Good morning, welcome to the IDEAYA 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. I would now like to turn the call over to your host, Yujiro Hata, President and Chief Executive Officer. Please go ahead, sir. Good morning, and welcome to our 2022 Investor R&D Day. My name is Yujiro Hata, and I'm the founder and Chief Executive Officer of IDEAYA Biosciences, and I'll serve as your host today. Please note we will be making forward-looking statements today, and please refer to our SEC filings as appropriate. I would like to first start with welcoming our registered online listeners and provide a special thanks to our KOL speakers for their participation. Today, we have brought together a phenomenal lineup of speakers that bring deep expertise and are the foremost leaders in oncology spanning basic research to clinical development. Our KOL speakers today will be Dr. Frank McCormick from UCSF, Dr. Carol Shields from Thomas Jefferson University, Dr. Karlene Cimpric h from Stanford University, Dr. Mathew Garnett from the Wellcome Sanger Institute, Dr. Timothy Yap from the MD Anderson Cancer Center, Dr. Ben Schwartz from GSK. To our KOLs, we are grateful for each of your time and very much look forward to hearing your deep insights today. To facilitate a smooth presentation, I will ask each speaker to please note, next slide, when you would like your slide advanced. In terms of today's agenda, we'll first begin with the synthetic lethality paradigm, which Dr. McCormick will kick us off. Next, we'll go through darovasertib to clinical evaluation in the neoadjuvant uveal melanoma space, which Dr. Carol Shields will walk us through. Next, Mike White, our Chief Scientific Officer, will go through combination approaches and MTAP deletion. Then we'll go into the section around our DDR synthetic lethal pipeline. Dr. Karlene Cimprich will kick us off on targeting replication stress as an emerging synthetic lethality paradigm. Dr. Tim Yap will cover IDE161, which earlier today we announced the IND filing for our PARP inhibitor, and he will also walk through that clinical development plan. Dr. Mathew Garnett from the Sanger Institute will then cover Werner Helicase. Dr. Ben Schwartz from GSK will finish us off with Pol Theta, and we'll go into closing remarks and analyst Q&A. With that, we'll have Dr. Frank McCormick from UCSF kick us off. Take us away, Frank. Okay. Thank you, Yujiro. Good morning, everybody. I'd like to explain to you the concept of synthetic lethality, which is at the core of IDEAYA's technology and a really important paradigm in cancer therapy. Synthetic lethality occurs in genetics when the simultaneous perturbation of two genes results in cellular or organismal death, whereas the perturbation of individual genes has no effect. In cancer, this translates to a synthetic lethal target. It's a protein that is dispensable in normal cells but becomes essential in cells expressing an oncogene or losing a tumor suppressor. This protein is therefore an ideal cancer target. This little cartoon explains how this works, and I'll give you a couple of examples to clarify it further. In the bottom left, we have two genes, A and B, which are expressed in normal cells. Everything's good. In the tumor cell on the left, in this case, gene A is mutated either because it has a direct role in developing cancer or because it's a bystander in some mutational event. A is missing in these cells. The point here is when we treat these cells with an inhibitor of protein B, in the normal cells, nothing happens because B is not essential in the presence of A. In the cancer cell, the cell is killed. Again, this makes it a, this concept a perfect paradigm for treating cancer because the target is essential in the cancer cell in the context of mutations, but is not essential in normal cells because of the presence of other genes which makes it non-essential. I'll just show you a couple of examples just to explain how this works perhaps a little more clearly. The next slide, please. This is a classic example of synthetic lethality in cancer drug development, the synthetic lethal relationship between PARP inhibitors and BRCA1, BRCA2 mutations. The way this works is in normal cells, if a cell acquires a single-strand DNA break, this can be repaired by the enzyme PARP, and everything is okay. In the second panel, in the case of normal cells again, if we inhibit PARP with a PARP inhibitor, the single-strand break cannot be repaired by PARP, obviously. Luckily, BRCA1 and BRCA2 can take over and fix the damage to the DNA using a somewhat different biochemical mechanism. In this case, the cell survives because BRCA1, BRCA2 fixed the damage in the absence of active PARP. In the bottom panel, obviously in a tumor cell in which the BRCA1, BRCA2 complex is defective for some reason, if we now inhibit PARP, then the single-strand break cannot be fixed, and the cell then dies. The lack of a backup system, the BRCA1 system, enables PARP to kill cells in the tumor cell environment situation, but not in normal cells because of this backup of the BRCA1 complex. Next slide, please. This shows a slightly different take on the synthetic lethal concept in the world of signal transduction. In signal transduction, many pathways are redundant in normal cells. In this case, I show that KRAS activates RAF kinases, of which there are three varieties, A-RAF, B-RAF, and RAF 1. If we ablate any one of these RAF proteins, the cell doesn't really care because they have functional redundancy. However, we find that in a cancer cell with mutant KRAS driving the oncogenic process, the oncogenic signal from KRAS goes exclusively through RAF 1. This means if we ablate RAF 1, then the tumor cell driven by KRAS will die, whereas normal cells will tolerate that ablation because of the redundancy between the RAF, three RAF isoforms. Unfortunately, we don't have a way of ablating RAF1 as a therapeutic modality at this point in time, but this just makes the concept that in normal cells, redundancy makes the cells able to take these kind of hits. Next slide, please. Now we can identify these synthetic lethal relationships by a deep understanding of the pathways involved in DNA repair and related activities shown on these very complicated pathways on the left, or by understanding the signal transduction networks shown on the right panel. The scientists at IDEAYA and the advisory board members are indeed experts in these areas and can certainly identify novel synthetic lethal partnerships based on their deep understanding of these pathways. Next slide, please. In addition to analyzing literature and databases which explain how these pathways work, IDEAYA has developed novel methods for identifying new synthetic lethal pathways using CRISPR technology and other state-of-the-art technologies for identifying functionality in normal cells and cancer cells, and identifying new relationships that could be exploited by using the synthetic lethal paradigm. That's one of the real major strengths of IDEAYA, the ability to integrate public databases, novel techniques to identify and prosecute synthetic lethal targets. Thank you. I think that was my explanation of synthetic lethal paradigm. Thank you. Great. Thank you so much, Dr. McCormick, for kicking us off. We'll now go into the next section, which I'll go through just two slides here on IDEAYA's vision, strategy, and broader pipeline. Since the company's founding over 7.5 years ago, we've never been more excited about the progress at IDEAYA, and the field has made in advancing first-in-class synthetic lethality targets, both pre-clinically and clinically. We believe the next several years will be an extraordinarily exciting period for IDEAYA and the broader biotech and pharmaceutical industry in the field of synthetic lethality, as punctuated by the announcement of the IND filing to the US FDA on first-in-class PARP inhibitor IDE161 to treat PARP inhibitor-resistant BRCA1 2 breast and ovarian cancer patients earlier this morning. IDEAYA's vision and strategy to build a leading synthetic lethality-focused precision medicine oncology company has been driven by the following key strategic imperatives. First, since our founding, building a pipeline of first-in-class synthetic lethality programs that target high unmet medical needs has been at the epicenter of our corporate strategy, as exemplified by PKC inhibitor darovasertib, MAT2A inhibitor IDE397, PARP inhibitor IDE161, Pol Theta Helicase development candidate in our Werner Helicase program. Next, our underlying thesis to build IDEAYA has been on the importance of having a biomarker to enrich for the responder population, as clearly exemplified by the GNAQ/11 biomarker for darovasertib, the MTAP-deletion biomarker for IDE397, the BRCA HRD biomarker for IDE161, the BRCA HRD biomarker for the Pol Theta development candidate, and the high MSI biomarker for the Werner Helicase program. Next, we believe a key strategy to deliver maximal patient benefit will be through enabling compelling rational combinations such as PKC and cMET, MAT2A and PRMT5, Pol Theta and PARP, and Werner Helicase and PD-1. We will continue to invest in this area, specifically in the partnerships we form and with our next-generation synthetic lethality programs. From a strategic capabilities perspective, we believe the data explosion in synthetic lethality and cancer genetics more broadly creates a unique challenge, but more importantly, an unprecedented opportunity. With that, we have built leading capabilities in bioinformatics and AI machine learning to enable robust synthetic lethality target and biomarker discovery platform that will continue to enable our existing and next-generation pipeline. Next, in terms of strategic capabilities, IDEAYA has built truly differentiated drug discovery capabilities in synthetic lethality, where we now have a proven track record of successfully drugging historically challenging target classes such as helicases and polymerases. This point is exemplified by our structural biology success in resolving the co-crystal structures for the MAT2A, PARP, Pol Theta Helicase, and Werner helicase programs, amongst many others. Lastly, due to the breadth of our targets and patient selection biomarkers, we believe ctDNA will be a core technology that will enable our pipeline, as well as the broader field of synthetic lethality. For example, liquid biopsy technology provides a powerful platform to enable non-invasive patient selection and a non-invasive method to measure tumor pharmacodynamic response. Perhaps most importantly, it provides a potential tool to be able to intervene earlier in the patient's journey. Our pipeline slide provides a compelling snapshot of the progress we have made in executing on our vision and strategy. With three potential first-in-class clinical to IND stage programs with darovasertib, IDE397, and IDE161, and the GNAQ/11 MTAP-deletion and BRCA HRD biomarker settings. In the near term, we are targeting to have five potential first-in-class clinical programs with the advancement of Pol Theta Helicase to phase 1 in the first half of 2023, and a Werner helicase candidate nomination next year. Within our 2026 cash runway, we anticipate we will have six or more potential first-in-class synthetic lethality programs in the clinic, all of which with an associated patient selection biomarker to help enrich for patient response. The next sections of the presentation that will be presented by our KOLs and Chief Scientific Officer will provide key highlights and insights across each of these programs. With that, we'll move on to our next KOL speaker. It just gives me absolute great pleasure to introduce Dr. Carol Shields, who will walk through darovasertib clinical evaluation and neoadjuvant uveal melanoma. As several listeners are very aware, we're targeting to initiate a potential registrational trial in the metastatic uveal melanoma setting. We wanted to take this moment on R&D day to cover a new expansion opportunity, neoadjuvant uveal melanoma, which we know, we as well as various KOLs are quite excited about. With that, Dr. Shields, please take it away. Thank you very much. Good morning, everybody. Today I'd like to talk to you about uveal melanoma. This is the most common eye cancer, primary eye cancer in the United States and in Europe. This eye cancer develops from a mutation in the GNAQ, GNA11 region of the cell that leads to the PKC or the protein kinase C pathway. This is where darovasertib interacts and inhibits this pathway. This pathway leads to the MAP kinase pathway that eventually leads to the development of ocular melanoma. Darovasertib, or I'll call it Daro, is an investigational potent and selective PKC inhibitor that is administered orally. GNAQ and GNA11 mutations occur in over 90% of patients who develop uveal melanoma. This is a common pathway. Now in the bottom, we see two schematics. These were two preclinical in vivo experiments on primary uveal melanoma with GNAQ mutant cell lines. You can see on the left graph, there was a robust dramatic dose response to Daro. The black line indicates vehicle only, the blue line Daro 15 mgs per kg. The red, the orange, and the purple line with increasing dose, you can see the tumor volume was completely controlled with Daro. On the right graph, we see that Daro maintains sensitivity. The black line shows vehicle only with no response, and the purple line shows Daro causing tumor volume to drop down to zero. When we stop dosing, the volume eventually comes back, but it's still sensitive. If we redose, the tumor goes away again, and this is very important. Currently, there are no approved systemic therapies for uveal melanoma, and Daro could be the first approved systemic therapy for neoadjuvant uveal melanoma. Next slide. There's a high unmet need to improve patient outcomes with uveal melanoma, and Daro could fit this unmet need for neoadjuvant and adjuvant setting for the management of uveal melanoma. Currently, we treat uveal melanoma with eye removal or enucleation for patients who have large tumors, and those that have small and medium tumors, we're able to save the eye, but we need to use radiation. This leads to poor vision in about 80% of patients, blindness in these patients. To top that, metastatic disease occurs in about 50% of patients who have uveal melanoma, so this is a terrible disease to deal with. We need a neoadjuvant or an adjuvant systemic therapy because it could reduce or prevent micrometastatic disease and save lives. In addition, we might be able to save the eye by avoiding enucleation, and we might be able to shrink tumors to the point that the amount of radiation we need to give to the eye is much less, and patients may have lives saved. Eyes saved, and they may actually have some vision saved. This could impact 8,000-9,000 patients in the US and Europe. Next slide. There is preliminary clinical proof of concept from our colleagues in Australia for the use of Daro as neoadjuvant for uveal melanoma. In this waterfall plot, I show you 5 cases of patients who had primary uveal melanoma who received Daro in the neoadjuvant setting. The 3 blue columns indicate patients who had Daro monotherapy for only 1 month. You can see that the primary tumor in the eye showed a response in all 3 cases, with 10%-20% reduction in thickness. This is amazing. We've never had a drug to do this before. In the yellow column, this was a patient who had primary eye melanoma and metastatic disease, and Daro monotherapy for 2 weeks caused 75% reduction in the tumor in the eye, again, measured by PET scan and a very impressive response. The last purple column is perhaps the most amazing of the 5 cases. This patient had primary uveal melanoma and metastatic disease, received Daro and crizotinib for 10 months, and the tumor completely resolved with 100% tumor reduction. All five of these cases show consistent and clear evidence of response even within one month of the use of Daro. This provides a rationale to treat to the maximal response for clinically meaningful improvement in primary therapies. It should be stated that this was a well-tolerated oral treatment. I'd like to talk about that last column, the purple column on the next slide, please. This was a 50-year-old patient who had a large melanoma in his right eye. You can see on the MRI imaging, the top shows axial views, cross-sectional axial views, and the bottom shows cross-sectional sagittal views of the tumor. This patient received Daro and crizotinib. In the first, on the upper left, you see a baseline axial view showing the tumor filling almost half the eye. At month 5, next to it on the right, you can see a response where the red arrow is. Month 8, further response, and at month 10, on the far right upper level, there was 100% response. The tumor was completely gone. On the bottom, on the sagittal view, you see the same with the red arrow showing the mass at baseline month 5, month 8, and completely gone at month 10. This patient remains on treatment at 11 months, and this was 100% response. Again, very impressive. I've been in the field for 37 years, and we've never had a medication that could cause such dramatic response in the eye. Next slide. We have plans for phase 2 study of neoadjuvant and adjuvant Daro monotherapy treatment. This will be a phase 2 study. The neoadjuvant component will have 2 cohorts. Cohort 1 are those eyes that we would normally submit to enucleation. Cohort 2 would be those that we would normally treat with plaque brachytherapy. That's the small to medium tumors. Enucleation, the large tumors. We'll give neoadjuvant Daro and treat until maximum benefit with our definitive primary therapy to hopefully obtain organ preservation and vision preservation. After we deliver the definitive primary therapy, we will move on to adjuvant therapy, monotherapy of Daro, to look for relapse-free survival and useful vision in these 2 cohorts of patients. Again, for cohort 1, our goal is for the primary endpoint for neoadjuvant therapy of Daro. We would want eye preservation, so we could shrink the tumor and save the patients from having the eye removed and maybe move on to radiation. In cohort 2, our goal would be to reduce the tumor to a point where radiation does not impact the vision as much as it currently does. These neoadjuvant endpoints are anticipated to be proximal in time to the definitive primary therapy. Then our secondary endpoints for the adjuvant trial would be relapse-free survival and useful vision. Next slide. I'd like to thank you for allowing me to speak to you on the clinical applications of Daro monotherapy as neoadjuvant and adjuvant therapy for the most common eye cancer, uveal melanoma. Thank you. Great. Thank you so much, Dr. Shields, and it's wonderful to have your perspective as an oncologist and clinician, coming on 40 decades, in this important area. With that, we'll shift gears here. Pass it on to Dr. Michael White, our Chief Scientific Officer, that will go through mechanistic advances to support combinations to treat MTAP deleted tumors. Mike, take it away. Thank you, Yujiro. I'd like to start out by just harkening back to Frank McCormick's introduction. On the next slide, noting that IDEAYA's MAT2A inhibitor program was really launched to address disease that arises as a consequence of the most common homozygous deletion observed across all tumors. This occurs on chromosome 9p21.3 and disables a cell-intrinsic barrier to tumorigenesis by eliminating the CDKN2A and CDKN2B tumor suppressors. More often than not, this deletion also eliminates a nearby gene, MTAP, methylthioadenosine phosphorylase, and this creates an Achilles heel in these tumors that can be attacked by inhibition of MAT2A, a methionine adenosyltransferase. The mechanistic basis of this well-appreciated synthetic lethal relationship is illustrated on the left. I'll quickly go through that. Elimination of MTAP causes an accumulation of the MTAP substrate, MTA, methylthioadenosine. This is a metabolic intermediate that directly binds and partially inhibits the arginine methyltransferase PRMT5, and PRMT5 is an essential enzyme required for mRNA maturation. Inhibition of MAT2A reduces the cellular concentration of S-adenosylmethionine, SAM, the methyl donor required for PRMT5 activity, thereby further reducing PRMT5 activity in MTAP null tumor cells below the threshold required for life. Over there on the right, you'll see that IDE397 is a potent MAT2A inhibitor, reducing cellular SAM with a low, low nanomolar IC50. This in turn impairs PRMT5-dependent protein methylation selectively in MTAP null cells, which as expected, is selectively lethal in MTAP null cells. Based on the prevalence of MTAP deletions, this synthetic lethal relationship potentially arises in over 75,000 cancer patients per year. On the next slide, please, Andres. Consistent with this mechanistic data, clinically relevant doses of IDE397 display broad antitumor activity across MTAP null patient-derived xenografts derived from multiple tumor types. In the panel on the upper left, we're plotting percent tumor growth inhibition by IDE397, where 100% indicates complete tumor stasis and greater than 100% indicates tumor regressions. You'll note that while tumor control is histology agnostic, tumor regressions are enriched within distinct tumor types. As shown on the bottom left, maximal PRMT5 inhibition as measured here by drug-dependent reduction in tumor SDMA, the product of PRMT5. This is also enriched within distinct histologies. The most notable is squamous cell lung cancer disease with high M met need, where fully half of the models tested respond to IDE397 monotherapy with tumor regressions, middle column, top panel. As expected, tumors that shrink upon IDE397 exposure show marked perturbation of RNA splicing on drug, a key consequence of PRMT5 inhibition. You can see that on the bottom panel, contrasted with an example of a treatment-resistant tumor labeled here as PDX 7. This particular analysis employ replicate multivariate analysis of transcript splicing from ultra-deep RNA-Seq data. Collectively to us, these observations really indicate that MTAP deletion is necessary but not sufficient for a maximal antitumor response to PRMT5 pathway inhibition. Context matters. This became even more evident when we examined baseline PRMT5 activity in MTAP wild type versus MTAP null tumors. This was evaluated by SDMA staining of tissue microarrays of sections from over 600 PDX models, where MTAP status was confirmed by both NGS and IHC. As you can see on the top right panel there, in our most responsive tumor type, there is a highly significant reduction of SDMA accumulation in MTAP null tumors at baseline compared to MTAP wild type. Exactly what you would expect if the PRMT5 pathway was partially suppressed in MTAP null tumors due to the accumulation of MTA. On the bottom are a couple of examples that show you what the mean H-scores actually look like in this histology. You can see it's a big difference. Contrasting example shown on the upper right, here's a tumor type with no discernible differences in SDMA accumulation in MTAP null versus MTAP wild type, and we don't see regressions in response to IDE397 monotherapy in PDX models derived from this particular tumor type. Two take-home messages here. First, context matters, and we are leveraging this knowledge to prioritize our clinical POC strategy in tumor indications most likely to respond to monotherapy. Second, are there combination strategies that can broaden the frequency of deep therapeutic responses to IDE397 in MTAP cancers across histologies? We believe the answer to this question is yes, because we find that inhibition of MAT2A in MTAP null cancers confers mechanistic vulnerabilities to multiple clinically actionable synthetic lethal drug combinations relevant in multiple tumor types. I'll show you how we got there on the next slide. To identify rational IDE397 combination partners, we employed a comprehensive three-pronged approach. This dovetailed molecular profiling of IDE397 drug effects in vivo, computational identification of selective drug sensitivities in MTAP null cancer cell lines across the CCLE, and empirical high-throughput in vitro drug combination screens. As you can see in column 1, unbiased pathway analysis of IDE397-dependent gene expression changes in MTAP null PDX tumors revealed perturbations of RNA splicing, DNA damage repair, and mitotic spindle assembly as drug effects that are shared across tumor types. Notably, as indicated in column 2, single agent response to drugs that inhibit these same processes were enriched in MTAP null versus MTAP wild type cell lines. This suggests that the biology altered by IDE397 in tumors is already partially impaired by MTAP deletion. Finally, as indicated in column 3, an IDE397 drug combination with viability screen of over 400 compounds across multiple cell lines return hits that engage these same mechanisms, namely taxanes, platins, DNA damage enzyme inhibitors, splicing inhibitors, and anti-folates such as pemetrexed that synergize with IDE397 to kill MTAP null cancer cells. When you put all this together, these observations indicate that MAT2A inhibition can induce cell states that are now vulnerable to important approved chemotherapies and targeted therapies. This is important because it potentially provides a predictive biomarker strategy for multiple IDE397 synthetic lethal combination opportunities. That concept, chemically conferred synthetic lethality, is illustrated on the next slide. As shown there on the far left, we think that within disease contexts like squamous cell lung cancer, there's already an optimal cell state for a single agent intervention with IDE397. Importantly, in disease contexts that are suboptimal for monotherapy response, IDE397 exposure installs a new vulnerability selectively in the MTAP null setting that can be exploited with an appropriate combination partner. The two standouts for us are the folate cycle and the PRMT5 pathway itself. As noted in the center panel, a pemetrexed combination with IDE397 exploits the tight interconnectivity of methionine salvage, de novo methionine synthesis, and folate metabolism to disrupt purine and pyrimidine production required for rapid cell proliferation and resistance to environmental stress. As noted on the right, an MTA cooperative PRMT5 combination with IDE397 delivers maximal SDMA pathway suppression. I'll show you what these interactions look like in vivo on the next slide. On the far left there is a lung adenocarcinoma PDX model where the maximum benefit with IDE397 or pemetrexed monotherapy is tumor stasis or partial tumor growth inhibition. In contrast, the drug combination flips this phenotype into robust regression. Combination benefit was observed in other tumor types as well, and we are now testing this drug combination in the clinic. In the middle panel, you'll note complete responses in a lung adenocarcinoma model with a combination of IDE397 and an MTA cooperative PRMT5 inhibitor using doses well below those required for any notable single-agent activity. As much as 10-fold below, in fact. Similarly, on the far right, we saw tumor regression in a very challenging pancreatic cancer model exclusively in combination. Based on the strength of this preclinical data, we've begun a collaboration with Amgen to evaluate this combination in the clinic. On the next slide, the last slide for this section, our CAROL feedback advocates a novel combination development strategy for a MAT2A PRMT5 combination that employs a crossover dose escalation design to capitalize on compounds that are expected to show combination benefits at doses well below those required for single-agent activity. Based on the preclinical data, proof of concept could come quickly. With that, Jiro, I'd like to switch gears and introduce today's section on selective essentiality in DNA damage repair, another important therapeutic paradigm that holds great promise for many cancer patients. As Frank and Jiro alluded to, cellular genomes are constantly dealing with damage control due to replication errors and exposure to environmental stressors. As such, defects in the cellular machinery preserving genomic integrity lead to the accumulation of mutations that can promote cancer. They also lead to cancer cell-specific dependencies on backup DNA repair systems. This, of course, presents synthetic lethal opportunities to kill those cancer cells by dragging their backup DNA repair systems. IDEAYA's DNA damage response synthetic lethal pipeline aims to do just that and is maturing quickly. As you heard from Udro, a potential first-in-class PARG inhibitor, IDE161, is on target to enter the clinic early next year to address synthetic lethal opportunities in HRD cancers, including PARP inhibitor-resistant disease. PARG inhibition also has the potential to address a newly appreciated synthetic lethal opportunity with oncogene-induced replication stress. This is a widespread phenomenon in cancer cells whereby dysregulated DNA replication can generate a cascade of damage-producing lesions in tumor DNA. You'll be hearing about that from Dr. Cimprich and Dr. Yap in a moment. Our Pol Theta Helicase program in collaboration with GSK is also on track to enter the clinic next year as a potential best-in-class asset to drive deep and durable responses in combination with niraparib in patients with HRD cancers. Our Werner Helicase program, also in collaboration with GSK, has established preclinical proof of concept in cancers with high microsatellite instability, and we expect to nominate a clinical development candidate next year. You'll be hearing about Werner's from Dr. Garnett and Pol Theta from Dr. Schwartz. With that, Dr. Cimprich, I am completely delighted to turn the floor over to you to tell us about targeting replication stress as an emerging synthetic lethal paradigm. Thanks, Mike. Good morning, everyone. My lab is interested in understanding how genome instability arises in cancer cells. These two images here illustrate this instability in a couple of ways by examining metaphase chromosomes on the left and by sequencing on the right. What you can see in both are translocations and aneuploidy, or the loss or gain of whole chromosomes. What you can't see are the smaller changes that are also quite abundant in cancer cells, ranging from smaller insertions and deletions to point mutations. Next slide. Genome instability is one of the so-called hallmarks of cancer. With each segment of this circle shown representing one of the hallmarks articulated on the right. Genome instability is a driver of many of these hallmarks because it allows cells to accumulate mutations rapidly. Thus, cancers can more quickly gain the other characteristics that allow them to become tumorigenic. Next slide. Importantly, genome instability is often induced by DNA damage and by replication stress, which is also quite common in cancer. This is really the heart of what I do in my lab. Notably, there's been an intense interest in replication stress since it was learned that oncogenes and tumor suppressors, as well as activated growth factor signaling, can lead not only to sustained proliferation, but also to replication stress, thereby driving the genome instability that we just looked at. Next slide. What is replication stress? I want to define that more clearly with this illustration, which shows you two replication forks in the process of copying DNA and approaching in the center a number of potential barriers to replication fork progression. These can range from lesions in the DNA to secondary structures such as R-loops or limiting nucleotide conditions. These types of barriers can arise in cancer cells from alterations in metabolism that lead to oxidative damage, to defects in repair, changes in the control of DNA replication, or changes in nucleotide pools. When these barriers persist due to loss of resolution factors, the replication fork can slow at these barriers, causing so-called replication stress. While slowing itself is not necessarily a bad thing, a fork stalled at a lesion or other barrier is prone to double strand break formation and can be difficult to repair, leading then to breakage and rearrangement. To be clear, replication stress itself is not damage, but damage can lead to replication stress, and replication stress can result in damage. Next slide. Fortunately, the cell has a robust response to stalled replication forks, known as the replication stress response, and this response can be activated by many DNA-damaging agents, chemotherapeutic agents, and by oncogenes. That helps slow down cell cycle progression and DNA replication. It can also help promote and coordinate different forms of repair, and in the extreme, promote cell death. ATR is a key regulator of this response, acting at the level of DNA to effectively sense the damage that causes stress. A question we asked ourselves was how does the ATR kinase acting upstream of the CHEK1 kinase detect all of these different types of damage? A key finding that's been made is that these different types of damage effectively activate ATR in S-phase by turning those lesions into the same common intermediate as shown on the left. That intermediate results when the replicative helicase moves past a lesion or barrier and continues to unwind the DNA, but the DNA polymerase stalls at that lesion. That leads to the formation of single-stranded DNA and other structures that can be a platform to recruit the single strand of binding protein RPA, then ATR and its activator TopBP1, inducing the stress response. It's not really the different lesions per se that activate ATR, but their common effect on DNA replication. Importantly, ATR activation effectively stabilizes forks and prevents the dangerous continuation of replication. We now know that loss of ATR, its inhibition, particularly under conditions of replication stress, can lead to extensive DNA break formation. This replication catastrophe, which is sometimes called, is shown on the right, and can result from premature origin firing and premature cell cycle entry. Because cancer cells have high levels of replication stress, they may rely heavily on this pathway to keep them alive. That's led to the idea that ATR and its effectors could be targeted in the clinic. There's still a lot about this response that we don't understand, and resistance to ATR inhibitors can emerge, at least in cell culture systems. Moreover, it's important to recognize that cancer cells also somehow tolerate replication stress and damage. Despite their high levels of stress, they somehow continue to replicate their DNA, and they don't persist in this arrested state. An important question is how is it that they tolerate that damage and that stress? Next slide. One process really relevant to the idea of tolerating damage and replication stress is replication fork reversal, which can be observed following a variety of different types of DNA damage. That idea is shown here. Fork reversal is a rearrangement of the replication fork that occurs when the two parental strands, shown here in black, are re-annealed, sort of like a zipper being closed. That's accompanied by the hybridization of the two nascent DNA strands, which are shown in green, to form a fourth arm at the fork. This rearrangement effectively backs up the progressing fork, slowing its movement. When a lesion is present, which is cartooned here in yellow, it puts that lesion back into the context of double-stranded DNA so that repair can occur. It turns out this is a relatively common event observed by electron microscopy at about 25% of forks in cells treated with DNA-damaging agents. Next slide. Fork reversal is actually an active process. Mediated by a variety of enzymes, among which are a set of ATP-dependent chromatin remodelers, which help reverse the fork and form that structure, and another enzyme called PARP, which stabilizes this structure. Fork reversal can also be countered by other processes that promote fork progression, and inhibition of certain steps in these different pathways can really tip the balance between these processes to prevent persistent fork stalling. To introduce you to these pathways, one pathway that allows the fork to continue in the presence of damage is translesion synthesis, or TLS, shown on the lower right. During this process, the cell uses an alternative polymerase that can accommodate a lesion in its active site to continue DNA replication. Another process that can occur is known as re-priming, and this involves the PrimPol enzyme, which has both primase and polymerase activities. As shown on the upper right, PrimPol can bind single-stranded DNA to restart DNA replication downstream of a lesion. That also keeps the fork moving, but leaves behind gaps in the DNA that can be filled either by TLS or by other recombination-like processes. While both processes are thought to be mutagenic in nature, they can allow replication to proceed, and they can help the cell tolerate damage. Hence, they can lead to the emergence of resistance. It's worth noting, though, that some mutations observed in cancer can alter this balance. For example, treatment of BRCA-deficient cells with cisplatin can lead ultimately to upregulation of PrimPol, driving the cells toward this outcome. We've also observed that the loss of a protein called HLTF prevents fork reversal, promoting continued replication and resistance to replication stress-inducing agents and ATR inhibitors by allowing PrimPol to act. Next slide. Just to sum up that idea and a number of others, I think a lot of new work is suggesting that the replication fork is a highly adaptable process, and that there's remarkable plasticity in the ability of the fork to respond to stress that cancer cells take advantage of to tolerate that stress by tweaking the balance of these pathways. This makes some of these pathways potentially interesting new targets. For example, PARG inhibition prevents the restart of reversed forks, keeping forks in the state in the lower right and unable to adapt to or tolerate replication stress by continuing through other processes. Similarly, TLS polymerase inhibitors can block continued synthesis and gap filling on the left. Very recent evidence also suggests that Pol Theta may play a role, along with TLS, in filling gaps at the fork, creating an opportunity for use of inhibitors to this enzyme as well. Next slide. Our interest in understanding how cancer cells tolerate and respond to replication stress also led us to another question, and that is: What are the natural sources of damage and replication stress in cells that activate proteins like ATR? To get at this years ago, we did a genetic screen asking what pathways suppressed damage in human cells. Somewhat to our surprise, one of the most common sources of damage we identified were perturbations to RNA processing and to splicing. This observation ultimately led us to realize that R-loop structures, which are shown here, are likely an abundant source of replication stress in human cells. First, to explain an R-loop, this is a structure that forms co-transcriptionally when newly synthesized RNA rehybridizes to DNA near RNA polymerase II to form a hybrid and a stretch of single-stranded DNA. You see that in the center here. What we found is that there are many different perturbations that can cause the formation of these structures, which can in turn cause DNA damage, and in particular, DNA double-strand breaks. At the same time, it's known that these structures are present throughout the genome at low levels, and they have physiological roles in the cells, for example, controlling transcription. The cell seems to dedicate a lot of resources to prevent the accumulation or persistence of R-loops, and they're turned over rapidly by helicases, nucleases, and some repair factors like the tumor suppressor genes BRCA1 and BRCA2. Next slide. Another complexity in our genome is also that transcription and replication happen on the same template, and that can create conflicts with R-loops at the center of many of these conflicts. To better understand these collisions, we actually studied the interaction of R-loops with the replication fork, approaching in both orientations, as you've seen here. While both types of collisions are a problem for the cell, what we learned is that cells can activate ATR when the replication and transcription machineries collide head-on, but they could activate a different damage response kinase, ATM, when they're moving in the same direction. Recent studies have indicated that ATR activation seen in the context of R-loops may help prevent damage at the stalled forks. ATR inhibitors may be effective in settings where R-loops are elevated. For example, MAT2A inhibition could promote R-loop accumulation in MTAP null tumors by inhibiting mRNA splicing, elevating replication stress, particularly in combination with ATR inhibitors. Next slide. In recent years has also come the discovery that cells can signal the replication stress response to the tumor microenvironment by activating a pro-inflammatory response. This can happen in a couple of ways. For example, in certain conditions, stalled fork processing has been linked to the formation of cytoplasmic single-stranded DNA, shown on the top here, and that can lead to activation of the cGAS-STING pathway in an interferon response. Additionally, aberrant DNA replication can lead to mitotic defects and micronuclei formation, as shown on the lower right, that appears to activate a related pathway through cGAS as well. While activation of this pathway could, in principle, lead to cell death, it also appears that cancer cells have often adapted to this state. Next slide.. Recently, we've also made the observations that R-loop processing can lead to activation of this response. Specifically, we found that deregulation of nuclear R-loops by various means leading to their accumulation, leads to a problem with their clearing and their efficient resolution. We find that these persistent R-loops can be processed by two endonucleases, leading to the accumulation of RNA-DNA hybrids in the cytoplasm and DNA breaks. That, like single-stranded DNA, can in turn trigger IRF3-mediated immune signaling through cGAS and TLR3, and ultimately lead to apoptosis and other responses. Next slide. I'll just kind of conclude by saying that our efforts, and that of many labs, to understand fundamental mechanisms of the replication stress response have really shown that replication stress is a common characteristic of cancer with many causes and many consequences. We've also learned that cancer cells can critically depend upon this response and have found ways to adapt to and really tolerate that stress. This really opens the doors for new treatments, of course. ATR inhibitors and others targeting the stress response pathway are now under active clinical investigation. IDE397, as mentioned earlier, may be an intriguing combination partner in this setting due to its ability to safely promote R-loop accumulation in MTAP-depleted tumors. As you'll hear from Timothy Yap in a moment, PARG inhibition can also be attractive, inducing the collapse of stalled replication forks. This may be a new target opportunity in tumors that have high replication stress. Finally, there's a lot of emerging, very recent evidence that implicates Pol Theta in the resolution of replication stress-associated DNA damage by preventing the conversion of single-stranded DNA gaps into double-stranded DNA. I suspect that we've really probably just begun to tap into the potential of drugs targeting the damage response, the replication response, and R-loop processing pathways. There will be many ways to think about this in the future. I'll just wrap it up there. Thank you for your attention. Great. Thank you so much, Dr. Cimprich, for a really elegant walkthrough of very complex biology. Thank you so much for that. With that, gives me great pleasure to introduce Dr. Timothy Yap from MD Anderson Cancer Center. As was earlier noted, we announced earlier today the IND filing on potential first-in-class IDE161. And we're delighted to have Dr. Yap introduce the program as well as the molecule and the first outline of the proposed clinical development plan. With that, Dr. Yap, we'll hand it off to you. Thanks very much, Yujiro. Thanks again for the very kind invitation, and thanks, all, for being here. PARG really is a poly ADP-ribose glycohydrolase that removes the PAR chains from proteins that have been modified by PARP. As you heard Frank describe earlier, PARP activity initiates the repair of damaged DNA by recruiting DNA repair proteins to the DNA break. PARG is the enzyme that actually completes the DNA repair cycle by releasing those DNA repair proteins from the restored double helix. This activity places PARG in a clinically validated pathway that is synthetically lethal with HRD. The hypothesis here is that the position of PARG in the PARylation cycle really presents opportunities for a PARG inhibitor that are distinct from PARP inhibitors. These include tolerability, activity in the PARP inhibitor-resistant BRCA-mutated cancers, and a potential to work in tumors beyond BRCA and HRD. The latter is particularly evident in the context of replication stress, which, as you just heard from Karlene Cimprich, is a potentially widespread phenomenon in cancer cells that leads to a heavy reliance on PARG to maintain replication fork stability through S-phase. Where things get really interesting is that PARP and PARG inhibition in the setting of replication stress can lead to two distinct cellular outcomes. PARP inhibition promotes unrestrained fork progression and DNA damage that needs to be repaired by translesional synthesis, template switching, NHEJ, MMEJ or HR. In contrast, PARG inhibition leads to stalled replication fork reversal, creating these so-called chicken foot structures, which have not resolved as followed by endonucleolytic attack, pangenomic replication fork collapse and mitotic catastrophe. This difference potentially accounts for the observed distinct cellular response to PARG inhibition versus PARP inhibition, and leads to a synthetic lethality concept, whereby any context that increases the number of stalled forks in a cell would be expected to increase reliance on PARG activity. The data to date suggests that replication stress is indeed a tumor-selective vulnerability that can be exploited by PARG inhibition. Next slide, please. The clinical candidate, IDE161, is a potent orally bioavailable PARG inhibitor that was discovered through extensive chemical compound screening in a biochemical PARG activity assays, coupled with crystal structure-based design strategies. If I can draw your attention to the right, cellular PARG inhibition with IDE161 results in accumulation of PAR chains and the induction of the DNA damage response pathway in HRD cancer cells, consistent with the expected mechanism of action. Next slide, please. The team at IDEAYA have tested the response of over 260 molecularly characterized cancer cell lines to IDE161. They found that the most sensitive cell lines are shown to the left of the vertical dashed line. The first panel had molecular features associated with defective DNA repair systems, high PARylation activity and replication stress. As shown, an example of this is shown in a middle panel, where you can see very strong enrichment of HRD as defined by mutations in key HRR genes among breast cancer cell lines with low IDE161 IC50s and the p-value here is 0.008. Finally, as shown in the right panel, it's important to note that many HRD cell lines are indeed selectively sensitive to PARG inhibitors versus PARP inhibitors. Next slide, please. Consistent with all this, there are indeed many instances where IDE161 induces strong regression of HRD tumor models in vivo. As shown on the left, these responses can be quite durable over time at well-tolerated doses. As expected from IDE161's mechanism of action, we see very nice PAR chain accumulation in tumors as early as 1 hour post-dosing, which we expect to be able to follow in patients as a robust pharmacodynamic response biomarker. On the right are examples of IDE161-induced regressions in BRCA-mutated breast cancer PDX models that are only marginally responsive to PARP inhibition using the maximum tolerated dose of niraparib. Next slide, please. IDE161 has demonstrated a favorable safety profile in preclinical pharmacology and toxicology studies. This differentiates it from PARP inhibitors. Consistent with myelosuppression observed in a clinic, PARP inhibitors show clear evidence of myelosuppression in non-clinical toxicology studies at systemic exposures that are associated with clinically relevant doses. As shown in the graph on the left, PARP inhibitors show a reduction in circulating red cells and neutrophil counts in the rat following repeat oral dosing for either 4 weeks or 13 weeks. IDE161 did not show decreases in these parameters in the rat at exposures equivalent to or several multiples of the systemic exposure at the estimated human therapeutic dose. These data point to the possibility that the combination of IDE161 and chemotherapy may be better tolerated than PARP inhibitor chemo combinations tested to date. As noted in the bullets on the right, the human efficacious dose predicted is based on the preclinical dose required to induce tumor regressions, as you saw in the previous slide, and we expect to get there within the first few cohorts of our dose-finding study. Also shown here, IDEAYA has successfully developed a robust IDE161 API synthetic process and a late phase ready tablet formulation, and produced high-quality GMP tablet batches in 3 strengths. Next slide, please. The clinical development plan will be built and driven directly on the pillars that have been laid out from the preclinical work, namely the ability to impact tumors that have evolved through prior therapies with platinum agents and/or PARP inhibitors. Patients who have progressed on PARP inhibitors certainly represent an ever-increasing population with high clinical unmet need and unfortunately currently very few available effective therapeutic conditions, options. The trial will also provide the ability to impact tumors that are not expected to respond to PARP inhibitors. The potential to move beyond HRD as we characterize the additional tumor cell states that define PARG inhibitor sensitivity. Finally, the preclinical safety profile predicts a large therapeutic window to both maximize monotherapy benefit while allowing a broad potential for combinatorial synergies that are not directly limited by myelosuppression. Thank you very much for your kind attention, and back to you, Yujiro. Great. Thank you so much, Dr. Yap, for that terrific walk-through, we look forward to collaborating with you as this program proceeds in the clinic. Thank you again, very much for that walk-through. Next speaker will be Dr. Mathew Garnett from the Wellcome Sanger Institute, to go through Werner helicase. Dr. Garnett and his lab has tremendous experience on this target and high MSI, and I know has also collaborated with GSK in the past, we're very grateful for your time today to walk through this program and this broader space of Werner helicase. Great. Hello, everybody. It's a pleasure to be here. Microsatellite instability is caused by a deficiency in the DNA repair process called mismatch repair or MMR. It's actually quite co-common in colorectal cancer, endometrial cancer and gastric cancer. It occurs at a lower frequency in a broad spectrum of other cancer types. It's estimated there are approximately around 600,000 MSI patients worldwide each year. These patients respond reasonably well to immune checkpoint inhibitors, as observed here in some of the results from the KEYNOTE-158 trial, where the waterfall plot is showing response. There do remain a significant number of patients who do not achieve a durable response to this treatment and for whom alternative treatments are needed. Next slide, please. Now, we and others have shown, using genome-wide CRISPR-Cas9 screens in cancer cell lines, that microsatellite unstable or MSI cancer cell lines have a synthetic lethal dependency on Werner helicase, shown here by the long fold change in viability following Werner knockout. Now, this is extremely prominent in these MSI-predominant lineages, such as colorectal cancer, where MSI most frequently occurs. In stark contrast, microsatellite stable cell lines, those that are proficient in mismatch repair, are not dependent on Werner helicase. Next slide, please. Now, Werner is actually an extremely fascinating gene, and loss of Werner causes an autosomal recessive disease that's associated with premature aging, as illustrated by this woman here with a mean survival of around 50 years. Werner helicase has two enzymatic activities, as a helicase and an exonuclease activity, has wide roles in maintaining genome stability through activating and resolve multiple different DNA substrates. Next slide, please. We've shown that using tumor xenograft studies, a genetic knockdown of Werner leads to tumor growth suppression, as shown here, by the yellow line following genetic ablation of Werner, this is observed selectively in MSI cells. On the right-hand side, these data show using functional rescue studies following Werner knockout that reconstitution of cells with wild type Werner helicase or an exonuclease deficient version was able to rescue the loss of viability. Actually if we reconstituted with two different helicase-deficient versions of Werner helicase, we did not rescue this viability effect. This indicates that it is specifically the Werner helicase activity that is required and essential for microsatellite unstable cancer cells. Next slide, please. The mechanism of Werner dependency is increasingly being understood. As shown on the left-hand side, MSI causes the accumulation of these TA dinucleotide repeats in the DNA of cells. These then go on to form secondary structures in the DNA. Werner is actually re-required to resolve these three-dimensional structures. Of course, if you then knock out Werner, the cell is unable to resolve these structures. This leads to deformation of DNA double-strand breaks, extensive DNA damage, and ultimately cell death in the absence of Werner helicase. Next slide, please. A future application of any Werner-targeted medicine will likely be in the clinical setting of treatment-refractory disease. Using a range of cell models resistant to existing therapies, including for example, chemotherapy and immunotherapy, we've shown that they retain a dependence on Werner helicase for viability. When you knock out Werner helicase with CRISPR, these cells die. This really supports the concept that Werner medicines would be effective in the setting of advanced disease. Next slide, please. Very excitingly, we've now developed a selective Werner inhibitor. This inhibitor inhibits DNA unwinding in vitro, as shown in the upper left-hand panel, and in the bottom left-hand panel shows that it has selective selectivity over other RecQ helicase family members. Werner helicase domain adopts many different conformations. To develop these inhibitors rather, required the solving of over 80 funnelite X-ray crystal co-structures. These efforts have led to a massive increase in the affinity and improved inhibitors with high affinity and drug-like properties. Next slide, please. Notably, treatment of cells with this Werner inhibitor leads to the accumulation of massive DNA damage. This is observed selectively in the microsatellite unstable cells, where there is no effect in microsatellite stable cells. The activity of the Werner inhibitor is highly correlated with CRISPR gene knockout, collectively indicating that this inhibitor phenocopies the data I've shown you with some of the genetic studies. Next slide, please. We've also gone on to show that Werner dependency and inhibitor sensitivity is recapitulated in patient-derived microsatellite stable colorectal cancer organoids. Shown on the left-hand side, following CRISPR knockout, you can see acute dependency on Werner in the setting of MSI colorectal cancer organoids. The MSI organoids are selectively sensitive to the Werner inhibitor, shown in the middle panel. On the right-hand side, again, confirming that organoids derived from treatment immunotherapy refractory patients retain their dependency and sensitivity to the Werner helicase. Next slide. Finally, in tumor xenograft studies, Werner inhibitors led to selective inhibition of tumor growth in MSI cells, but not in MSS cells. We also observed dose-dependent modulation of PD biomarkers when using immunohistochemistry. This included induction of a DNA damage marker γH2AX, and arrest of cell proliferation, as illustrated by p21 staining. In summary, Werner is a selective lethal target in MSI cells, and Werner inhibitors are selectively active in vitro and in vivo in MSI cells. Thank you. Great. Thank you, Dr. Garnett, for that wonderful walkthrough. Also a special thanks. I know Ben's on the line as well from GSK. Just been a terrific partner to continue to advance this program. With that, we will start the final walk through the selective essentiality in DNA damage repair and going through the POLQ or Pol Theta program. I know GSK has been really a terrific partner for this, and we're very grateful, Ben, that you're going to walk through our progress here today. Thank you, Yujiro. If I could have the next slide, please. Thank you. You've heard a little bit already today about the Pol Theta. The structure of the protein is shown in the left-hand panel. It's actually got multiple functional domains. It has an N-terminal helicase domain. It has a C-terminal polymerase domain, and it also has several structural domains in the middle of the protein that are capable of binding RAD51. As a result of the kind of very careful and elegant construction of this protein, it's able to help cells survive when they lose other mechanisms of double-strand DNA break repair, in particular homologous recombination, and that's shown in that blue square on the bottom left. Consistent with this mechanism, what's been shown is from genetic screens is that Pol Theta is synthetic lethal in cells that have a loss of the ability to carry out homologous recombination. The IDEAYA GSK team has been developing helicase inhibitors of Pol Theta. They're quite potent. They're based on a lot of structure-based design, which is indicated with that middle panel, and have very good physical properties and can be dosed orally. The team selected a development candidate earlier this year, and as Yura mentioned earlier, will be in the clinic early next year. Consistent with the fact that both PARP and Pol Theta share a similar biomarker, which is homologous recombination deficiency, they actually show very strong synergy that's indicated by the heat map on the right, where the deeper blue color indicates where there's very, very strong synergy. You can see that over a range of concentrations of the Pol Theta inhibitor when co-dosed with GSK's PARP inhibitor, niraparib. Please go to the next slide. The way that that is translates in terms of translational efficacy can be shown on the left. This is an in vivo study where the... This is the TNBC model, where you can see it has modest sensitivity to niraparib as a single agent, but with the addition of the Pol Theta inhibitor, we can drive down to deep regressions that are quite durable. That's one rationale for the value of Pol Theta to patients. Another comes from emerging studies on mechanisms of resistance to PARP in the clinic. There's been many suggested potential mechanisms from in vitro studies, but actually very few that have been clinically validated with patient samples. Probably the most well-validated is the development of second site mutations in BRCA or HRG components, which can restore functional forms of that protein. The figure in the middle shows that in a majority of cases, those second site reversions are actually carried out or bear a scar of kind of alternative enjoining or MMEJ type of pathway that Pol Theta plays a key role in. The implication from this data is that not only will Pol Theta deepen responses when combined with PARP, but also could potentially prevent the development of these resistance-associated mutations in patients. On the right, kind of summing that up as potential clinical opportunities for a Pol Theta inhibitor, we could potentially deepen the effect of PARPs in patients, especially where they may be getting only partial responses. We could potentially be preventing the emergence of PARP resistance based on the fact that a lot of these resistant mutations bear a scar of Pol Theta catalyzed MMEJ. Some early data, as was mentioned by Karlene, as well as, some data that's been in the literature recently suggests that it's possible that Pol Theta, in addition, could potentially help in settings where resistance has already occurred. Plenty of opportunities for us to try and find benefit for patients. Great. Thank you, Ben, for that walkthrough, we'll look forward to the targeted advancement of the Pol Theta development candidate into the clinic. Again, thank you so much. Thank you again to all of our KOL speakers and for our listeners today. Since founding the company over 7.5 years ago, we believe IDEAYA's pipeline has reached an important inflection point with 3 first-in-class clinical to IND stage programs and PKC inhibitor darovasertib, MAT2A inhibitor IDE397, and PARP inhibitor IDE161. With the near-term opportunity to advance 5 first-in-class clinical programs or the Pol Theta Helicase program targeting phase 1 in the first half of 2023, and the Werner Helicase candidate nomination on track for next year. To extend our industry-leading synthetic lethality, and to continue to pioneer the next generation of first-in-class targets in this emerging field of precision medicine oncology, we will invest in several key areas, including data informatics, structural biology, ctDNA technology, and compelling clinical combinations. Lastly, our perspective is that the interest from pharma and the broader scientific and medical community in the synthetic lethality field has never been greater. We'll continue to execute on our strategy to collaborate with the pharmaceutical industry and leading academic centers as we have with GSK, Amgen, Pfizer, the Broad Institute, UCSF, CRUK, among others, to build a deep and diversified first-in-class synthetic lethality pipeline and to enable compelling combinations to deliver maximal clinical benefit to patients. This concludes our prepared remarks. Operator, please open up the line for the analyst Q&A portion of our webcast. Thank you, Yujiro. This opens up the Q&A session. As a reminder to the analysts, please raise your hand to indicate you would like to join the queue, and please hold for a brief moment while we pull for questions. Okay, the first question will come from Charles Zhu at Guggenheim. Hey, good morning from New Orleans, everyone, thanks for taking the questions. Start off by saying apologies, I joined really late, you know, thanks for taking this. My first question on PARP. In terms of translating towards clinical doses, correct me if I'm wrong, I think I saw a tidbit on your GLP tox study saying that you're seeing effectively no toxicity at levels that translate to half of potential efficacious exposure in humans. In this context, how might you be able to advance dosing in the clinic? How should we think about, you know, potential starting dose as well as step-ups in a dose escalation, including in context of FDA Project Optimus? Thank you. I know there was that, the one slide on the myelosuppression, and I think the starting or at least the anticipated starting dose. Mike, do you wanna lead us off there? Yeah, sure. Just to step back for a second, we're very, very excited because if you look at the HNSTD from our GLP tox studies, those are indicating that our safe starting dose is within one half of our predicted efficacious human dose. What that means is we're gonna be getting into our predicted human efficacious dose within the first couple of cohorts. This is not common in oncology, so we're extremely excited about this. To your point about Project Optimus, I think this program is sitting in a very nice place to be able to evaluate the optimal biological dose as well as the maximum tolerated dose because we have a really snappy pharmacodynamic biomarker, which is PAR accumulation. We have evidence that we can follow PAR accumulation peripherally, in PBMCs, as well as in the skin and as well as in the tumor. We certainly intend to follow target engagement, the exposure response, curves in patients using that biomarker, and we will be excited to start, you know, seeing benefits. Early on in the dose escalation, given the safety profile and our starting dose, which again, is 0.5x of our predicted human efficacious dose. Great. Thanks, Mike. I think you covered each of the sections of the question. Got it. Sounds great, thanks for that color. Then maybe one more quick follow-up on PARP, perhaps. I know this, you know, obviously very interesting target, given some of the data that you had presented. I'm also kind of wondering, you know, it looks like you guys will be first in class in the clinic, undoubtedly, as with many things in target oncology, once a promising target gets derisked, you have many follow-ons. I guess from that perspective, could you also describe, you know, perhaps the campaign that you had perhaps undertaken on the chemistry side of things, and how we should think about barriers to entry against this target? Thank you. Yeah. We, you know, we've been working with CRUK on this. This is a very challenging target. I would say, collectively, we've been doing chemistry for probably over six years, so it's definitely not a trivial target. You know, we've been, you know, I would say, done a very thorough job on the IP side as well. At least our experience here is that, you know, this is a fairly long road in terms of chemistry and sort of barriers to entry. You know, we appreciate, we think there will be enthusiasm and excitement around this target. Got it. Great. Maybe one last high level question from me. I guess, you know, how are you guys thinking about, you know, PARP given that HRD is a heterogeneous collection of different biomarkers? I guess, how are you thinking about it specifically within HRD as well as, you know, in context or relative to, let's say, a whole data development? Thanks. You know, we think these are different profiles in terms of targets and programs as I know Ben walked through with POLQ. We think a big application there is around the combination opportunity with PARP and specifically around this MMEJ aspect as it relates to reversions. In terms of PARP, you know, we do think there is a viable opportunity here based on our preclinical data around monotherapy development. As we saw, which Dr. Yap walked through, we do think a delineated profile from PARP in terms of sensitivity. We also do see a different profile and different types of histology, in particular, with highlight breast cancer. you know, we think there are several key pieces and we think the clinical development strategy for POLQ and PARP are differentiated. Mike, any other you would add there? Yeah. I think the only last thing I'll point out, Utro, is our anticipated tolerability profile. If that translates, we really have wide open opportunity landscape with respect to combination opportunity, as Dr. Yap noted. Yeah. Maybe just the last I'd mention, Charles, is, you know, we mention it, biomarker expansion opportunity that, you know, the team is also evaluating additional biomarkers, specifically in the replication stress area. I would say more to come on that front, which, you know, we believe will continue to drive the differentiation. Great. Thanks for taking the questions. Sure. Thanks, Charles. The next question comes from Priyanka Grover at JP Morgan. Hi, everyone. This is Priyanka Grover on for Anupam Rama. We just have one question. For IDE161, will the initial study focus be on a broad range of solid tumors, or will we have a more targeted focus like ovarian cancer? Thank you. Yeah. That's being discussed now. I think as you probably saw from the press release as well as the presentation today, I would say in particular, we have an interest in breast cancer. Also within breast cancer, we see a sensitivity within a certain subset of breast cancer. In addition, we do think ovarian cancer as well. I would say initially that will be the focus with the emphasis on specifically on breast cancer. Understood. Thank you for taking my question. Sure. Thank you. Thank you, Priyanka. The next question comes from Yigal Nochomovitz at Citi. Hi, Yujiro and team. Thanks very much for taking the questions. Dr. Shields did a nice job explaining some of the endpoints for the neoadjuvant trial, enucleation rate and the potential for reducing the radiation dose, and then in an adjuvant trial, the relapse-free survival and useful vision. I'm just curious, how likely are these endpoints to be regulatory endpoints? To what extent have you discussed the design of a registrational trial in both neoadjuvant and adjuvant uveal melanoma with the FDA? Thank you. Sure. I think Dr. Shields is still on, so I'll let her maybe talk about the endpoint, so then I'll cover the registrational piece. Dr. Shields, are you still? Yes, I'm still on. I think the five cases that I showed were very strong cases indicating the power of Daro in just one month of Daro in reducing intraocular tumor size. In every one of the five cases, the size of the melanoma in the eye reduced. In that last case I showed, it reduced down to zero. It completely reduced. I do think it was powerful, the five observations from Australia. I think we're gonna be able to hopefully reduce the rate of enucleation. About 10% of eyes currently are enucleated. That means removed, when a patient's found to have melanoma in the eye. The remainder, hopefully, will be able to reduce the amount of radiation that we need to give. I do think that endpoint is definitely achievable. Just even if you reduce a melanoma by one or two millimeters in thickness, you're gonna reduce the radiation dose to the center of vision, and you're gonna protect the vision a little bit better. I do think these endpoints are fairly easily achievable given the five cases that we saw. Thank you, Dr. Shields. Yeah, I think, Yigal, just to, the latter part, we did recently submit a clinical protocol to the FDA to initiate a phase 2 company-sponsored study, in the neoadjuvant uveal melanoma setting. Dr. Shields, as well as, several other KOLs, since this is, you know, we think really the first time a systemic therapy is attempting this, we did get their input, on drafting the clinical protocol and specifically the endpoints. In terms of registrational trial, I think here, the goal will be first to generate data from the phase 2 study. Then, you know, depending, as we see how the data evolves, we hope, that there could be an opportunity for, an accelerated approval type path, we hope, in a fairly near-term timeframe. Okay. Gotcha. Then on 397, you showed some very nice scientific rationale for the combination with pemetrexed as well as with the PRMT5. You've also talked about, and I believe you have cohorts enrolling for with the taxanes, with docetaxel and paclitaxel. Can you just comment, is the taxane combo rationale similar to that of the pemetrexed combi-combo rationale, or there's some nuances there in terms of the scientific arguments for combo? Thanks. Sure. Mike, do you wanna take that? Sure. Thanks for that question. The taxol rationale is based on the ability of MAT2A inhibition in the MTAP-deletion setting to perturb splicing of gamma-tubulin ring complex and other components that perturb mitotic spindle fidelity. This is a conferred liability. As I mentioned, we think that that mechanism actually may be quite distinct from the pemetrexed combination. The pemetrexed combination may, in fact, be unique to MAT2A, given the three hits in the metabolic cycle in order to be able to allow for purine and pyrimidine synthesis. Those two mechanisms are a little bit different, I think, in that for the taxol combination, it's through PRMT5 inhibition of or perturbation of mRNA splicing. Pemetrexed is through these three hits on those interconnected metabolic pathways and may be PRMT5 independent. I see that. Thanks. Then just one last one on the preclinical programs. I was just wondering, with the Pol Theta and the Werner helicase, given they both do have helicase domains, is there any structural homology on those two domains? If so, did that in any way help you in terms of designing inhibitors to both those targets, leveraging the biology from both, or were they just very different? Hi, Yigal. Yeah, this is Jiro. You know, I don't think we're gonna get too much into kind of the overlay between the two, but I would say high level, you know, there were two distinct drug discovery campaigns. Understood. Thanks. Sure. Thanks for the questions, Yigal. The next question comes from Robert Driscoll at Wedbush. Great. Thanks. taking my questions. lots of exciting data today. It looks like you did a really comprehensive assessment looking at the penetrance of that HRD biomarker for PARP inhibition, and the differences, you know, versus PARP inhibitors. Have you been able to assess how prior PARP inhibitor treatment and resistance to PARP may affect PARP inhibitor activity? just wondered if you'd seen any synergy with IDE161 with Pol Theta inhibition or the HRD-targeted therapeutics. Thanks. Mike, do you wanna take that? Yeah, those are great questions. A lot of that is underway. you kinda hit on some really compelling mechanistic relationships there, where a PARP inhibitor plus a POLQ inhibitor could do something quite interesting. we haven't released any of that information yet. With respect to, how a PARP inhibitor plays in the acquired resistant setting, we have empirical data, both, from models that were derived from patients on relapse, where in some cases we can see, tumor regressions with 161. We also have laboratory-derived, PARP-resistant models. Sometimes those models actually induce, sensitivity to PARP inhibitor. Sometimes they are, independently connected, so they will be resistant to a PARP inhibitor but not a PARP inhibitor. In one case, we did in fact have cross resistance, and that was in a model that was a RAD51 model. Turning RAD51 back on actually caused this resistance to both. We're very interested in, you know, the mechanistic framework that you're alluding to here. What is the difference between HRD status that's PARP responsive versus PARP inhibitor responsive? That data is continuing to evolve. Got it. Super helpful. maybe a question for Professor Shields, if she's still on the line. you know, you mentioned it briefly at the end of the talk. I wonder if you could expand more on the idea that the common toxic lesion, if you will, to many of these DDR inhibitors is unrepaired single-stranded DNA gaps. I think it's been shown for PARP inhibitors, you know, more recently Pol Theta inhibitors. one might expect some other DDR inhibitors in the clinic as well. Dr. Shields, yeah. I mean, you're right. There are quite a number of studies indicating that these unrepaired single-strand gaps are a potential intermediate, or the toxic intermediate. I mean, I think there's still work to be done there. There are some examples that seem to indicate that gaps can form in settings where they are not necessarily leading to toxicity, but there's quite a number of scenarios where that's the case. I'm not sure if you had something further in mind with that question or? No, that's super helpful. Thank you. Okay. Operator, next question. Thank you for the questions. The next question comes from Maury Raycroft at Jefferies. Hi. Congrats on the progress, and thanks for taking my question. I was gonna ask about PAR accumulation. You mentioned, you can see accumulation of PBMCs, skin and tumor. The slide deck also mentions potential phospho-K AP1 as a biomarker for IDE161. I guess based on the preclinical data, do you have an idea how these biomarkers will translate in the clinic? Assuming the IND clears, what could timelines look like for dosing initial patients and getting initial data from the study? Mike, do you want to take the first part? Sure. I'll take the first part. We are in, you know, in the midst of establishing these procedures now for the clinic. The preclinical data indicates, as I noted before, that we can see exposure-dependent accumulation of PAR in PBMCs. We should be able to follow that exposure-response relationship. We also see it in tissues, we should be able to follow that exposure-response relationship, and we intend to take the appropriate samples during dose escalation to be able to establish that very quickly. Ugur, you wanna take the second half of that? I think, Maury, your other question was just related to timing of FPI. I think here, you know, we have several plans set. We'll probably be giving guidance on that here, not too far in the future. Yeah, we feel good about the filing and, you know, there's already been some back and forth, I know, with the FDA. Yeah, we'll hopefully be able to give some update on that here, very shortly. Got it. Okay, that's helpful. Maybe one other question just on Werner helicase getting into where you're at with that program. You've mentioned the co-crystal structures that you have. Is that an area where you're still doing work, or are you now in later stages, primarily assessing candidate function in biological assays? Yeah. I would say there, you know, we haven't given all of that detail except to say that our candidate nomination target is next year. I would say we have, you know, several advanced series, Maury. I think at this point that's all we could say. Okay. Okay, makes sense. Thanks for taking my question. Sure. Thanks, Maury. The next question comes from Matt Biegler at Oppenheimer. Hey, guys. Thanks for doing this event. As it relates to the DDR targets like Pol Theta, do you think since they act downstream of ATR, and/or ATM, do you think they would have a better therapeutic window? Because I think that that's kind of been the Achilles heel so far for some of these agents. Yeah. Mike, do you wanna take that? I think what we've seen so far suggests that POLQ is gonna have a really exceptional safety profile. Okay. Fair enough. I think just to kinda jump on top of that one, and then I think, you know, as we've picked the next wave of programs, I think POLQ, PARP, Werner, you know, I think several of these in the DDR space, I think one of the reasons why we've been intrigued is, you know, related to their selective essentiality. Got it. Cool. Maybe one for Dr. Shields if she's still on, because I think all of us are kind of undergoing an education session on, you know, the opportunity for this neoadjuvant setting. Can you just kinda walk us through how you choose a patient for cohort 1, the enucleation, versus cohort 2, the BRCA therapies? Is that something that's standardized, or is there quite a bit of physician decision there, and does that variability, like, can that impact, I guess, the trial in any way? Thanks. Sure. It's fairly well standardized among ocular oncologists. Most of us can irradiate a melanoma in the eye up until a thickness of about 10-12 millimeters in thickness. Anything that's 10-12 millimeters or greater, we tend to recommend eye removal, enucleation. Anything that's 10-12 or less in thickness, we tend to irradiate. I'm not saying radiation protects the vision. I mean, we have 3 concerns here. Number 1 is patient's life, number 2 is saving the eye, and number 3 is vision. We pretty much throw in the towel for vision for all patients with uveal melanoma. We tell them all that your vision's not gonna be good. You're likely to be legally blind in this eye by the time we're done with treatment. Again, it's fairly well standardized 'cause most of us use the same radiation isotopes of radioactive I-125. Now in Europe, they use a different isotope called ruthenium, and ruthenium can only irradiate up to about 6 millimeters. It's a bigger problem in Europe because they enucleate many more eyes than we do in the States because their radiation can't reach to the depth that our radiation reaches in the U.S. Understood. Thanks for the questions. Thank you, Matt. The last question will come from Benjamin Burnett at Stifel. Great, thanks so much. I also have a question for Dr. Shields. Appreciate all the commentary around darovasertib in the uveal melanoma space. To the question of, I guess, how long would it take to show a vision benefit with less radiation? Looking at that kind of cohort 2 study design, how long do you expect to see a vision benefit with these types of efficacy profiles? Does vision loss correlate with the size of the tumor initially, or is it more about the location of the tumor or is it, I guess is it both? Sure. Regarding the first part of the question, how long to appreciate vision loss? On average, it takes about a year to appreciate a little drop in vision in an eye that's received radiation. If we're taking a tumor from 10 millimeters in thickness down to 5 millimeters in thickness, I think within a year we're gonna see a difference in visual outcome. If we take it from 10 down to 8.5 millimeters, it may take longer to appreciate, you know, when the curves separate regarding vision outcome. Your second part of that question was what does vision rely on? Well, you nailed it with your question. It relies on tumor thickness and tumor location. The closer the tumor is to the center of vision or to the nerve, the optic nerve that gives us vision, the more vision loss the patient's gonna have. We use both of those facts when we decide or estimate what vision outcome is. If a patient has a thin melanoma and it's located way out in the side of the eye, we feel pretty comfortable they're gonna have preserved vision. If we take that same thin melanoma and put it right next to the center of vision, we call that the macula, they're gonna have bad vision. It's 2 factors. Okay. Understood. Well, thanks so much. Thanks for the questions, Ben. This concludes today's Q&A session. I'll now turn it back to you, Yujiro, for concluding remarks. Great. Well, thank you so much, again for everybody's time, and thank you again for the KOL speakers today. We very much appreciate the opportunity to walk through our R&D day. With that, operator, you can close the line now.