know, we had a late breaker oral presentation in Barcelona at the end of last year and we have a core focus on enabling combinations. We do anticipate being able to provide a clinical data readout specifically on the Trodelvy combination with Gilead here. We just announced recently the expansion of that combination effort from urothelial cancer to also now include lung cancer. In addition, Yigal, as you know, we also are planning to bring our own PRMT5 inhibitor in the clinic in the middle of this year. And that's a core strategic objective to enable that combination as a wholly owned combination for the company. I would say next is really just a broader thesis on other assets that are in the clinic. Werner helicase, as we anticipate, will be presenting at a major medical conference in the first half of this year here targeting high microsatellite instability solid tumors. We've also guided towards a clinical data readout on the DLL3 Topo ADC program also this year. We do anticipate, at least we're targeting for that program, a data readout at a major medical conference later this year as well. Okay, and there's even more I think that we have to get to beyond those. But let's start with the late stage. So for MTAP, you mentioned the PFS at the end of the year. So assuming you know, you achieve the similar benefit over standard of care. Just give us the timelines. I mean, when could this drug potentially be approved? How quickly could you file it and approved? Yeah, so we haven't given the specific timelines to actual launch, Yigal, but as you can imagine, if we are able to have the PFS readout by the end of the year and some of that will really be driven by the final piece of the enrollment. As you know, we recently announced enrolling over 230 patients in the study. And of course as an event driven endpoint, ultimately when the events occur both on the comparator arm as well as the treatment arm, but assuming that we do get it by the end of the year, we do have Fast Track designation which would accelerate the review process and the time that it would take to assemble the NDA, submit that, and then that waiting period. So I think what we can highlight is our commercial readiness has begun. We've already hired a chief commercial officer. We have several ongoing searches right now to build that organization out in preparation for that PFS readout. So help investors understand the reasons to be confident in a positive PFS. I mean obviously as you pointed out, you've got a very nice separation versus standard care already. But are there other things that should be pointed out as far as why to be confident and if there are any risks that, you know, obviously there are always risks, but in terms of, you know, some things that you believe, you know, need to watch out for, you know, to make sure the study ends up being successful? Yeah, we feel good, Yigal, about the prospects for our PFS readout. I would say primarily because of where we've seen the PFS in the past, including what we presented at a major medical conference. We powered the study where as long as we're above that five and a half month mark, we believe we'll be in good shape based on historicals that we've seen in the control arm. And at least for PFS that number has been pretty stable including for Immunocore. Tebentafusp reported roughly a three-month PFS. So we feel pretty confident in that number as well as from large meta-analyses that have been done that have shown that two- to three-month range. So we're fairly confident that control arm is going to behave in a similar fashion. And because so far we've been well north. Of that five and a half month mark and again slightly above seven months, we do feel good about this endpoint specifically. And you know, in terms of the patient population, we don't believe there's going to be any major differences from what we've enrolled in the past. So obviously here the focus is in HLA-A2 negative, but as you know, we have not seen a difference whether A2- negative or A2- positive at least as it relates to PFS or response rate or other efficacy type endpoints. So I mean obviously that would be a conversation with the regulators. But is the expectation that the label would be HLA negative out of the gates or could it be broader? Yeah, so our base case you know. Because the registrational trial enrollment is focused on HLA-A2 negative, that the focus there would be HLA-A2 negative and that we would take a compendia strategy for pricing and reimbursement in the U.S. for HLA-A2 positive based on published data, data we've already published in a medical conference setting and data we will continue to plan to publish moving forward in the future. And at the time when we target to have the NDA submission occur, could there be an upside? But it's not in our base case scenario. But could there be an upside if we submit real world data on HLA-A2 positives? Because we'll have a lot of data at that point of that submission. Could there be an upside opportunity where it isn't labeled? I suppose that's possible as a scenario, but at least right now we don't view that as base case. Okay, now this, the phase II update that you referenced on the OS is very interesting, especially since it's coming ahead of the PFS for the phase III. So I mean, what should be the expectations there relative to standard therapy and assuming that looks really good? I mean, I would think that that should, you know, advance or improve the chances on the PFS just because we have, you know, a hard survival endpoint, but just help frame what could happen at that OS event, which is, as you point out, you know, we haven't seen any of that before. Yeah, yeah. So, you know, you'll also appreciate, as we get closer and closer to that PFS readout, you know, I think the obvious question, and absolutely a fair question I think investors and analysts will want to understand is, you know, well, how about OS and any sense of where OS may be. And so that's where we think this data set will be valuable. Obviously it's not a randomized data set. You know, typically it's all about a hazard ratio survival. But we do know historical survival here has also been fairly consistent, again based on other studies that have been done, large meta-analysis, you know, where we anticipate that survival OS will be, you know, roughly in that 12- to 13-month range. Here, you know, similar to other studies that have been run, that where they have seen approval based on OS was a plus six month improvement. That's how we've powered our fall approval study. That's the bogey. You know, where are we relative to that, I think, will be the question when we provide this update. I do think it'll be a data point and hopefully an informative data point. In other words, 18, you're looking for something in the high teens, 18 to 19 versus 20, 12 to 13, is that correct? Yeah, high teens are, you know, 20 plus is probably, you know, the range you want to be in ideally. Okay. All right, so let's talk about the neoadjuvant, which is obviously great interest as well. So you mentioned you're going to have some updates in terms of the, well, two things, the 95 patients and then the now final lockdown of the phase III. So can we get into a little more detail on that, like. And some of that's really important as far as understanding the vision endpoint for the phase III. So what are we going to get in that update, that next clinical update that will help investors, you know, get more clarity or understanding on that vision piece? Yeah, so it's going to be a much larger data set. So, you know, now we have roughly 95, you know, patients from our company sponsored portion of the study, I think on the eye preservation enucleation cohort. I think that data I think people felt quite good about. And at least in our FDA briefing book, the target that we had set was to exceed a lower bound of 10% confidence interval. And as you know, our eye preservation rate was the majority of patients. So we're well north of that objective. So I do think a lot of the focus was on the plaque therapy cohort group and specifically around data on vision preservation. And at that time of the update in the fall, we just didn't have a lot of patients. You know, we had about a half a dozen patients. That data set's now grown. So you know, we have multiples of that number. We also have more longitudinal data as well. That dataset is still maturing, but I think directionally hopefully it'll be an informative data set to you know, with obviously our objective to put that cohort also on solid footing as well. And then finally we are considering a possible omnibus-type update where we also include the regulatory piece. We are having a lot of back and forth with the FDA currently just to try to fine-tune the last remaining pieces around the clinical protocol. And I would say probably the biggest piece really outstanding right now is I think you've all, as you know, we talked about can we utilize macular edema as an endpoint. And I think there, the main topic is really around. Is it a co-primary, can we utilize it as a co-primary endpoint or will it be utilized as a secondary endpoint? So we're continuing to go back and forth and hopefully we'll have sort of final resolution on that and be able to hit our objective to get the second registrational trial up and started this half. The other aspects are more or less clarified, like using the disease, the metastasis-free survival, if I have that right, and the BCVA. It'll be around a 15-letter-type vision readout in terms of time to vision loss. And then for the secondary endpoint for both cohorts will be around no detriment to event-free survival. And that is another piece that we're finalizing. You know, what does that look like in terms of no detriment to EFS? Okay. And then as far as timelines there, that's as you'd articulated previously. Or that could potentially be modified based on further clarity with the regulators? In terms of timing, you go, study start. Yeah, I mean, I think we should be in good shape to get that started this half. I mean, that's, I think the FDA has been extremely supportive to date. You know, very communicative. So I think we feel good about our objective to get that study started in the first half. The trial enrollment will likely be in that four to 450 patients, which we do think we can enroll that group in roughly four to five quarters based on the pace we've been going and as well as our objective to get a lot more sites activated. So. And as we've seen with our existing phase II study, the enrollment cadence has been extremely robust, as you know. Okay, so anyone, as a reminder, if there are questions, just. I'm happy to relay. So let's move on and talk about some of the mid-stage, early mid-stage work, of which there's a lot. So try to move quickly here. DLL3 ADC is certainly a hot topic, shall we say, with multiple players. Talk about why your DLL3 is special or differentiated based on payload linker, you know, internalization, cleavage of the linker, etc. There's a lot there which we could learn as far as why it might be different? Yeah, yeah. So I would say there's a lot of aspects about our DLL3 Topo ADC that we, that we like quite a lot and we think it's very well positioned. So first, as you know, in small cell lung cancer, there are several assets or category assets that are being advanced right now, including bispecific cell engagers. You have B7-H3 ADCs as well. We, at least our view is that we believe DLL3 is the optimal ADC antigen, a it's very highly expressed in small cell lung cancer. Second, it's connected to a key survival oncogene ASCL1 which impacts expression of DLL3. And as you know, one of the key bypass mechanisms for resistance to ADC is to lower the expression of that antigen. So we think DLL3 is very well positioned from that aspect. Now when you look at it at the lens of the DLL3 Topo ADCs, that competition is more limited right now. There's us in the clinic, there's another group that we believe is roughly side by side. And then as you know, Roche recently came in with the acquisition of the asset of a company called nVent. You know, probably about 10, 12 months behind here. We did recently publicly note that several expansion doses have been selected. So we have seen a larger data set from our partner in China, Hengrui and we continue to feel confident about the data set that's emerging. And here I think the key question will be three pieces. One is what will the ultimate confirmed overall response rate be? Second, what does that durability look like? And of course third, you know, how does that, how does the adverse event profile stack up relative to other ADCs as well as other classes like the bispecific T cell engagers? I would say the last part really is, you know, why we think our asset is unique. So one, you may know that Hengrui's used this Topo-ADC platform across multiple assets. It's about a half a dozen clinical programs including that platform that's been licensed to Merck in the past. Two of GSK's ADCs, their B7-H3, B7-H4 also is from this Hengrui platform set up. So it's been in about 4,000 patients. And then lastly the cleavage happens once it's internalized. I would say there's another asset out there where the cleavage is in the tumor microenvironment. So that MOA is different. I would say our preference is around this internalization in particular because once you go into combinations, we think that could potentially play out. But ultimately that data is going to get generated clinically and we'll see where we end up. But we feel quite good about the profile to date. Okay, and what is this clinical strategy going to look like? Obviously small cell lung cancer is on the table. But that's not all there is. I mean there's a lot else in neuroendocrine which you could leverage maybe. Yeah. So I think here you know based on the response rate and obviously we ultimately need to see what the ultimate confirmed response rate and mDOR is. But at least you know based on the early data we do believe there should be a potential regulatory path as monotherapy agent in the later line setting in small cell. And here you know similar to what Amgen did within Imdelltra, they ran a single-arm study with a primary endpoint response rate and mDOR. So I think there we would take that same approach in the frontline setting of the small cell. I think here or at least our current thinking is post the chemo platinum doublet to combine with checkpoint randomized versus checkpoint in the maintenance phase. Then, as you know, one of our big focus areas is also on this PARP combination IDE161 in our portfolio. One of the main reasons why we brought this asset in is because we believe that's a very compelling rationale combination that could hopefully enhance the durability of this DLL3 ADC. Next, there are other tumor types, and so obviously neuroendocrine tumors we think also is a very high unmet need. You know, we think roughly about 100,000 patients annually here. So it is a large population. And as you know, I forwarded you that paper the other day that we talked about, which you know DLL3 expression was one of the largest studies done to date is being seen upregulation in multiple tumor types. I thought interesting was specifically around findings like you know fairly large upregulation in tumor types like melanoma as well as others. Okay and then the timelines there will be data this year for that. Yeah, so that was part of our recent earnings release. So we were given an update both in terms of data and also communication from our partner Hengrui that they plan to present data this year. And you know we also know which medical conference they're targeting. But you know until all of that goes through you know we'll wait to give that more specific guidance. But at least that's the plan at this time. Okay, let's talk about MAT2A. So obviously you have the combo with Gilead so let's start with Trodelvy. Your rationale certainly makes a lot of sense for the reasons you've explained and now non-small cell as well. So is the biology the thesis there the same or is there some specific differences in terms of the reason to combine in non-small cell? Yeah, so the reason would be identical. So here this is really about the topoisomerase payload and the impact on the purine, pyrimidine and folate pathways specifically. And I know you had gone through this before also at a past R& D days that we've held as it relates to the MAT2A mechanism specifically impacting around nucleotide pools. As you recall, we've had interest in the past on other chemo combinations like pemetrexed. That rationale is exactly the same. At least our perspective is that the urothelial cancer connection as well as lung cancer should be the same. That clinical POC would be the same. Based on what I just walked through, we have an early but emerging data set urothelial cancer. That data set Gilead did review as we made the decision together to expand that effort into lung cancer. We're excited to get that going. We're getting fairly close to picking the expansion dose with Trodelvy. Hopefully that'll be happening in the next couple of weeks. Basically we have seen multiple confirmed responses as part of the escalation. And I think importantly, at least based on the data so far, we don't appear to be exacerbating some of the myelosuppression that's been noted with Trodelvy monotherapy. I think that's great. And that was really probably one of the key questions we wanted to answer. At least right now we feel good about it. And now our objective is to build out a larger data set with duration. And our goal is to provide a data update on this combo sometime this year. Okay, and what do you? I mean, obviously, in addition to the tolerability that you mentioned, what sort of rough bar for taking the combo forward? Or what would you like to see? Or Gilead, what would Gilead like to see to, you know, quote unquote, resurrect Trodelvy and UC. Yeah, so we, you know, we've had quite a few conversations with Gilead. I also know we had a bunch of meetings at ASCO recently this past week and spoke to a lot of the KOLs to get their input. And I think historical response rate here, at least in urothelial for that ADC class is probably in that 20%-25% range. And so ideally we're well north of that and can hopefully observe what's going to be attractive durability. So that's really the objective you've all. And I think once we have a bigger data set, we can sort of get a sense of where we are. So I think here our hope is we have a data set that should hopefully position at least us well in that second line type setting. Obviously depending on how strong the data is, we could also perhaps consider an earlier line setting beyond that. We'll just have to see how the data set matures. So then obviously, you know, you've been spinning up the engines on your own development of your own PRMT5 and you're advancing that with your IDE397. So talk about that and how and how that study is evolving and just, you know, maybe very briefly touch on the choice to move past the Amgen compound. Sure, yeah. So Yigal, as you know, for several years now, you know, we've been communicating very consistently a core strategic objective for the company is to enable wholly owned combinations in the MTAP pathway. And our program, PRMT5, has been ongoing for probably about five years now. So we've been doing chemistry and lead optimization for many years. We feel we've identified a great candidate molecule that's really fit for purpose to be combined with IDE397. We got through critical toxicology studies at the end of last year where we announced the candidate nomination last fall and then obviously profiled the molecule at the R&D Day end of last year. So I think that that's really our core strategic objective. And we have a third program, Yigal, as you know, an MTAP where that candidate nomination is also slotted for this year. So we think all three of these programs and targets will be extremely valuable pieces of the puzzle to hopefully deliver optimal value to patients. As you know, we've been in the clinic with Amgen for about five quarters with our PRMT5 inhibitor. And I think first and foremost we wanted to mention that we're extremely grateful to Amgen for being our partner for the last five quarters. We give them a lot of credit. They really came out. We published work together preclinically published that at major medical conference, actually multiple major medical conferences throughout preclinical data and they were the first pharma company to try to generate that clinical POC data. So again we're very grateful on that. I think here the decision was made to mutually wind down the combination study. Ultimately our perspective is that we did well achieve the target clinical exposures that we were targeting for both the PRMT5 mechanism as well as MAT2A, and this was based on our preclinical modeling work, so you know we think we could hopefully be able to utilize those learnings and implement them very quickly as we get our PRMT5 inhibitor in the clinic middle of this year. Our strategic objective here is to continue to be a leader in MTAP and specifically are on this mechanistic combination, and that's exactly what we're going to attempt to do through 2025. I mean, obviously there was a very, very strong synergy data with IDE397 and AMG 193. Are we going to see that for preclinical? I assume you have it already or you haven't. I guess we haven't seen it yet. But will we see that before we get clinical data or is it essentially going to be the same very, very good story again on the preclinical side with that combo with your PRMT5? You're talking about our preclinical combo data? Yeah, yeah, yeah, yeah. So we did publish some of that work. You know. I know. All I can say is there's other, you know, medical conferences that are upcoming that we have some placeholder abstracts on where we may be able to profile and showcase more of that work preclinically and why we're excited specifically about our PRMT5 inhibitor in combination specifically with IDE397 so that we definitely have a lot of different plans for that in terms of publishing that hopefully throughout the year. How are you thinking about the prioritization of your proprietary combo with the original monotherapy work with 397? Where does that. Yeah, yeah, great question. We're continuing to interrogate monotherapy data. We do have a bigger data set. You know, we're getting more longitudinal data. You know, as you know we've been focusing on specifically on lung cancer, high interest in squamous lung cancer as well as urothelial cancer. So that work is ongoing. But as we've said in the past, our central strategy here is around combinations. We are having quite a few other discussions on other combination mechanisms beyond also PRMT5 and so I think those will be hopefully activities we'll be able to bring across the finish line in the relatively near term to hopefully see what our broader combination strategy is in MTAP. So I think that's what you're going to continue to see from us is our focus on combinations as really the central theme to deliver the most benefit to patients. As far as the first combo study, are you focusing on specific tumor types, or is this going to be more of a basket study initially for? The PRMT5 asset. You know, yeah. I think here, front and center for us is lung cancer. I mean, we believe the indication that the greatest opportunity lies for this mechanistic combination is in lung cancer, so that's really number one by fairly long margin, so I think here we'd like to remain focused. We do believe there should be an opportunity to see responses across multiple tumor types. But I would say at the outset, we want to be focused as much as possible, obviously be as capital efficient as possible, and we think there, the best place to focus will be in lung cancer. Okay, and so that study starts this half. The objective for our PRMT5 in the clinic is in the middle of this year, and we hope to be able to enable the combo in the second half. You know, we've kind of gone through this, including with GSK, with Pol Theta, fairly recently at least. Our perspective is we can do a fairly integrated escalation where you clear one or two cohorts as monotherapy and then starting to seamlessly integrate the IDE397 into the combo as part of the escalation. We have experience with that with other programs that we've been doing in partnership. That would be the plan here. Our expectation also is we should see activity very early in that combination escalation. Then second, we know exactly what dose to start with with IDE397. So I think we should have, at least based on that, a very truncated process prior to hopefully going into expansion quickly. And to state the obvious, your PRMT5 is wholly owned. It's yours, so you control it, which is a key advantage. But is there anything else in terms of the molecule itself that may provide some additional benefit versus your former partner, or is it really more just about the control of the molecule? Yeah, I think there are sort of three pieces for us in terms of TPP. Yigal, also, first is having that balance between potency and selectivity. I would say there, you know, we think our compound's probably most similar to the BMS compound. Second, we do think this candidate has excellent DMPK properties. So at least our anticipation is that we shouldn't have to have a very large pill burden. At least that's what we anticipate not to have a large pill burden in patients in the clinic. And then finally, third, Yigal, we've communicated this in the past. Our perspective is that for this target in particular, you do not want to have a brain-penetrant molecule. And so as I'm sure you know, that's what also I guess similar to BMS there as well. So we think for this combination that's really the ideal profile. Just so everybody heard that correctly. You do not want, We do not w ant a brain penetrating. And the reason for that is just to remind everyone why because that doesn't. It's basically, you know, at least our perspective. It's based on the target biology of PRMT5 and you know, based on the impact in RNA splicing. So our preference for the TPP was not to have a brain penetrant molecule. Okay. Okay. For cancers where there would be expected brain metastases that you would need a different approach perhaps or that wouldn't be the focus for this development if there were tumors. And we wouldn't be focused in certain tumor types like GBM for people. But as you know, you are going to have still some, you know, just exposure in terms of the blood-brain barrier for a lot of patients that may have brain met. But I think having a specific compound that's targeting to get into the brain at least we believe is not the right profile specifically also for this combination. Okay. Let's hit some of the other earlier ones and there's a few. So Werner, the Werner helicase compound is in the clinic. Is that right? It's in the clinic. Patients start being dosed at this time. You're going to have an update on what I understand is essentially, you know, proof of biology and proof of MOA very soon, but and then perhaps some early look in the MSI/MSS patients later in the year. Yeah, I think on that latter piece, Yigal, we just need to be coordinated with GSK. But the first part is correct. So you know, we did now publicly guide that it's been accepted and it's to be presented at a major medical conference. So we're excited about that. We'll be showcasing, you know, why we think this molecule has best in class properties and specifically a unique profile relative to the existing clinical stage inhibitors that are in the clinic right now. So I think it'll be an exciting story for people that saw our patent publish or patents published in this area. They'll know that the chemistry that we did is quite unique. And so you know, we're very excited with GSK to be able to tell the story to the public And just r emind everyone for those less familiar, I mean Werner helicase is one, quote unquote, one of those holy grail targets, as I understand. Why is it so critical? And how broad is the applicability across solid tumors? If this shows POC, how broad could it be? Yeah, so you know, we do think, as you mentioned Yigal, we do think this is really one of the holy grail targets, not just in synthetic lethality, but in precision medicine, oncology more broadly, and a big part of that is mainly because how exquisite the activity has been in the biomarker setting of high MSI. As you know, there have been very, very large CRISPR screening efforts done in synthetic lethality, including by the Broad Project DRIVE by Novartis as well as others that people have published and consistently. Werner drops out is perhaps the most robust synthetic lethal target in the cancer genome. It's a very hard target to drug and hopefully we'll be able to tell that story. In this upcoming medical conference presentation, primarily because it is a helicase. Second, it's very hard to find viable chemical matter against this target. In terms of the patient population with high MSI, we do believe that's a large opportunity here. Key cancer types like endometrial cancer, which probably over a third of patients have high MSI, CRC, colorectal cancer, gastric cancer, about 20% of patients. We do think here there should be an opportunity for patients that are refractory to checkpoint and high MSI as well as to be utilized in combination with checkpoint. And that's at least from what we've understood with GSK. That's their plan to pursue both, both as monotherapy and in combination with their checkpoint dostarlimab. And this has been a really just phenomenal partnership with GSK. You know, we've been working side by side with them since this program was an early discovery stage. So I know they're extremely excited to, you know, now we're in patients and dosing patients. Okay. Quickly, the Pol Theta is another important one. Remind everyone what, how that's different from Werner helicase and what the opportunity there is. Yeah, Pol Theta helicase is another really novel, exciting target and also another helicase. And at least you know that we believe we are the first biotech to deliver back to back clinical molecules that are helicases in oncology and hopefully that showcases our chemistry capabilities as an organization. Here, Yigal, we think the main application is going to be in combination with PARP inhibitors. So unlike Werner, where there will be a big focus on monotherapy development for Pol Theta helicase, we think the primary focus will be in combination with PARP specifically. You may know that one of the key mechanisms that we're trying to address through that combination is the role of Pol Theta specifically in the backup DNA repair mechanism called microhomology-mediated end joining, which we believe is really the central Achilles heel of why PARP inhibitors get acquired resistance through a process called BRCA reversions. You may know there was a study I believe called the OlympiA study, which noted in, I believe it was BRCA2 breast cancer. The majority of acquired resistance through PARP was through that, a BRCA reversion of MMEJ mechanism. So I think this is a real rifle shot to address, you know, what was unfortunate, a really big challenge for PARP inhibitors. I think if we can address that, our hope is we should be able to deliver great value to those patients. Another great aspect of this agent is it's a non-essential gene like Werner. So we do anticipate, at least based on the preclinical data, a very wide therapeutic window. So unlike a lot of the first generation DDR agents, these are really kind of the new wave of DDR agents and targets that are now in the clinic. So they were both obviously very hard to find, as you say, the right chemical matter. Yeah. Can you talk about? I'm just curious, just this is more just I guess for the history books, but it is still fascinating, you know, which of these, which one did you figure out first and then did that once you solve the one, did it help you bootstrap to solve the other one faster for the helicase? Yeah, I know you took a little bit of a tour of our office when you were in South San Francisco, showed you some of our labs. We solved Pol Theta helicase first, Werner next. We had some learnings, I would say, but not exactly transferable. You know, the binding pockets are just completely different. But without a doubt you have to have an extremely capable chemistry organization in particular related to structural biology, computational chemistry. We've also were successful in integrating some of our AI/ML capabilities as well and you know, which we've utilized across a lot of other programs in addition. So, you know, I think hopefully it's a testament to our ability to really solve a lot of these difficult targets. We're continuing to do that as you know, with KAT6/7 and other targets deeper in our pipeline as well. I mean, I think some may just not appreciate the level of effort in the med chem side and how deep your bench is, I guess, pun intended in terms of. That effort, can you spend just 30 seconds a minute just kind of explaining to people what you've got and how many chemists you have, and you do a lot of outsourcing too. I mean, it's quite a remarkable effort and I don't think it's widely understood. Yeah, no, no, thanks for bringing that up, Yigal. So, total research, we have about 70 folks, you know, I would say probably 40% of that are chemists. We leverage external chemistry very aggressively. So, you know, we can go where we're bringing on, you know, 50 external chemists if we want to go full force on a project. So we can really compete with anybody as it relates to that. I think, really, here, as you mentioned, Yigal, we have an extraordinarily deep bench in chemistry., So at each level within the organization, we think we've built an extraordinary capability and we're not afraid to try to go after any target, frankly, in chemistry. And we've done it. We've shown time and time again our ability to solve really hard chemistry challenges that other companies have not been able to solve. So. And you know, and for the Pol Theta helicase, Werner helicase, obviously it was a partnership, but you know, it was ultimately our team that saw that delivered on both of those candidates. So for Pol Theta as well as Werner, I think the last part I will mention, Yigal, is we've also been able to integrate that with deep cancer biology knowledge. And I think that cannot be underscored because sometimes it's really the nuances of the target that can really make all the difference in terms of what you're trying to optimize for. And hopefully front and center in terms of a core example of that will be Werner helicase that we'll showcase at this medical conference. Because as we'veYi said, we believe the way our molecule binds is different from these first generation molecules. That was really based on our understanding of the biology. It wasn't just. A random event. It was based on our deep understanding of the biology. Okay. And then there's one more clinical asset we semi glossed over, but we don't want to forget about the PARG inhibitor, not to be confused with the PARP inhibitors. So PARG, you've got a few studies there with Keytruda and then with the Topo1- ADC. Can you just elaborate on strategy on those? And again, the same question on when we're going to get some data. Yeah. So I would say on monotherapy, there you go. Amazingly we're still with ongoing dose escalation there and our focus on monotherapy will be largely in endometrial cancer. But I think similar to some of our programs like an MTAP or Pol Theta here, our core focus for PARG will be on combination development and specifically I would say a very focused interest on combining with Topo ADCs. So, and I think we've been very upfront when certain programs are more focused on monotherapy like DLL3 or Werner, or when they're more focused on combination, for example MTAP or in this case the PARG asset. What makes us excited about PARG and Topo ADC specifically is, you know, goal. You know, one of the main challenges with Topo ADCs has been around durability, right. And we saw that really play out in 2024 with some of the TROP, sorry, the TROP2 ADC data, whether it was PFS and OS. So we think there is a major unmet need there as it relates to identifying the best combination partners with the topo ADC class to enhance durability. The challenge is there's not a lot of great options. And so I think for a lot of those companies, they're basically searching hard of what is the right combination partner. I think historically people looked at PARP1, we just think PARG is a mechanism that just makes a lot more sense. As we've said before, PARG is the key enzyme that is involved in the resolution of the DNA damage that delivered by topoisomerase specifically. The mechanism is very tight and we know we have a lot of interest right now from large companies to work with us on that combo. That's in our public guidance. You know, we've now committed that we're going to enable multiple combinations with PARG and the Topo ADC class, not just with our internal pipeline, but our expectations with external assets as well. And then the reason for the Keytruda combo is what exactly? Yeah, so this. So we have data which we'll be also planning to publish all around data such as neoantigen refresh with the PARP mechanism and obviously which would interplay with checkpoint inhibitors. You may know that there has been some interesting data with Keytruda and PARP combinations specifically in endometrial cancer here. This is not going to be HRD related. This is going to be looking at patients with high microsatellite instability as well as microsatellite stable, as it probably won't surprise you, ours as well as Merck's interest, at least that we understand is going to be in that microsatellite stable population because that's where the higher unmet need is. So that work is ongoing, that dosing is ongoing. So we're continuing to accumulate that data. Okay, so you would still, you would advance that combo if it looks good, in addition to the. Exactly, yeah, The Topo1. Okay. All right. Now then, as far as preclinical. Was there another? I maybe have this wrong, but I thought there was yet another. MAT2A pathway target, which you had somewhere in the discovery phase that you were looking at. Is that right or? Yeah. So there's a third MTAP program,Yi gal, I think is what you're referring to, where that development candidate is on track for this year. So just so it's clear, that target is not a MAT2 inhibitor and that target is not a PRMT5 inhibitor. So it's a completely distinct target. I think here, you know, look for us to be sharing more information on this one. But what I could tell you at a high level is it's focused on targeting what we think is a very key co alteration with MTAP. So it's a very unique profile. It's a profile that no company that we're aware of has achieved before. And we've been at this for many, many years and kind of similar to a lot of other programs like Pol Theta, Werner. It's been an unbelievably difficult chemistry challenge, but we think we've solved it and we made great progress last year, which is why we're now guiding for the candidate for that program this year. So it should be exciting to have a third sort of piece of the puzzle that we hope will, at least in the medium long term, position us well in the MTAP arena. So that, that sounds like a target that either people know about but just have passed over since the level of difficulty is just immense, but you've solved it or is it just not on people's radar screens or both? Yeah, you know, we haven't revealed all the specific Yigal, but it is probably a set of targets people know about, but a profile at least that we're aware no one's been able to accomplish. And that one, and I mean, I know you can't really say a ton right now, but is that, is the idea there that it would be standalone as a monotherapy, or could you also do a combo with your own PRMT5 or the IDE397? I think a triple combo may probably would not make sense, but. But what's the longer? term thinking with that program, if you can. Yeah, it'll be interesting at all because, you know, no one's been in the clinic with this asset before. So, you know, what could they see in terms of monotherapy? I think that's going to be an open question. What we know preclinically is the data is quite robust. So I do think there's going to be a monotherapy evaluation for sure. And that will hopefully be frankly quite distinct from PRMT5 MAT2A. I think what's exciting about this asset is we could do a doublet with MAT2A. We could do a doublet with PRMT5. We could consider a triplet as well. But as you know, those get more complex, but it just gives us flexibility, another critical shot on goal. You know, as you know, our objective at MTAP is, you know, once all the dust settles, at least our strategic objective is to be a leader here, to be the industry. At least we believe the way you're going to do that is by wholly owning the key targets in this pathway. So we feel if we deliver this third one, you know, we'll hopefully be extremely well positioned relative to the competitive landscape. Does that sort of complete the triad in terms of the key targets, or are more lurking? Yeah, no, it does, it does, yeah. I mean, obviously, as you know, you go for lung cancer, you know, got to be thinking about checkpoint, right? In PD-1. As you know, MTAP or another genetic alteration, PD-1 is going to be thought of there. I think there it's just about, you know, what is that, right? Setup and combination strategy. Is it a doublet? Is it triplet? But that's one that we're also having fairly advanced dialogue on. And then of course TROP2. But a bit, as you know, Yigal, there are several companies with TROP2s. And all I could say is we've seen broad interest there. So, you know, we think with the three we have with PD-1 and TROP2, those five, at least we feel that we'll have our bases covered. And you know, and obviously we know others are thinking about co- alterations. Our third program, at least from our perspective, is sort of the mother of all co- alterations. You can go after it. Just that compound doesn't exist today, and we're going to try to be hopefully the first one to deliver it. So that one doesn't have a number. I'm just looking at your PowerPoint. That one doesn't have a number yet. Is that right? Yeah. So that DC goal is this year you know. So okay, once we get it, I'll be sure you're one of. The first get your ducks in a row. I'll be happy to be with the announcement. But yeah, we're getting close. I think we may already have the molecule in hand. We'll see. And then two more that are still just very quick comments on the KAT6. And then the other interesting about that is that it may have some differentiation versus Pfizer's. Given you say you hitting the KAT7 domain too. Yeah, exactly. So it's a very unique profile. So as you know there's several KAT6 inhibitors out there, including Pfizer that we're aware of. There's no selective KAT6/7 dual inhibitors. So we should be the first hopefully in the clinic on that one. We're targeting an IND this year and really our hope with that biology is that we'll be able to do several things. One is, at least, we believe we'll have the potential to hopefully remove fulvestrant out of the equation because as you know, at least existing data requires fulvestrant to see activity. Second is our hope through this dual selective inhibitor profile we'll be able to expand the opportunity beyond breast including lung cancer as well as pursue certain biomarker thesis like 8p11 amplification. I think the key piece and key question is really about therapeutic window and what would be the result of bringing seven on board. I think there what we can say is we've done a lot of deep work, extensive work and we know what that profile needs to look like to have the path forward. That's really our sort of quote unquote secret sauce that we've identified and it took us a lot of years and the chemistry here also Yigal is extremely challenging. So we've, you know, even just from you know, past conferences we've talked to quite a few pharma, you know, they said yeah, KAT6/7 is sort of an obvious one but we just didn't know how to approach it chemically. So again here was an extremely challenging chemistry problem. But over time our team figured it out. Okay, and then, is this the very last one that we didn't hit on, was y ou have your own B7-H3, PTK7 and I don't know much about that PTK7 target? What exactly is that, and what's the genesis of that one, and where could it go? Yeah, so PTK7 you may know that there are companies out there. I won't name them that are sort of early clinic or about to be in the clinic on PTK7. There is less data. On that antigen, we were specifically interested in pairing that with B7-H3 specifically, whereas, as you know, there are more assets against that antigen. There's several, and I think their data looks interesting. Clearly seeing what we believe is a clinical signal, but perhaps maybe we'd like to see a wider therapeutic window. Our hope is with the bispecific, we're going to be able to drive greater selectivity, greater internalization by targeting both of these antigens. This is just so it's clear you have either/or formats or bispecific format. This requires expression of both to appropriately bind and get internalized, and so we should, we believe, theoretically that should drive a greater therapeutic window, and the reason why you want to pair these two together in particular were two reasons for us. One is there's high co-expression of B7-H3 PTK7 versus a lot of other pairs that you might try to create. So that percentage is significant. Tumor types like lung cancer as well as CRC well into the double digits. Based on the preclinical data we saw, we did see much greater selectivity as well as efficacy versus these mono ADCs. Lastly, at least that we're aware of, we do think it's going to be the first bispecific with this format in the clinic. So yeah, so we're excited to have that go in. I believe we're in the middle of GLP tox studies right now, but all the non-GLP look good so we anticipate we'll have that in the clinic this year. Obviously a big focus will also be the combination efforts with IDE161 PARG. Okay, we covered a lot of territory. Did I, did I miss anything? Because I want to make sure that covered all the programs. I think, I think we got to everything but if not, please let me know. Yeah, no, I think you got it. I think you covered pretty much most all of it. You know, I think here we would just emphasize is, you know, we've been expanding our pipeline. You know, we feel great about darovasertib direction that's going. We're getting ready for that commercial readiness, and I think important for us is to ensure that we're continuing to maintain a growth story by investing deep into our portfolio. I would say next is MTAP. Obviously what we're doing with PARG and on the Topo ADC side with multiple clinical assets, at least from our perspective, we think we have one of the deepest pipelines in the industry. Then lastly is our continued focus to leverage pharma relationships to allow us to scale and to run as many programs as we're doing. Like we did with GSK. Right. Like we've been doing with other pharma collaborations. So I think continue to look for that theme that will hopefully enable us to scale the organization as well as our P&L. And, as you know, extremely capital efficient. I think in our 10-K, we just reported, you know, just over 130 headcounts for everything that we're doing. So I think that's something that's been also an extremely significant focus for us to ensure our capital efficiency. Awesome. All right, well, thank you so much. Appreciate the time. I look forward to coming to see your labs at some point and enjoy the rest of the visit down here, your San Diego office. Thank you. Thanks so much. For those listening, please, at 1 o'clock, we'll have Roche with Geoff Meacham starting now.