Good morning, and welcome to the IDEAYA Biosciences Investor R&D Day. At this time, all participants are in a listen-only mode. An analyst Q&A session will follow the formal presentations. As a reminder, this event is being recorded, and a replay will be made available on the IDEAYA website following the conclusion of the call. I would now like to turn it all over to your host, Yujiro S. Hata, President and Chief Executive Officer. Please go ahead. Good morning. This is Yujiro Hata, IDEAYA's Founder and Chief Executive Officer. I wanted to welcome everyone to our 2023 IDEAYA Investor R&D Day event. Note, we'll be making some forward-looking statements, and please refer to our SEC filings as appropriate. I wanted to first thank all of our listeners for dialing in today and provide a special thank you to our guest speakers for their participation, including Dr. Timothy Yap from MD Anderson Cancer Center and Dr. Ramon Kemp from GSK. For today's agenda, I'll kick us off to walk through IDEAYA's vision and strategy to build a leading precision medicine oncology company. Then Dr. Michael White, our Chief Scientific Officer, will present our efforts in computational drug discovery. Next, Dr. Timothy Yap from MD Anderson will provide a clinical program update on our first-in-class PARG inhibitor IDE161. Next, Dr. Michael White and Dr. Darrin Beaupre, our Chief Medical Officer, will walk through our multi-pronged strategy in MTAP deletion. Then Dr. Ramon Kemp from GSK will provide an update on Pol theta helicase and Werner helicase, and then I'll provide our closing remarks, and at the end, we will open up the line for the analyst Q&A portion with IDEAYA management. As an organization, we believe there are several major key themes that will drive the precision medicine oncology field in the next decade. During the R&D day today, we will highlight several of these key strategic pillars that we believe will continue to guide IDEAYA's growth as a leading precision medicine oncology company. First and foremost is our deep commitment to advancing the scientific understanding of first-in-class targets. As evidence of this, IDEAYA has made important scientific contributions and delivered potential first-in-class development candidates against several important precision medicine oncology targets, including MAT2A, PARP, Pol theta helicase, and Werner helicase, all of which we'll discuss later today. Next is our resolute focus on predictive biomarkers as a central strategy to enrich for the responder population, as demonstrated by our work on key patient selection biomarkers such as MTAP deletion, HRD, MSI-High, among many others. As further demonstrated by the collaboration we announced with Gilead this morning, as IDEAYA's continued strategic focus to enable what we believe are high-conviction clinical combinations. IDEAYA has been an industry trailblazer in enabling potential first-in-class combinations, including PKC and c-MET with Pfizer, MAT2A and PRMT5 with Amgen, MAT2A and Trop-2 ADC with Gilead, Pol theta helicase and PARP with GSK, and Werner helicase and PD-1, also with GSK. An additional topic we will focus on today is data informatics. We believe the technological revolution occurring in computational drug discovery, driven by AI and machine learning, will disrupt the small molecule drug discovery paradigm. IDEAYA has built significant capabilities in this area for several years, which we are excited to share with you today. The vision and strategy that we've been executing on for the past 8.5 years has resulted in what we believe is one of the most exciting and diverse clinical pipelines in precision medicine oncology today, with five potential first-in-class programs, which includes PKC inhibitor darovasertib in a phase II/III registrational study targeting first-line MUM, MAT2A inhibitor IDE397 in phase II, targeting MTAP deletion solid tumors, PARG inhibitor IDE161 in phase I, targeting HRD solid tumors, Pol theta helicase inhibitor GSK101 in phase I, also targeting HRD solid tumors, and Werner helicase development candidate in IND-enabling studies targeting MSI-High solid tumors. Beyond that, we have an emerging next-generation portfolio, where we are targeting multiple development candidates in 2024, including an MTAP deletion. With that, we'll start the first portion of the presentation with Dr. Michael White walking us through computational drug discovery at IDEAYA. All right. Thank you, Yujiro. I'm excited to tell you guys a little bit about our drug discovery efforts. Now, as everybody knows on this call, drug discovery is very hard, fraught with unknowns that can hamper progress, yet obviously, the need for effective cancer therapies is broad and urgent. To my mind, a real strength that IDEAYA brings to the table to help address unmet need for oncology is the breadth, quality, and pace of the drug discovery enterprise here. Some examples are on the left, all challenging targets, multiple target classes, and all potentially first-in-class. Now, part of the IDEAYA enterprise leading to molecules like these has been the early and productive adoption of a computer-assisted discovery. We're obviously not a software company or a GPU company. We're a company that seeks to compress time to IND for new chemical entities, and to do that, we've really invested in battle-tested technologies that, in the right hands, can help deliver high-quality molecules with fewer design cycles. In the next few minutes, I'll give you a high-level view of our internal cheminformatics and computational chemistry teams, what they're doing to help prioritize and optimize small molecule designs to get us to the right compound quickly and efficiently. So on the next slide, Yujiro, we'll start with prioritization of compound synthesis. Now, for that, drug-like property prediction has obviously been in widespread use for quite some time as an important approach to triage design ideas that may produce a compound that's insoluble and stable and active, some combination of all three. Partial least squares, you can see that as a literature example on the top left, is really a conventional statistical method that uses linear regression to assess where a new design might fall in chemical property space based on what has been observed with similar-looking compounds. Now, a limitation of this method for first-in-class drug design is the need for the user to handpick parameters believed to be correlated with response based on prior experience. Now, our team found that this can work well if you're starting with a heavily benchmarked model, but it performs poorly once your med chem team begins to design highly original molecules in order to process and prosecute novel target classes, and we do that all the time. To solve for this, we turn to advances in the field of artificial neural networks, in particular, multilayer neural networks that build models connecting observations to molecular features with no pre-selection bias. And in our case, this is a feature space with a combinatorial complexity across about 2,000 dimensions, and this is in a deep neural network we call Harmony ML. You can see the results of implementation of this approach on the right. We have substantially reduced the frequency with which we make compounds with unattractive properties across our programs. And I've highlighted a particularly challenging program with respect to avoiding poor solubility, labeled Project A on the bar graph, where this method was highly impactful for acceleration of lead optimization. Compare the red bar before versus after implementation of Harmony ML. We're making really a lot of nice compounds against this program now. On the next slide, Yujiro, given our focus on structure-based drug design, we've also invested in approaches like free energy perturbation that allow us to model how a small molecule or protein will interact with each other in space over time, and therefore design molecules that will optimally relax into the protein target to block its function. This is a computationally expensive approach that solves a discrete quantum equation across an incredibly high combinatorial complexity of molecular interactions to predict binding affinity, and has only relatively become practical at scale with the advent of cloud computing. Now, one of my favorite examples using this approach here at IDEAYA is illustrated here. We arrived at a really potent compound against a first-in-class target labeled IDCA in the table on the right, but it was greasy, unstable, poorly soluble, hard to move forward. Now, to get past this roadblock, hundreds of design ideas from our med chem team were evaluated by FEP, clustered within a 2,000-dimensional chemical feature space, and as indicated in the t-SNE plot on the left, this revealed a predicted binder where we had no previous experience that was potentially within an attractive chemical property space. So we made it, and it worked. That one labeled IDCB, giving up only a little potency, and that was corrected with a single modification to give IDCC. So only two molecules made to solve a tough problem. Next slide, Yujiro. This last example comes from our new MTAP program that I'll introduce later today. Here is our FEP prediction performance at the beginning, and it really kind of fell off a cliff, which can happen when dealing with something very new, and the solution was parameter optimization via machine learning. This delivered a new model that returned accurate predictions for the subsequent designs for new molecules that have advanced this program at a heady pace. I'll stop here, Yujiro, so we can transition to the PARG program. Great. Thank you, Mike, for that walkthrough. For the next section, we'll have Dr. Timothy Yap from MD Anderson walk through IDE161 clinical and program update. Dr. Timothy Yap has been a lead investigator on this study, and I'd have to say for this year, IDE161, we've made absolutely tremendous progress. We went from IND filing, IND clearance, initiating phase I, as well as a dose expansion, all in 2023. So Dr. Yap, with that, we'll hand it off to you for the next section. Thank you very much, Yujiro, and thank you for the invitation to present here in your R&D day again. Good morning, everyone, and thank you all for being here. I presented the rationale, preclinical data, and trial design for IDE161 at the last IDEAYA R&D days, and so it's a real pleasure for me to now share the early exciting clinical data from the IDE161 phase I trial, and to provide you with an update on the program. So the slide that you can see here shows how PARP is a mechanistically differentiated target along the DNA repair pathway, which is, of course, a clinically validated pathway, given the success that we have seen with PARP inhibitors. And in the panel on the left, you'll see how PARP activity is required to resolve DNA repair. PARG is essentially an enzyme involved in DNA damage and repair, which helps remove PAR chains once DNA repair is completed, as shown in the bottom figures. PARG inhibitors therefore prevent the removal of PAR chains from areas of DNA damage, and IDE161 is a first-in-class PARG inhibitor. The panel on the right shows how PARG inhibition is mechanistically distinct from PARP inhibitors, which is a critical point as we think about the clinical application and line of sight for IDE161. Firstly, it's key to note that the mechanism of inducing cell death for a PARG inhibitor is distinct from that of a PARP inhibitor. PARP inhibitors trigger unrestrained fork progression, resulting in single-strand and double-strand DNA gaps and breaks that trigger cell death. In contrast, PARG inhibitors induce fork reversal, which results in nucleolytic degradation, leading to mitotic catastrophe and subsequent cell death. And therefore, one might expect overlapping and/or distinct cell killing between the two different classes of agents, depending on the tumor landscape. Next slide, please. So here's some background on IDE161, which is a potential first-in-class PARG inhibitor. And as you can see on the left, IDE161 is a potent and selective inhibitor of PARG with an IC50 around 2 nanomoles. In the bottom row, you can see that treatment of tumor cells with IDE161 results in PAR accumulation, very consistent with its mechanism of action. IDE161 also induces a time-dependent increase in markers of DNA damage, such as phospho-ATM, phospho-KAP1, and phospho-RPA. The panel on the right on the slide shows a waterfall plot from a large panel cell line screen, demonstrating that tumors with HRD and other mechanistically related biomarkers were sensitive to IDE161. Next slide, please. This slide shows how IDE161 is active and well-tolerated in HRD, ER-positive, HER2-negative breast cancer models. In the panel on the left, you'll see how in preclinical studies comparing sensitivity between IDE161 and the PARP inhibitor niraparib in various tumor cell lines, IDE161 was active in cell lines that were both sensitive and resistant to niraparib. But a few lines were sensitive to PARP inhibitors, only consistent with the idea that PARP and PARG inhibitors have distinct mechanisms of action. And in the panel on the right, these in vivo PDX models demonstrate that IDE161 is highly active in tumors that are relatively insensitive to PARP inhibitors. You can see tumor regressions with IDE161 versus niraparib, which leads to only modest growth inhibition in BRCA-altered breast cancers. These data thus strongly supported us proceeding to the phase I clinical trial of IDE161 in the human setting. Next slide, please. And here is the IDE161 phase I first-in-human trial design. The study started with a standard dose escalation using a BOIN, also known as a Bayesian optimal interval design. Expansion into ER-positive, HER2-negative breast cancer and ovarian cancer, both with HRD, was planned based on preclinical models. A basket cohort for patients with tumors harboring HRD was also included to identify activity in other cancer types. Also planned was a cohort for dose optimization. Dose escalation proceeded, and based on evolving clinical data, an expansion cohort was opened to further dose optimize and focus on tumors of highest priority. That included not only HRD-positive breast and ovarian cancer, but also prostate, gastric, CRC, and endometrial cancer. The breast and ovarian expansion cohorts were also opened to obtain more efficacy data in these indications at a therapeutic dose level. Next slide, please. Here are the PK data of IDE161 at the expansion cohort dose. Based on preclinical data, the exposure seen in the dose expansion are at or higher than the therapeutic exposure expected to be needed in humans. What is interesting, too, is that the patient with the highest exposure had little in the way of adverse events, while the patient with the lowest exposure had a tumor response with a -31% tumor reduction on their second scan. Next slide, please. And here are some preliminary pharmacodynamic data assessing PAR accumulation in PBMCs in patients treated with IDE161 at the expansion dose. You can see that all subjects in the expansion dose showed evidence of PD effects in surrogate tissue, providing emerging evidence for proof of mechanism. Next slide, please. To provide further evidence of PD activity in patient tissue, the following images are of nuclear PAR levels assessed by IHC on skin biopsy samples collected pre and on treatment from a patient treated at the IDE161 expansion dose. You can see the nuclear staining with IHC for PAR-positive nuclei showed PAR accumulation on treatment, as shown by the brown staining, consistent with that observed in the PD assessment in PBMCs that I showed on the previous slide. Next slide, please. The preliminary clinical experience of IDE161 shows a manageable safety profile at the expansion dose. The majority of treatment-emergent adverse events were low grade, and no drug-related discontinuations or treatment-related SAEs have been reported. Dose evaluation is currently ongoing to determine the phase II expansion dose or doses to move forward. As mentioned, dose expansion was initiated in priority HRD solid tumor types, including HR-positive, HER2-negative breast, ovarian, prostate, colorectal, gastric, and endometrial cancers. Next slide, please. This is the preliminary clinical efficacy at the expansion dose of IDE161. We have observed two confirmed RECIST partial responses, one in a patient with metastatic colorectal cancer with a BRCA1 mutation and another in a patient with endometrial cancer harboring both BRCA1 and BRCA2 mutations, who also had a RECIST 1.1 response. The observation of these clinical responses is encouraging, with more patients coming onto trial with indications of interest based on preclinical data and clinical data from the first few cohorts. Fast Track designation was recently granted for IDE161 in BRCA1 and BRCA2 mutated HR-positive, HER2-negative breast cancer and ovarian cancer, post PARP inhibitor therapy. Next slide, please. Here is one of the patients who achieved a confirmed RECIST partial response. She is a patient with advanced endometrial cancer who received multiple prior therapies, including carboplatin-Taxol bevacizumab, followed by paclitaxel maintenance, and then the PD-L1 and atezolizumab. The patient had a reduction in her cervical lymph node target lesion, as indicated on the scans, and a complete response in her non-target mediastinal lesions and overall, a confirmed partial response that was confirmed. Next slide, please. This is the other patient who achieved a confirmed partial response. This is a patient with advanced colorectal cancer who had previously received FOLFIRI chemotherapy. The patient had a -31% tumor shrinkage in their pelvic mesenteric lesions, as shown on the slide, and overall, a confirmed response. So in summary, IDE161 is a first-in-class PARG inhibitor that thus far has shown great PK properties as evidence of PD proof of mechanism in surrogate tissue, has what appears to be a manageable safety profile, and is showing early exciting signals of anti-tumor activity. Thank you very much for your kind attention, and back to you, Yujiro. Great. Thank you so much, Tim, for that wonderful walkthrough and, again, we really appreciate all your contributions to the program. Thank you very much. For the next section, we'll be moving into the topic of emerging therapeutic opportunities for MTAP-deleted cancers. Over the last several years, IDEAYA has had several significant efforts in the area of MTAP deletion. In addition to our efforts on IDE397, which is currently in a phase II expansion, as well as clinical combination studies with Amgen, we've had multiple initiatives in the MTAP deletion space, spanning multiple programs at preclinical phase, including programs where we're targeting a development candidate in 2024. In addition, we've been evaluating multiple, what we believe are first-in-class clinical combination opportunities. As noted earlier, we announced earlier this morning a partnership with Gilead to evaluate the combination with Trodelvy, specifically in MTAP deletion bladder cancer. It gives me great pleasure to introduce our next set of speakers, Dr. Michael White, our Chief Scientific Officer, and Dr. Darrin Beaupre, our Chief Medical Officer, that will now walk through this next section. All right, thank you, Yujiro. I'd like to begin this section by just reminding everyone why MTAP-deleted cancers are one of the most exciting precision medicine opportunities out there to address unmet clinical need. That's because loss of MTAP activity results in two distinct targetable vulnerabilities: reduced capacity for the nucleotide synthesis required to support tumor cell DNA replication and repair, and reduced capacity for the mRNA splicing activity required to support tumor cell growth and survival. As outlined in the schematics shown here, leveraging the synthetic lethal interactions within this system to kill MTAP null tumors is a major focus for IDEAYA. On the left, inhibition of MAT2A with IDE397 creates a double hit on the production of metabolic intermediates required for de novo synthesis, de novo nucleotide synthesis. On the right, inhibition of MAT2A with IDE397 creates a double hit on the PRMT5-dependent methyltransferase reactions required for spliceosome function. In the next few slides, we'll take you through how we're exploiting these mechanistic relationships to bring monotherapy and combination therapies to the clinic that fully leverage the precision medicine opportunities associated with MTAP cancer. On the next slide, let's start with our lead molecule in this space, IDE397, an allosteric inhibitor of MAT2A enzymatic activity. As shown on the upper left, consistent with the synthetic lethal hypothesis, the cell biological consequences of MAT2A inhibition are highly dependent on MTAP status. There's at least a 100-fold selectivity window for perturbation of cell viability in MTAP null versus wild-type cells and at least a 1,000-fold selectivity window for perturbation of PRMT5 activity. We know from functional genomics efforts that MAT2A and PRMT5 have highly correlated dependency profiles across 1,000 cancer cell lines, and consistent with IDE397's biochemical activity, the same is true for IDE397 and PRMT5. You can see that in the panels on the lower left. Now, as many of you know, the mechanistic basis of this synthetic lethal interaction is accumulation of the MTAP substrate MTA, which is a direct partial antagonist of PRMT5. Now, this means that the strength of the synthetic lethal relationship depends on accumulation of cellular MTA, which is a function of both MTA production and MTA clearance via active transport. You can see an example of that for the HCT116 isogenic pair in the middle panel, top row. Now, in MTAP null tumors, variability of MTA accumulation is a major source of variability of PRMT5 pathway suppression because MTA competes with SAM for binding to PRMT5. Thus, the higher the MTA/SAM ratio, the deeper the suppression of the PRMT5 pathway activity. As shown on the upper right, IDE397, through suppression of SAM production, can dramatically increase that ratio selectively in MTAP null cells, which corresponds to dose-dependent inhibition of mRNA splicing in MTAP null tumors in vivo. The volcano plots in the upper right show drug-induced intron retention events that block production of functional proteins. Now, as we've noted in the past, this mechanism delivers a monotherapy opportunity in tumors with optimal MTA accumulation, as shown in the squamous lung cancer and bladder cancer PDX models on the lower right. And as we noted at the AACR meeting earlier this year, this mechanism delivers a very important activity, a very important opportunity, sorry, more broadly across MTAP null tumors with variable MTA accumulation when combined with an MTA cooperative PRMT5 inhibitor. More on that on the next slide. As we heard earlier this year, both Amgen and Mirati have established clinical proof of concept with MTA cooperative PRMT5 inhibitors, and I've noted some key mechanistic features of these molecules on the left. All disclosed next generation PRMT5 inhibitors reinforce the MTA-bound inactive conformation of the PRMT5 active site by filling an open space in the MTA-bound pocket, as indicated in the top left. They also avoid SAM-occupied PRMT5 via charge-charge clash with SAM itself, as shown in feature two. Finally, some compounds, perhaps most notably the Mirati compound, additionally incorporate super cooperativity with MTA through charge-mediated attraction to potentially maximize selective inhibition of MTA-bound PRMT5. Now, the take-home message here is that combination benefit with IDE397 is observed irrespective of the balance of those features that I showed on the left. As shown on the right, with the Mirati compound and the Amgen compound, we see durable, complete responses with IDE397 combination therapy, using exposures that are a fraction of the clinically relevant monotherapy doses in humans. On the far right, I'd like to point out that we're not seeing any preclinical tolerability issues with these combinations, including in a 14-day rodent hematology study using the Mirati preclinical compound, MRT9768. On the next slide, the next question is: why does this combination work so well? Now, we think there are two important mechanisms at play. First, shown in the top row, is the ability to extinguish PRMT5 activity selectively in MTAP null tumors to safely deliver a deep response. As shown in the upper left, using a cellular target engagement assay based on displacement of a fluorescent analog of a first-generation PRMT5 inhibitor, we find that IDE397 enhances the binding of MTA cooperative PRMT5 inhibitors to the target. You can see that as a function of the IDE397-dependent increase in the Mirati compound target binding potency, as indicated by a reduction in the area under the dose response curve. This is exactly what you would expect from an IDE397-dependent increase in the MTA/SAM ratio in MTAP null cancer cells, summarized in that schematic in the middle. This translates to amplified PRMT5 pathway suppression in MTAP tumors, as indicated by single agent versus combination drug effects on both gene expression and mRNA splicing, shown on the far right. Second mechanism, in the bottom row, is the ability to deliver a durable response, and we find that the low-dose combination produces biological responses in the tumor that are not achieved with the maximum effective monotherapy doses. Notably, IDE397 uniquely delivers pathway modulation that we think contributes to a durable antitumor response by inhibiting the function of adaptive resistance pathways. On the next slide, based on everything I just summarized, we're very excited about our collaboration with Amgen, that's evaluating the IDE397/AMG 193 combination as a potentially transformative therapy for MTAP null lung cancer. Also, as you drew and noted, we're continuing to build a multipronged approach to address unmet need across MTAP cancers. And to that end, our internal efforts to deeply evaluate the mechanistic vulnerabilities conferred by MTAP loss have delivered a new target hypothesis. Pharmacological evaluation of that opportunity is shown here and indicates the potential for meaningful therapeutic benefit that is mechanistically distinct from PRMT5. We're seeing durable, complete responses in a challenging MTAP null model, 8 out of 10 complete responses and minimal impact on body weight with daily oral dosing. This is a first-in-class opportunity, not yet tested in people. We think the mechanism operates broadly in the setting of MTAP loss, and we anticipate a tolerability profile that will combine well with other assets in the MTAP space. Now, the next slide, Darrin and I will wrap up this section by turning to our freshly announced collaboration with Gilead to evaluate a Trodelvy IDE397 combination that we believe will address unmet need for bladder cancer patients harboring MTAP null disease. Now, the mechanism underpinning this opportunity really turns on the combinatorial roles that MTAP and MAT2A play in one-carbon metabolism, and how that can be targeted by IDE397 to disrupt de novo nucleotide synthesis. As illustrated here, there's a tight coupling of the methionine and folate cycles to replenish nucleotide pools. This is an essential activity in cancer cells to meet the demands of accelerated DNA replication, transcription, and DNA damage repair. You can see the relevant endpoints highlighted in those red boxes. Now, upon loss of MTAP, MTA can no longer be recycled into adenine and methionine, thereby cutting off resources to that arm of purine synthesis. Furthermore, MAT2A inhibition in this context interferes with SAM-dependent generation of homocysteine, thereby cutting off a key resource for production of tetrahydrofolate, a metabolic intermediate in the folate cycle for production of both purine and pyrimidines. Now, the coincident inhibition of PRMT5 makes all of this worse from the standpoint of genomic instability due to the replication stress that occurs when mRNA splicing is inhibited. This all creates a perfect storm, if you will, that sets up MTAP null cancer cells to be killed by an IDE397 topoisomerase inhibitor combination, as noted on the left. A combination, by the way, for which a therapeutic index can be maximized by employing an ADC, like Trodelvy, to deliver the topoisomerase inhibitor in a tumor-selected fashion. Now, you can see the relevant IDE397 MOA in action on the right. Here, global metabolic profiling of IDE397 drug effects uncovered heavily disordered methionine metabolism, selectively in MTAP null cells, with knock-on consequences on the concentration of a number of key cellular metabolites, as highlighted in this Cytoscape plot. Now, in particular, we saw a significant depletion of pyrimidines and purines in MTAP null cells that was not observed in the wild-type setting. This effect underpins the strong correlation of cellular sensitivity to IDE397 with sensitivity to antifolates, topoisomerase inhibitors, and inhibitors of nucleotide synthesis that we reported at the AACR meeting earlier this year. It also translates, obviously, into induction of DNA damage in MTAP null tumors by IDE397 in vivo, as shown on the bottom right. Next slide. As Darrin and I will describe in a moment, bladder cancer, or as Darrin actually will describe in a moment, bladder cancer is a priority indication for IDE397 in the clinic, and we believe this mechanism that I just reviewed is particularly relevant in that setting. A key example illustrated on the left is work from MD Anderson that noted a compelling enrichment of pemetrexed antitumor activity in MTAP null bladder cancer patients. Recall, pemetrexed directly interferes with de novo nucleotide synthesis. Preclinically, we see tumor regressions with IDE397 in bladder patient-derived xenografts, and we see combinatorial benefit with a topoisomerase inhibitor together with IDE397 in a bladder cancer model that's difficult to control with either single agent alone, as shown on the far right. Last slide for me. I'll turn the floor over to Darrin. In the interest of time, just close by iterating that the biology outlined in this schematic underpins our mechanistic conviction that IDE397 Trodelvy combination has a potential to create a synthetic lethal pair that fully capitalizes on the mechanistic vulnerabilities associated with MTAP loss. So, Darrin, please. Thanks a lot, Mike, for providing the background that supports the IDE397 and Trodelvy combination. It's really intriguing to consider the opportunity for these two agents to serve as a synthetic lethal pair in tumors associated with MTAP loss. Also, and importantly, the fact that Trodelvy allows tumor-specific delivery of a topoisomerase inhibitor provides the opportunity to maximize the therapeutic window with this novel combination. What I'll be doing over the next few slides is providing some of the clinical correlates that suggest that this combination is well-positioned to potentially make a significant impact in MTAP-deficient urothelial cancer patients, particularly in the setting of first line. And these clinical correlates will be further supported by some of the early efficacy data that we've seen in our IDE397 early phase clinical study, which I will also share. On this particular slide, what I'd like to do is summarize for you some of the key findings from the UNITE study that was presented at ASCO and ASCO GU this past year. What the authors did in this particular retrospective analysis was to review the data from patients with urothelial cancer who were treated with standard of care therapy, and determine whether molecular correlates from the subjects' tumors could predict patient outcomes. On the left is a data set from approximately 90 patients treated with Trodelvy, where the authors correlated a number of biomarkers to treatment response. Interestingly, and consistent with some of the biological rationale that Mike shared for Trodelvy in the MTAP-deficient setting, patients who were MTAP-deficient had a much higher response rate to Trodelvy than those patients who were wild type for that marker. The response rate was 50% in MTAP-deficient subjects, versus 19% in those subjects who were MTAP wild type. On the right, and contrary to the findings seen with Trodelvy, subjects treated with enfortumab, who were MTAP-deficient, actually had a worse progression-free survival and overall survival relative to those who had wild type, wild type MTAP status. Enfortumab, as you know, is an ADC that targets Nectin-4, which is currently approved for urothelial cancer subjects who have progressed after chemotherapy and checkpoint inhibitor therapy, but also is a relevant treatment option for subjects that are platinum ineligible. The clinical data presented on this slide, however, implies that subjects with MTAP deficiency may benefit more from Trodelvy or a Trodelvy-based regimen relative to other standard of care agents. Next slide, please. On this slide, we demonstrate additional information you may not be aware of, in that similar findings to that shown for enfortumab have also been reported in urothelial cancer subjects treated with checkpoint inhibitors. This is a study that was published in Nature Communications in 2021, looking at urothelial cancer patients treated with either pembrolizumab or atezolizumab, evaluating their progression-free survival and disease-specific survival after therapy. Interestingly, those patients who are MTAP-deficient did significantly worse with checkpoint inhibitor therapy compared to those subjects who were MTAP proficient. Combined with the information shared with enfortumab, these data once again suggest that urothelial cancer subjects who are MTAP-deficient may require a novel treatment approach. Next slide, please. Also, highly relevant to the results just shared are the findings shown on this slide from a study that was recently presented at ESMO, evaluating the enfortumab vedotin and pembrolizumab combination versus standard of care first-line chemotherapy in advanced urothelial cancer. Here it was found that EV + P had a better progression-free survival and overall survival versus a platinum-based regimen, and importantly, based on data from this study, many treating physicians feel this is a practice-changing result, implying that EV + P will become the new standard of care for first-line treatment of advanced urothelial cancer. Again, highly relevant to our discussion today is the fact that patients who are MTAP-deficient tend to do poorly with either of these agents as compared to those who are MTAP wild type, suggesting that urothelial cancer patients with MTAP deficiency will likely need additional options. Next slide. So you may wonder what proportion of patients with urothelial cancer have MTAP deficiency? And this slide shows that MTAP deficiency occurs in approximately 25%-30% of subjects with urothelial cancer, and this disease represents one of the most common tumors for which MTAP deficiency is found. Therefore, this is a relevantly sized subject population where additional therapies will likely be needed. Next slide. So therefore, you may ask, what have we seen in our own early phase trial of IDE397, the IDEAYA MAT2A inhibitor in subjects with MTAP-deficient urothelial cancer? This slide represents very early data from a small number of urothelial cancer subjects treated at therapeutic doses who were evaluable for disease response. On the left, we show five subjects who had evaluable disease at the time of the data cutoff, with three subjects showing evidence of relevant tumor shrinkage. In fact, one subject had a complete response to therapy at the third post-baseline scan, and the other two subjects who remain on study have shown improvement in their tumor measurements as treatment has continued, and it's our hope that these subjects will achieve a partial response after further continued therapy. Also of importance to note is that all three subjects had received prior standard first-line chemotherapy and checkpoint inhibitors and had progressed. On the right is data from three subjects who had cell-free DNA available for evaluation, and importantly, once again, all three subjects showed evidence of a molecular response posttreatment. These clinical findings are encouraging and appear consistent with the concept that IDE397 is itself an active agent in advanced MTAP-deficient urothelial cancer. Next slide, please. So this now sets the stage for the IDE397 and Trodelvy combination, which we plan to evaluate in the context of our current ongoing clinical trial. This is a collaboration with Gilead, where the objective will be to demonstrate a significantly improved response rate and duration of response than that seen with either single agent alone. The target patient population will be subjects with advanced relapsed urothelial cancer with MTAP deficiency. The benchmark for Trodelvy is the patient population that's based on their registration trial, which received accelerated approval, which showed an overall response rate of approximately 27% and a median duration of response of approximately seven months. In this line of therapy, a median progression-free survival of approximately five months is expected. As shown in the schema on the bottom right, the plan is to dose escalate IDE397 with standard doses of Trodelvy, and once the recommended Part 2 dose is identified, we will expand into patients with advanced urothelial cancer to gain more clinical data that will allow further advancement of the combination. In summary, the IDE397 and Trodelvy combination is a novel treatment approach for patients with advanced MTAP-deficient urothelial cancer, a patient population who generally does poorly with current standard of care agents, such as enfortumab and checkpoint inhibitors. Our hope is this could represent a novel opportunity for urothelial cancer subjects with an unmet medical need. And finally, not only is the biology supporting this novel combination intriguing, but the fact that based on the current clinical data, the agents appear to have non-overlapping toxicity, is further support for testing this novel combination. And with that, I'll pass it back to you, Yujiro, for the next speaker. Great. Thank you, Mike and Darrin, for that terrific walkthrough. And again, thank you also to Amgen and, obviously, our new collaboration with Gilead to enable what we believe are both first-in-class, potential best-in-class combinations in the area of MTAP deletion. Now, going on to our next section gives me really tremendous pleasure to introduce Dr. Ramon Kemp. GSK has been a collaborator with IDEAYA for several years, and we just wanted to make several comments before Ramon starts here. First, I believe there's been really just terrific strategic alignment between the two organizations in terms of pursuing target areas where we believe we have the opportunity to be both first-in-class and deliver tremendous patient benefit. In addition, the last several quarters in our partnership with GSK has been tremendously productive. We recently delivered the development candidate for Werner helicase, and Pol theta helicase recently just entered phase I. As far as we're aware, we believe, IDEAYA GSK, we are, from our understanding, the first group that has delivered back-to-back helicases, in terms of development candidate, and hopefully, we'll have our second here in the clinic shortly. So with that, Ramon, we're gonna pass it to you. Great. Thank you, Yujiro. It's my pleasure to be here to be on behalf of GSK, discuss two of the key programs that we have in collaboration. At the outset, I'd say that we have a very strong collaboration, as you've already highlighted. In our partnership with GSK and IDEAYA, there's quite a bit of excitement around these two programs that I'll talk about today. Both the polymerase theta program, as well as the Werner helicase programs, they both very much align with our GSK priorities and strategies that we have, and ambitions we have for precision medicine. Developing medicines that are really tailored to specific patient characteristics to ideally enhance the efficacy of our medicines, well, minimizing toxicity and tolerability concerns. Secondly, they really leverage two of our more established medicines that we have within our GSK pipeline for use in combination, notably our GSK PARP inhibitor, niraparib, for a potential combination with polymerase theta program. Then also our GSK PD-1 inhibitor, dostarlimab, for potential combinations with Werner helicase. Next slide, please. So the hypothesis behind the polymerase theta program really focuses on reducing the resistance to PARP inhibitors, and therefore, extending the depth and duration of PARP inhibitor response. In this vein, our niraparib PARP inhibitor is well-positioned as a combination partner. Key mechanism of resistance to PARP inhibitors is reversion of BRCA mutations, and this BRCA reversion is mediated by a process known as microhomology-mediated end joining, or MMEJ. The polymerase theta mediates this MMEJ repair. Therefore, the inhibition of polymerase theta prevents the PARP resistance by this mechanism, which is estimated to account for about 30% of PARP inhibitor progressors. The data slides below, highlighting three different preclinical BRCA mutant models, two of which are CDX models, and one of which is a patient-derived model, that we not only see inhibition of tumor growth, but also evidence of tumor regression when GSK101, or polymerase theta, is combined with niraparib. Next slide, please. Here, I'm simply highlighting our initial first time in human clinical trial, which you've highlighted. We've just started our phase I dosing. This is the phase I design in monotherapy, as well as in combination, and our trials are open right now. Next slide, please. The Werner helicase program is exciting for several reasons, and notably, we believe that we may potentially have the best-in-class Werner plus PD-1 combination. Our program centers on a target patient population with MSI-High dMMR cancers, which, as you know, our patient population is very much aligned with our overall strategy at GSK for dostarlimab. And so we know this patient population very well. We're very familiar with the patient needs. Our Werner inhibitor is very potent and selective to MSI-High dMMR cells, as outlined in the Chronos score in the picture on the bottom left. Werner is a multi-domain protein, and the helicase domain is the best domain to target for activity, as shown in the center panel. And on the right, these drug properties translate to robust antitumor regressions in preclinical animal model experiments, as illustrated by the red line as well. Next slide, please. Lastly, our development strategy to combine Werner helicase with our PD-1 inhibitor, with tremendous belief that dostarlimab is a top-tier, industry-leading PD-1 inhibitor in this regard. As you probably have noted, in the past 12 months, dostarlimab has distinguished itself as a very effective PD-1 inhibitor in MSI-High tumors. We've reported on our RUBY study in first-line endometrial cancer in combination with chemotherapy, as well as our data in rectal cancer, in neoadjuvant setting, demonstrating 100% clinical complete responses, obviating the need for difficult surgeries. Also, in non-small cell lung cancer, the PERLA study, which demonstrated robust and comparable results to pembrolizumab in non-small cell lung cancer. We believe Werner + dostarlimab has the potential to be a highly effective combination, and potentially best-in-class combination as well. We're currently executing the preclinical IND-enabling studies, and plan for IND submission and first-in-human dosing next year. And with this, I'll turn this back over to you, Yujiro. Great, thank you so much, Ramon, for that terrific walkthrough. And we'll go into now the final section with closing remarks. So thank you to all the presenters, and we're ecstatic about the progress we have made in 2023. And we believe we're positioned for another transformational year in 2024. We have built a world-class organization, a truly diversified, first-in-class precision medicine oncology pipeline, with multiple high-conviction clinical combinations underway, and built an industry-leading drug discovery platform that has a demonstrated track record, including two first-in-class helicase development candidates. As we look forward into 2024 and beyond, we will focus on the following key investment priorities to further extend IDEAYA's leadership in precision medicine oncology, including computational drug discovery to enhance our IND engine, structural biology to continue to unlock challenging first-in-class targets, neoadjuvant and adjuvant indications that have the opportunity to transform the patient journey, and our continued commitment to excellence in translational research and development to both the discovery and advancement of first-in-class targets and transformative combinations. IDEAYA was founded over eight and a half years ago with a singular mission of improving lives through transformative precision medicine, and I truly believe our journey has only just begun. We're now finished with our prepared remarks, and we'll open up the line to the operator for the analyst Q&A portion of our webcast. Thank you, Yujiro. The first question comes from Anupam Rama at J.P. Morgan. Hey, guys. Thanks so much for taking the questions, and thanks for hosting this Analyst Day. Two quick ones from me. Is there anything in the baseline characteristics or maybe any emerging predictive biomarkers for the 161 program from the endometrial and CRC patients that showed responses? My understanding is these tumor types may be potentially less sensitive than, say, ovarian and the subsets of breast. And then second question, what are the ongoing preclinical activities for the Werner's program and the sort of final gating factors to getting that program into the clinic in 2024? Thanks so much, guys. Sure. For the first one, Mike, do you wanna start with that one, in terms of potential predictive biomarkers in CRC and endometrial for 161? Yes, Anupam. So the situation there, we think, is the presence of HRD. You'll note that both of the, both of those patients that Darrin described as partial responses had BRCA mutations, so that is in frame with what we have been seeing with respect to the role that BRCA plays in replication fork stability. And we think we're going to particularly see advantageous activity in diseases where that BRCA status is on top of replication stress, and that replication stress is really dependent upon the collateral features that are present in those patient populations. And we're excited about the fact that there might be some enrichment with respect to overlapping HRD status with replication stress in those tumor types. We've shown that in the context, preclinically with the ER-positive, HER2-negative breast cancers, and I suspect that those mechanisms are in line with what we're seeing in those endometrial and colorectal cancer patients. Mike, if you don't mind, just I would just add one thing to that. When you say insensitive tumors, I presume you mean PARP-insensitive tumors, which they are. As Tim pointed out in the presentation, you know, the mechanism of action of PARG inhibitors is not precisely the same as a PARP inhibitor. And so, you know, there may be an opportunity to be in tumors where PARP inhibitors aren't, which is part of the excitement there. So that's another thing to keep in mind as we and that's the purpose of the basket part of the study, to look at tumors outside of what you typically see, but fit within the context of what Mike's described. Great. And then, Anupam, for the second part of your question, in terms of Werner helicase, and sort of, I think it was really around, you know, are, are any final gating items, from now to the IND filing? Here, I think all we could say is the IND-enabling studies are well underway, and we'll look forward to, to give, continued updates here as, as we get into 2024. But, but as you can see, you know, based obviously on, the discussion today, it's full steam ahead. Thanks so much for taking our questions. Sure. Thank you for the question. The next question comes from Maury Raycroft at Jefferies. Hi, thanks for hosting the event. Thanks for taking my questions. One of the potential benefits for the 397 plus AMG 193 combos is that you can decrease the respective doses of each drug due to synergy between the two drugs. What are your expectations for what the 397 plus Trodelvy combo doses could look like based on preclinical modeling? And based on slide 39, can you talk about how ctDNA response for UC matches with clinical responses? Great, yeah. Darrin, why don't you take both of those? Yeah, so, you know, listen, I think it's reasonable to think that perhaps, you know, the doses may not be sort of the standard doses. But you know what? You have to put the two molecules together clinically to understand that better. So, you know, within the context of that study, we'll have the ability to, you know, do whatever's necessary for the doses of both Trodelvy and our molecule in order to make sure we have a combination that works. As I mentioned, you know, the fact that, you know, we don't have overlapping toxicity based on what we've seen between the agents we plan to combine makes it hopefully a lot easier. And we'll be able to allow to potentially give the full dose of both agents. But, the expectation is it may be based on mechanistic reasons that less will be fine. So, you know, it remains to be seen. And then with respect to your other question, yes, some of those molecular responses did indeed correlate with the tumor responses we saw on the left-hand side, the tumor shrinkage. Got it. Okay, thanks for taking my questions. Sure. Thanks. Thank you, Maury. The next question comes from Gregory Renza at RBC. Yes. Hey, good morning, Yujiro and team. Congrats on all the progress, and thanks for taking the questions. Just Yujiro, on the new target opportunity and then MTAP-deleted tumors, solid tumors, just curious, what does the new target have to achieve to be either complementary to or differentiated from the current PRMT5 MAT2A approach? Is it faster kinetics, deeper anti-tumor response, maybe further combo opportunities? I'm just curious, you know, how we should think about hearing more on that. And then, just secondly, on the Trodelvy combo study, just curious, just the concept of adding a PRMT5 inhibitor, would that make sense scientifically for a triplet? And then lastly, just I know separately and outside item today, Yujiro, just curious if you could provide an update on, on the daro programs. Thanks so much. Sure. So, Mike, do you wanna take the first two, and I'll take the last? Yeah, that was a lot of good questions there. I think the first question, Greg, is you were asking what do we feel like we really need to do with this new target and how that would play with respect to the IDE397 MTA cooperative PRMT5 inhibitor combination. So on the one hand, I think what we have here is a brand-new opportunity, and we're not stopping until we really understand how to do the best we can for these patients. So we are pursuing this as a key opportunity to be able to evaluate how much we can have an impact in the space, where we are otherwise perhaps in a situation where we have to rely on the optimal MTA accumulation in these tumors. So this is an exciting opportunity that may be distinct from that particular need. We just don't know yet. But certainly, it's an important thing for us to evaluate. It's a very exciting opportunity for the field, the patients in general, that we have this new target opportunity to go after. Now, having said that, there also is obviously the possibility for the triple combinations. You mentioned some thoughts about triple combination with respect to Trodelvy. I certainly think that there's gonna be a triple combination opportunity with this new target based on the mechanism of action. It is distinct, and that's always a good thing if you're putting it together with other things that are known to have activity in that particular setting. Also, based on the mechanism of action, we are not expecting to see overlapping toxicities. Obviously, it's early days, and we'll learn a lot more about that very, very soon. But certainly, that's not off the table. But suffice it to say, Greg, that we just don't know yet how well the IDE397 PRMT5 combination is going to serve the full spectrum of MTAP-null patients. This is an additional opportunity in that space, and we're pursuing it very aggressively. With respect to your next question, asking about perhaps the mechanistic relevance of combining Trodelvy and PRMT5 with-- I believe you were asking also with, sorry, MAT2A, Trodelvy, and PRMT5 triple combination. That's something from a mechanistic standpoint. Yes, that's something from a mechanistic standpoint, Greg, that I guess would probably make sense. I mean, you're talking about the fact that inhibition of PRMT5 causes inhibition of splicing, which causes RNA polymerase stalling, which in turn causes R-loop formation. R-loops are a big problem with respect to replication stress, because they create these transcription replication conflicts during S-phase, and this needs to be resolved by topoisomerase in order to be able to release that before the replication fork comes through and creates havoc. So from a mechanistic standpoint, that does make sense, and certainly that's something that I'm sure Darrin and his team, together with Gilead, will be looking towards as the evaluation of the combination continues in the clinic. Yeah, the only thing I'd add to that, Mike, is again, we have to think about the overlapping toxicity. And, you know, the MAT2A inhibitor brings the dual-pronged approach, as Mike pointed out, you know, the effect on nucleotide pools and alternative splicing. Of course, that could be amplified on the alternative splicing side, perhaps with the PRMT5 inhibitor. But then you have to think about what baggage it brings along in terms of toxicity. So where we're starting, I think, is a good place to start. Being open-minded, of course, for the long run is fine. But I think the hope is that this, as Mike pointed out, you know, the MTAP space is gonna be very, very large. And it, it's possible that a PRMT5 inhibitor and a MAT2A inhibitor isn't gonna solve all of our problems in an MTAP-deficient setting. So this is another opportunity to get at perhaps some tumors, and perhaps it's bladder cancer, where we think this is really the lowest-hanging fruit for us for this novel combination. You know, it could be that it could be several combinations that are necessary to get at many of the tumors, or cover most of the tumors that are MTAP deficient. But we're taking our first step in that direction in any case. Great. I think the last question was related to Greg, just to darovasertib. Any updates there? I'll be brief, but I think it's just, you know, full execution mode. As you know, we've announced dosing our first set of patients for the registrational study. Teams working very hard on the international site activation. We anticipate 2024 will be a big year for the program, both in terms of enrollment, hitting our enrollment targets for the registrational trial. And then I would say second, as we noted earlier, around neoadjuvant application, both in terms of a potential clinical efficacy update in 2024, and potential also regulatory update, as it relates to, you know, what, what could a potential accelerated approval path look like, in that setting? Okay, thanks for the questions, Greg. The next question will come from Charles Zhu at Guggenheim. Hey, good morning, everyone. Thanks for hosting this event and taking our questions. I just have a couple across the, MAT2A and Trodelvy, as well as PARG. Regarding MAT2A and Trodelvy, so you mentioned Trodelvy's benchmark of, 28% response rate in about seven months of, DOR. Given that was an all-comers, and Trodelvy looks like it may have better activity in MTAP deletion, would you have to basically re-baseline the ADC single-agent activity with respect to determining contribution of components, or is that, you know, the all-comers OR are valid? And regarding PARG, could you also-- I may have missed it, but could you perhaps remind us which phase I dose you have expanded so far, as well as the potential or possibility of expanding future, higher doses in context of the phase I? Thank you. Sure. So, maybe I'll start with the second one first. So, Charles, we haven't disclosed what the expansion dose is. So first, I would just highlight that for IDE161, and that's mainly for just, you know, future IP reasons. Darrin, you wanna just finish off that one with IDE161, and then we can get into the Trodelvy and the, you know, kind of what our baseline view is as it relates to response rate and contribution of components. Yeah, I mean, the only thing I'd add on 161 is that, you know, we're still in a phase of optimizing the dose. You know, we're expanding out a dose that, as you saw, based on what Tim presented, we think is in the therapeutic range, has pharmacodynamic activity, likely to be active. But it's still, you know, early days. We don't have a huge safety set to evaluate, so we'll continue to enroll patients at this dose level. And, you know, if all works out, maybe we'll stay here. But we're being open-minded to what's necessary to deliver that molecule in the best way possible. And as you saw, there was one patient who had exposure that was much lower than the group, and that patient responded. So we're keeping an eye on where we're at and what the toxicity is, and we'll modify if necessary as we go forward. With respect to the Trodelvy combination, you know, you're right. I mean, it's possible that, you know-- To be quite frank, our expectations are fairly high with the combination, based on what we saw in the MTAP-deficient setting with Trodelvy. Now, admittedly, as you saw, it was a small sample size, retrospective analysis, et cetera. But that all being said, and based on mechanistic reasons, we think that the opportunity here is great. You know, as we establish the dose and schedule for the two molecules, if we see the kind of spectacular activity that we hope, you know, based on what we see with both molecules as a monotherapy, we'll be able to make some statements about what the contribution of components is. You know, similar to what we've done with darovasertib, right? We had two molecules there. We had to come up with a contribution of component argument there. As we talk to the FDA, I think a similar thing will happen here, but, you know, really, our expectations are quite high with this combination. And hopefully, with a relatively small number of patients, they'll be realized. So it's possible, you know, a year from now, we'll be able to tell you a lot about what that combination's doing. Great. Thank you. Okay, the next question will come from Yigal Nochomovitz from Citibank. Yeah. Hi, Yujiro and team. Thank you very much for taking this question. With respect to the Trodelvy combo idea, I was just wondering, since there's another ADC also approved in bladder cancer called Padcev, I know that's a different payload with auristatin, and that targets tubulin polymerization. Just wondering if you thought about that and whether there is any synthetic lethality argument with respect to biomarkers that may provide a platform for synthetic lethality with that type of mechanism in conjunction with an MTAP inhibitor. Thanks. Yeah, we, we appreciate the question, Yigal. So first, maybe I'll just lead with, you know, we have looked at the MOA around this, and, you know, we were very deliberate in our strategy with Trodelvy. And I would say very important here is that it's a topo payload. But, Mike, do you wanna go into further detail here? Yeah, I think you hit the nail on the head. It's a great question, Yigal, and as you noted, the MOA of the payload is very important here. We're talking about a situation where the topoisomerase inhibitor really plays into the mechanism of action to get the synergy that we're looking for, and so we're quite focused on the ADC with that payload to be able to deliver benefit in this combination setting. Okay. Thank you. A bunch of other questions. I think, early in the presentation, you referenced the MTA SAM ratio. Is that something that could function as a biomarker down the road, as a or a predictor of response in this setting, or that's sort of too theoretical right now? Well, that's an interesting idea. I mean, the question is: how would you measure that? This is a ratio that's present in the tumor itself, that is actually at baseline read out by SDMA. And you know, people have been doing that, looking at baseline SDMA, to try to understand whether the tumor sample in that particular patient has an inhibition of the PRMT5 pathway to begin with, which would be an indication of a reasonable MTA SAM ratio. But the really important thing here, Yigal, is that when you put 397 on these tumors, you're really dramatically enhancing that MTA SAM ratio. From a mechanistic standpoint, that is really key because you're now getting more of the PRMT5 antagonist in those cells to bind PRMT5, and you are promoting the ability of an MTA cooperative PRMT5 inhibitor to bind PRMT5. So we're, we're very excited about that from the mechanistic standpoint of optimizing target engagement, and really squashing PRMT5 activity in those MTAP null cells. And the hope there, Yigal, is that we can get away from needing additional biomarkers to be able to understand the patients that will respond, because MTAP status itself will be more representative of response with the combination, as compared to monotherapy, where you really need a pre-existing optimized MTA SAM ratio, which only is controlled by nature, rather than being controlled by the drug combination. Okay, makes sense. And just- I'll just put in one more. Going on the PARP, data, I guess it was kind of interesting that you saw the responses in the patients, that are typically, not treated with the PARP inhibitors. So I'm just wondering if the prior treatment with, with PARP in- for the ovarian, to ovarian and the breast cancer patients, presumably they were previously treated with PARPs. You know, is that a, perhaps a resistance argument with respect to whether PARPs should work downstream of the PARP drug? I think it's still early days and, you know, that's a patient population of great interest to us. Obviously, that's the patient population that the FDA gave us fast track designation, which was ovarian and breast cancer subjects who had failed standard of care therapy, had prior PARP inhibitors, and had homologous recombination deficiency. So I think it's still early days. We have small number of patients. It is intriguing, the fact that we've seen responses in tumors that typically don't respond to a PARP inhibitor. But we suspect we're gonna see responses in patients who had previously seen PARP inhibitors also. You have to remember, this is a phase I patient population also. I was looking at the number of prior lines many of these subjects had, and it was something like four-five prior lines. So these are, you know, multi-resistant subjects. So again, remember, dose escalation in phase I trial is all about safety. If you see efficacy, you're onto something. We obviously have seen efficacy. We're definitely onto something, and we're gonna be moving more towards trying to get earlier line subjects on the study. And I think, you know, seeing responses after PARP inhibitor therapy, it doesn't seem unlikely to me, but we'll, we have to prove that in the study. Great. Thanks. Thank you, Yigal. The next question comes from Christopher Liu at Leerink. Hey, guys. Thanks for the questions. So just two questions from me. So first, on IDE161, in terms of ER-positive, HER2-negative breast cancer, do you guys see value in combination? And if so, when could we start to see some progression towards that development pathway? And then in terms of the new target opportunity in MTAP null. Where exactly are you in terms of the development there? Is it kind of closer to lead optimization earlier, or is it closer to kind of IND? Great. Yeah, so Chris, maybe for the first part of the question, Darrin, do you wanna take that? Could you repeat it again? I kind of got lost listening to the second one. Sure, yeah, no worries. So I guess my question is, do you see value in combination? And if you do, when can we start seeing some progress towards combination? Yeah, definitely we're definitely looking into combinations that make the most sense. As you know, many people are testing PARP inhibitors with everything, and being very disappointed, you know, just in terms of toxicity, et cetera. And we think we can do better there. We're open-minded to combinations. We're talking to people about combinations. We have some really great ideas about combinations, and you're likely to be hearing something about that pretty soon, where we're headed in that respect. So yes, a PARG inhibitor, we think, has the ability to stand on its own two feet. However, you know, combinations make sense. Everybody who wants to do it with a PARP inhibitor can. We ought to be wanting to do it with a PARG inhibitor. We think we can, and so you'll be hearing more about that very, very soon. Great, and then the second question, Mike, as it relates to the new MTAP opportunity we shared today, and I would just say high level, kind of where we are. Yeah, Chris, we are in a situation where we are driving very aggressively to be able to get a clinical development candidate as quickly as possible. So, given that we're shooting for a clinical development candidate in 2024, gives you an idea of where we are in the program right now. Got it. Thank you. Thank you. The next question comes from Corinne Jenkins at Goldman Sachs. Good morning. Maybe a couple from us. First, how should we think about the scope for additional potential combination programs with 397? Should we look for more non-PRMT5 type combinations a la this deal today? Or, you know, how should we think about that? And given, in a related question, what you said about needing multiple combinations across the MTAP null space, is there a specific reason you selected bladder cancer for this kind of combination? And what factors do you expect to guide your decision on alternative combination opportunities, in different tumor types? Sure. So Corinne, I'll take that. So I think on the MTAP deletion combination, specifically with 397, I think all that we can say is there's several different discussions that are ongoing on that front. But we obviously feel very good about our relationship with Amgen and obviously our new partnership with Gilead. And we do think, you know, we're sort of covering our bases on what other possible combinations could be in place, whether that's with our internal portfolio or external opportunities. In terms of the tumor type focus in bladder cancer, and I think Mike walked through some of that, we felt, at least as it relates to the Trodelvy combination, bladder was really the most obvious place to start. There are other indications that we're considering there, but I think here, you know, in terms of proof of concept, starting in bladder cancer makes a lot of sense. And then obviously with Amgen and PRMT5, at least right now, our expansion focus is in lung cancer. But with that said, you know, we appreciate there could be several additional indications as well for that combination that we would consider moving forward. Mike or Darrin, anything additional you would add there? Yeah, I would just say, you know, regulatory path, Trodelvy is approved in bladder cancer, so more straightforward there. Mechanistically speaking, makes a lot of sense. The fact that we've seen enhanced activity in the bladder cancer patient population with Trodelvy, with an MTAP background, just makes the biology intriguing, makes us think that we're on the right track. So for all of those reasons, the stars aligned seemingly best for bladder cancer. And the fact that we've seen activity with our own molecule there makes us very bullish, to say the least, that the combination, you know, really has a great chance to show something. And like I said earlier, our expectations aren't low for this combination, they're high. So it's just the fastest path to POC for the combination, and I think we'd certainly be open-minded beyond bladder cancer too, if we're very effective there. Okay. The only thing I would add to that is, you know, this is a situation where we think the MOA is really enriched in that tumor setting, with respect to the metabolic liability. And that's also something that's special with a MAT2A inhibitor, to be able to get into that space and help Trodelvy work better. Great. Maybe, one final one from me. Outside of the tumor type, is there anything else you can share on the patient baseline characteristics in the colorectal and endometrial patients that had the response to 161, versus some of the breast and ovarian cancer patients? And in particular, do we know if those endometrial or CRC patients had prior PARP therapy? Darrin, do you wanna-- Yes, yeah, you know, without getting into the details, one of the main details I can tell you that's relevant here, really, because it's a small sample size, and I hate to compare demographics across a small sample size like that. But the one question you had that was very relevant, I think, is, you know, did they have PARP inhibitors before? But as you know, colorectal cancer and endometrial cancer, that's not where PARP inhibitors are approved, so therefore, those subjects did not see prior PARP inhibitor therapy. Great. Okay, thank you. Thank you, Corinne. Okay, and I think we have time for one last question. The question will come from Zegbeh Jallah at Capital One. Hi, guys. Thanks for the update. Just two quick ones here. I think the first one, you know, just because the deal was announced, and I know you've mentioned other MTAP targets in the past. So I was just wondering where you are with those other targets, and are you thinking about possibly combining those with Trodelvy as well? And then the second one is really just for Ramon. I think Pol theta is gonna be a big program for IDEAYA. So I was just wondering, if you could provide any clarity around, you know, what we might see some data from that program. I know the first patient was in just November, but I was just wondering if you could provide some color on the cadence of data. You know, is it gonna trickle out over time, or are you gonna wait until you have a, you know, large amount of data to present, or anything like that would be helpful? Sure. So, Zegbeh, for your first question, in terms of other assets for Trodelvy combination, I would say right now, our primary focus is with IDE397. And we do think there is a unique MTA with MAT2A versus PRMT5, around some of the biology Mike walked through, around the purine pyrimidine synthesis pathway, that we believe may differentiate MAT2A versus PRMT5. Mike, anything else you would add there, just with-- Yeah, I only add, I think-- Perspective. Yeah, I think, Zegbeh, you were also maybe asking about some of the other combination opportunities that we're pursuing, and obviously, things are going very well with Amgen, and, you know, Darrin can comment on that, if he wants. And we have close relationships with Amgen with respect to that PRMT5 combination in non-small cell lung cancer. The theme here for us with these various combinations is, as you know, lung cancer has been-- All cancers, very heterogeneous mechanistically, and we're really going to be needing multiple shots on goal to be able to take care of these tumors, and we're trying to be very, very judicious with respect to following the data, to put the best combination into the best setting. And we're also kind of delighted with the fact that many of these combinations seem to be lining up with mechanistic enrichment in various tumor types, which I think is really going to be able to simplify our developmental strategy. I'm sorry, Zegbeh, but just your second question, I just wanna make sure w e answer your question correctly. But can you just a little more color? Yeah, the second one was just for Ramon, asking about, you know, any color on how they plan to provide updates on the Pol theta program. Is it gonna trickle out, or is it gonna be a big reveal at a medical meeting, or something like that? Sure, yeah. I mean, I think here, you know, as Ramon from GSK mentioned, dosing, you know, just, just begun in November. You know, we would just wanna be in coordination on, on future guidance on that. But, hopefully, we'll be able to give more color as, as we get into 2024. Got it. Thank you. Sure. Okay, I think this concludes the Q&A session. I'll turn the call back to you, Yujiro, for concluding remarks. Great. Thank you, again, for everyone's time, today, for participating on IDEAYA's 2023 Investor R&D Day event. Wish everyone a wonderful happy holidays, and we can now conclude the call. Thank you very much, operator.