Good day, and welcome to the IDEAYA Biosciences IDE397 preliminary clinical data update conference call. Today's conference is being recorded. At this time, I would like to turn the call over to Yujiro Hata, CEO, IDEAYA Biosciences. Please go ahead. Good morning, everyone. I'll be making some forward-looking statements today. Today we're absolutely thrilled to provide a program update on IDE397, as well as our Q1 2022 earnings update. Full year-end 2021 has been an absolutely transformational year for the company. We've been able to advance two programs in the clinic, as well as make significant progress across two additional late-stage preclinical programs, in PARP and Pol θ. As part of this key advancement across our portfolio, today we'll be giving an additional update on the IDE397 phase I dose escalation program. Before we begin, I wanted to thank all of the employees of IDEAYA and our partner GSK for its contributions to the IDE397 program, both through our IDEAYA GSK MAT2A joint development committee, as well as the broader joint steering committee. GSK has been a phenomenal partner and invaluable in advancing our thinking on this program from both a monotherapy and combination development perspective. We also thank GSK for its review and approval of the presentation materials that we'll share today. The focus of today's IDE397 program update will be specifically on the data required to complete the GSK option data package, which includes key preclinical pharmacodynamic data, clinical PK, clinical adverse events, and clinical plasma and tumor pharmacodynamic data. At the end of the session, we will have an open Q&A session with our analysts, and we do ask for the portion of IDE397 to keep the scope of the questions to be within the data categories and what's enclosed in this presentation. That is the content that has been reviewed and approved by GSK under our partnership agreement. In terms of the agenda for today, I will first start with providing a high-level profile on the GSK option data package requirements, and a high-level overview of the collaboration economics. Next, Dr. Matthew Maurer, our head of Clinical Oncology, will provide a walkthrough on the phase I/II clinical development plan, the protocol amendment that has been submitted to the FDA to enable both the monotherapy expansion phase as well as the clinical combination initiation, for this program. Next, Matt will provide an overview of the clinical pharmacokinetic data, as well as the favorable clinical adverse event profile that we've observed to date. After that, Dr. Michael White, our Chief Scientific Officer, will provide a walkthrough of the IDE397 pharmacodynamic data, including a very robust data set around the preclinical tumor pharmacodynamic data, as well as the clinical plasma and tumor pharmacodynamic data. Then lastly, a PK/PD analysis, as well as projected clinical efficacy, tying the preclinical projections to our clinical both pharmacodynamic preliminary data. Then at the end, I will provide a summary of the presentation today as well as next steps for this program. We will transition to the next phase of the presentation and give a summary from our Q1 2022 earnings update, which Paul Stone, our Chief Financial Officer, will walk through. Moving on to the next slide, on slide three, this is a summary of the GSK option data package, both in terms of timing and scope of the data supporting the GSK opt-in decision. As noted earlier, today's clinical data update on IDE397 will be focused on these key parameters and data categories that are required under our agreement for the option data package. In terms of pre-clinical data, the contents include both non-clinical safety, pharmacokinetic data and pharmacodynamic data, as well as in vivo efficacy. This data package is now complete, and is being uploaded, currently, to the online data room. Next, the clinical data requirements for the MAT2A option data package with GSK is safety and tolerability data, pharmacokinetic data, and pharmacodynamic data, both including, plasma as well as tumor pharmacodynamic data. Based on where we are in the dose escalation, which is we are currently enrolling cohort six, we are targeting expansion for the monotherapy expansion phase in mid-year 2022. In addition, based on, where we are on the assembly of the data package to GSK, we also anticipate that we will deliver the option data package to GSK mid-year 2022. If GSK exercises this option, there would be a $50 million option exercise fee due subject to, HSR clearance. If GSK elects to opt in, the cost split would modify to an 80/20% cost share, with GSK responsible for 80% of the cost moving forward and IDEAYA for 20%. Next, there would be a set of milestone payments that could be potentially due, including $465 million in development and regulatory milestones, as well as $475 million sales milestones. In addition, we have retained 50/50 U.S. profit splits as well as ex-U.S. high single-digit to sub-teen double-digit percentage royalty. We believe this partnership structure with GSK in the scenario of opt-in is highly value creative for our shareholders and enables a very cost-efficient fashion to advance this program in the clinic. With that, I will now pass it along to Dr. Matt Maurer, our Vice President, Head of Clinical Oncology, to go through the next phase of the presentation. Matt, we'll pass it on to you. Yeah. Thanks, Sudhir. On this slide you can see the sketch of the IDE397 development plan showing a comprehensive approach to proof of concept evaluation of both monotherapy and combinations, which are supported by our preclinical evaluations. A parallel mono and combo strategy provides multiple shots on goal and optimizes our probability of uncovering transformational opportunities that can be rapidly brought to registrational follow-up studies. The tumor types of main interest include non-small cell lung cancer and esophageal and gastric carcinomas for both monotherapy testing as well as in combination with taxanes. These choices were based upon our preclinical monotherapy activity, as well as the high unmet medical need and larger addressable MTAP deleted populations. It should be noted that MTAP deleted cancers have a relatively poor prognosis and do not respond well to immunotherapy, given that they are generally cold tumors and thus require novel therapies. You can see that for each tumor type we are combining with a standard of care taxane, docetaxel for lung and paclitaxel for esophageal gastric. We and others have validated preclinical combinatorial activity with MAT2A inhibition and taxanes, and thus are excited about the prospect of clinical benefit. In addition, we have monotherapy basket cohorts for exploration across other tumor types and an opportunistic evaluation of another combination partner in which we have demonstrated preclinical synergy. We are targeting launch of expansion and combination testing in the middle of this year. Next slide. Shown on this slide are representations of our preclinical pharmacokinetic data. Key points to highlight are the well-behaved steady-state concentrations over time curves in the left panel, and dose proportional increase in exposure shown as fold increases on the right panel. We are most excited about the ability to deliver dosing that has reached our target efficacious exposures based on preclinical data. Dose cohort five, which is in our target range, has been cleared in preliminary tolerability, and we are currently enrolling into cohort six, where the first patient has cleared the DLT period. You can see the normalized relative fold increase in exposures across a 20-fold range. IDE-397 shows flat and consistent temporal PK profiles across doses with a low Cmax to Cmin ratios. In short, the favorable PK profile supports an acceptable clinical dosing regimen. Next slide. This slide provides a bit more detail on the safety experience thus far among the patients treated through cohort 5. The panel on the right shows the number of patients that have experienced drug-related adverse events per investigator broken out by grade. The side effect profile so far has been manageable, with low-grade GI events and mild thrombocytopenia that have not affected dosing. Specifically, dose-related AEs occurring in greater than 10% of patients include low-grade nausea, decreased appetite, diarrhea, dehydration, and thrombocytopenia. There has been only one drug-related grade three event of asthenia. There have been no drug-related SAEs or dose-limiting toxicities to date. We believe these data set the drug up for appropriate monotherapy testing as well as a therapeutic window useful for combination testing. This emerging safety profile also compares favorably to prior drugs targeting PRMT5 and MAT2A, which were limited by either hematologic or liver toxicities. With that, I'll pass it over to Mike to walk through some preclinical data as well as our clinical PD data. Thank you, Matt. Morning, everyone. I'll take a few minutes to walk you through our preclinical and clinical pharmacodynamic biomarker data. The key pharmacodynamic markers for the IDE397 program are directly related to the mechanism of action underpinning the MAT2A synthetic lethal interaction with MTAP deletion. As illustrated in the schematic on the left, upon MTAP deletion, which happens in 15% of solid tumors, the cellular MTAP substrate, MTA, accumulates and partially inhibits the essential enzyme PRMT5 in tumor cells, which is hit one of this pairwise synthetic lethal opportunity. The MAT2A inhibitor, IDE397, reduces the availability of cellular SAM, which PRMT5 needs to activate splicing factors via symmetric dimethyl arginine modification, SDMA. That's hit two. This one-two punch selectively disrupts essential pre-mRNA splicing in MTAP-deleted tumors. You can see that in action on the right. No inhibition of SDMA accumulation in MTAP wild-type cells, even with high doses of IDE397, and strong suppression of SDMA accumulation in MTAP-deleted cells, even at low doses. Notably, as shown on the far right, the disruption of essential splicing in MTAP-deleted cancer cells by IDE397 is equivalent to that observed with direct SAM competitive PRMT5 inhibitor. In contrast, IDE397 has very limited activity in MTAP wild-type cells, consistent with the synthetic lethal mechanism. The same can't be said for the PRMT5 inhibitor, which strongly perturbs mRNA splicing in all cells. Given this mechanism of action in patients on trial, we follow drug-dependent MAT2A inhibition by measuring the concentration of SAM in plasma. That's our peripheral PD. We follow the extent of inhibition of PRMT5 by measuring the abundance of SDMA in cancer cells from tumor biopsies. That's our tumor PD. On the next slide, please, Yujiro Hata. In slide eight, you can see in preclinical tumor models and in patient biopsies, we measure tumor SDMA by immunohistochemistry with an anti-SDMA antibody. In our workhorse, preclinical MTAP-deleted lung cancer model on the left, we validated dose-dependent reduction of tumor SDMA by IDE397 with complete inhibition of tumor SDMA and tumor growth by 30 milligrams per kilogram. That same dose extinguished tumor SDMA across a subset of MTAP-deleted patient-derived xenograft models, as shown on the right, demonstrating that MAT2A inhibition is sufficient to block PRMT5 activity in MTAP-deleted tumors in vivo. nine of 12 MTAP-deleted models evaluated had 80%-100% reduction of tumor SDMA as compared to time-matched vehicle controls. We'll give you two vignettes from one of our key indications of interest on the next couple of slides. On slide nine, non-small cell lung cancer is a patient population of high interest for the IDE397 program, and in this MTAP-deleted lung squamous cell carcinoma PDX model, we achieved 92% tumor growth inhibition by end of study. With respect to the PD, the vehicle arm, middle panel, showed extensive SDMA staining with an H-score of 85. The tumor SDMA H-score was reduced to 0 by IDE397 treatment, as shown on the right, indicating 100% suppression of the production of SDMA in the tumor. On slide ten, here is another example in the same disease indication where we saw tumor regression by end of study. This tumor had an SDMA H-score of 250 in control animals. Quite high. The max is 300, as you can see in the middle panel. 95% of that baseline signal is gone in residual IDE397 treated tumors, as you can see on the far right. On slide 11, as I mentioned earlier, in the clinical phase I dose escalation study, we're following plasma SAM as a peripheral PD biomarker and tissue SDMA as the tumor PD biomarker. We've observed significant plasma SAM reduction on treatment across cohorts one through cohort five to date. As an example, you can see the deep and consistent post-treatment plasma SAM reduction among evaluable patients in our recently cleared cohort five on the left, with a mean reduction of 77% after three weeks of therapy. On the right, you can see that across all evaluable patients on trial to date, the percent plasma SAM inhibition is associated with increasing drug exposure, indicating exposure-dependent target modulation. On the next slide, we'll move to the tumor PD from the trial. Here on slide 12, we were very pleased to see exposure-associated tumor SDMA reduction in target tumor types. Our first pre-dose and on-treatment paired biopsies came from a pancreatic cancer patient from cohort three, shown on the far left, and displayed little detectable modulation of tumor SDMA on treatment. The cohort four pancreatic cancer patient, middle panel, showed both nuclear and cytoplasmic SDMA staining in the pre-dose tumor biopsy. Those dark brown ovals are SDMA-positive nuclei which are surrounded by lighter brown cytoplasmic SDMA staining in the pretreatment biopsy, shown in the top panel. This patient's AUC plasma drug drug exposure is about 2.5-fold higher than the pancreatic cancer patient in cohort three. Notably, the cytoplasmic staining is absent on treatment, with also a detectable although modest reduction in nuclear SDMA staining, middle bottom panel, indicating an emerging pharmacological response to IDE397 in the tumor. Finally, on the right panel at the higher IDE397 exposures, you can see almost complete loss of SDMA staining in the post-treatment biopsy from this lung cancer patient in cohort five. The plasma drug exposure in this patient is almost six-fold higher than what we saw in that cohort three patient. We'll go in a deeper dive on the next slide. Slide 13 first. It's worth noting that the steady-state exposures for patients in cohort 5 are getting within the predicted efficacious concentration range based on preclinical in vivo efficacy studies using a representative MTAP-deleted lung cancer model. This patient was on the high side of exposures observed in cohort five, and the plasma SAM reduction is also on the high end at 79%. The central lab pathologist's tumor SDMA score for the pre-dose biopsy was 280. As shown in the bar graph on the right, the vast majority of tumor cells in the pre-dose biopsy had the maximum SDMA staining intensity, receiving scores of 3+. Now in contrast, the H-score for the on-treatment biopsy was only 13, and in the bar graph shown on the right, the vast majority of tumor cells in this sample were completely negative for SDMA, receiving scores of zero. I'll sum up on the next slide. Slide 14. Preclinically, we see strong tumor growth control as well as tumor regressions in multiple MTAP-deleted CDX and PDX tumor models using once-daily oral IDE397 doses from 10 milligrams per kilogram and above. Significant reduction of tumor SDMA is detectable at three milligrams per kilogram and is maximally suppressed by 30 milligrams per kilogram. We've pleotted those exposure response details for the MTAP null lung cancer model H838 on the right. Clinically, IDE397 achieved plasma SAM reduction of 60% or more across cohort 1 through 5 in phase I. We've plotted the steady-state exposures for the patients discussed in this presentation on the right, benchmarked against the preclinical observations. Clinical tumor SDMA is showing an exposure-dependent relationship with 95% reduction of tumor SDMA in cohort five. Based on these observations, cohort five is in the target exposure range for efficacy, and we are currently exploring a higher dose in cohort six. With that, I'll hand the presentation back to you, Yujiro Hata. Great, Mike. Thank you so much for that walkthrough, and thank you, Matt, for the walkthrough of the clinical data as well. In terms of key next milestones for IDE397, first is to deliver the GSK option package mid-2022, and then second, to initiate both the monotherapy expansion and combination studies in mid-2022. As noted earlier, the protocol amendment to the FDA has been submitted to enable this next phase of the clinical program. In terms of a summary of the presentation today, we believe we've demonstrated IDE397 shows robust suppression of tumor pharmacodynamics across multiple MTAP-deleted PDX models, including 100% reduction of tumor SDMA. We have completed the pre-clinical package for the option data package, and the data has been uploaded to the option d-data package data room. Next, IDE397 has demonstrated a favorable human PK profile that we believe supports once-daily dosing, as noted on clinicaltrials.gov. IDE397 has demonstrated robust clinical plasma pharmacodynamics across all cohorts and exposure-dependent tumor pharmacodynamics. To date, we've also observed a very favorable human AE profile, including no serious adverse events, and the maximum tolerated dose has not yet been reached. Importantly, the summary of this data, we believe we are seeing an emerging, preliminary risk-benefit profile versus historical. On the benefits side, as noted earlier, we have seen clinical activity, including robust plasma and tumor pharmacodynamics, and as reported earlier, tumor shrinkage in multiple patients. From a risk profile side, we believe we have observed a favorable AE profile, including, again, no SAEs, and an MTD that has not yet been achieved. To contextualize this risk-benefit profile, we wanted to highlight two additional molecules in this pathway, including GSK's PRMT5 inhibitor, who had an expansion dose selected at 400 mg once a day, and is noted here at that expansion dose, you saw approximately 26% SAEs and 53% grade 3/4 AEs. For AG-270 at the 200 mg QD expansion dose, they observed just under 20% grade three or higher AEs, and at the next dose level up of 200 mg BID, a 67% grade three or higher AE. At the outset of this program, IDEAYA's belief has been generating a molecule that has sufficient exposure, that can deliver robust pharmacodynamic modulation with an AE profile that is superior from previous compounds, would provide a unique profile to interrogate this opportunity within MTAP deletion. We believe this interim clinical data positions the molecule well to enter into the next phase of development. We believe this favorable risk-benefit profile will position IDE397 to potentially evaluate unique combinations as well as to explore potentially earlier lines of treatment as monotherapy agent. With that, this is the conclusion of the prepared remarks for the IDE397 phase I clinical program update. With that, I will pass it along to Paul Stone, our Chief Financial Officer, to provide an update across the portfolio as well as our financials as relates to our Q1 2022 earnings release update. Hi. Good morning, everyone. I'm Paul Stone, Chief Financial Officer of IDEAYA Biosciences. I'm going to report on our financial results for the full year 2021, as well as a corporate update. In 2021, for the full year, we had operating expenses of $78 million. This left us with a cash balance of $368 million, which provides us with a runway for planned operations into 2025. From a program perspective, our darovasertib phase II clinical and our preclinical programs are each maturing. Starting with darovasertib, we are currently enrolling patients in a phase II clinical evaluation of darovasertib in combination with crizotinib, in collaboration with Pfizer under clinical collaboration and supply arrangement. We are evaluating that combination in both metastatic uveal melanoma as well as GNAQ/11 mutated skin melanoma. We also opened recently a monotherapy evaluation of darovasertib in primary uveal melanoma, and we are considering and evaluating expansion opportunities pre-clinically, both with KRAS inhibitors in KRAS-driven tumors and in combination with crizotinib and potentially other c-Met inhibitors in c-Met-driven tumors. In terms of key updates and catalysts, we announced yesterday that we've expanded our relationship with Pfizer on our clinical collaboration and supply arrangement to support a potential registrational trial in metastatic uveal melanoma as well as support a phase I clinical evaluation of the combination in c-Met-driven tumors subject to preclinical validation. Finally, for this program, we are targeting FDA guidance as well as a clinical data update in mid-year 2022. Our next most advanced program is IDE161, which is a wholly-owned program targeting PARP for patients that have HRD or BRCA mutations. In this program, we've observed in vivo efficacy with enhanced tumor growth inhibition and/or tumor regressions in multiple niraparib-resistant models, which is a PARP inhibitor. We are targeting an IND in Q4 of this year. In our Pol theta program, also partnered with GSK, we've demonstrated in vivo efficacy in combination with niraparib, which is GSK's PARP inhibitor, and we are in IND-enabling studies first half of this year. Importantly, for this program with GSK, we have the potential for up to $20 million in aggregate additional milestones from preclinical through early phase I. Finally, on Werner helicase, we are targeting a development candidate with GSK in collaboration with them in 2023. Similarly for this program, we have the potential for up to $20 million in aggregate milestone payments from preclinical to early phase I. We're excited to see these programs mature. Great. Paul, anything additional for the financial results, or is that the conclusion? No, I think we've covered the financial results. As I said, $78 million of operating expenses for 2021, cash into 2025 with $368 million on the balance sheet for this year. Okay, great. Thank you. Thank you, Paul, for that summary. This will be the end of our prepared remarks. With that, the operator will open it up for the analyst Q&A session. If you would like to ask a question, please signal by pressing star one on your telephone keypad. If you're using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. Again, please press star one to ask a question. We will take our first question from Anupam Rama with JP Morgan. Please go ahead. Hey, guys. Thanks so much for taking the question. Just a logistical question from me. Can you remind us once sort of the data upload is complete and to GSK by mid-year, how long GSK has to make a formal opt-in decision? Will you be disclosing when the package is delivered or just ultimately the GSK decision? Thanks so much. Yeah. Yeah, Anupam. The timeframe for GSK's review period has not been disclosed. But I would say that, you know, we've been in very close communication with GSK. Towards the end of last year, you know, based on that communication, we've begun building the data room early. And a lot of the data room has already been occupied, including preclinical data, as well as several key pieces of the clinical data. Our view is that when the dose is selected for the expansion phase of this trial, it will be an incremental review, which we would hope would enable a time-efficient decision by GSK on the opt-in. In terms of, you know, would we provide guidance on when the option package is delivered, relative to the decision by GSK, we have not made a decision on that, Anupam, at this point. I think our hope is that those two events may be in fairly close proximity. Based on that, you know, I think it may not be a bad baseline assumption that we would, you know, make an announcement as part of an actual GSK decision on the option package. Thanks so much for taking my question. Sure. Our next question comes from Maury Raycroft with Jefferies. Please go ahead. Hi, good morning, and thanks for taking my questions, as well. I was just wondering if you can talk more about what exactly is gonna be submitted to GSK. It sounds like it's subject to initiation of expansion cohorts or MTD, and you're starting dosing with dose level six. I just wanted to see if you can talk more about what else could still impact or be included in the GSK data package. Will you include any data from cohort six in the package? I think, in terms of data categories that will be provided in the option package, that's noted in the schedule in our agreement was as outlined in one of the earlier slides of the presentation. In terms of cohort, Maury, here, I would say it depends on how cohort six goes. We are currently in that cohort, as I believe was noted in the print materials. We have cleared the first patient in the DLT window. My understanding is that second patient will likely clear sometime next week if they get through next week. It depends on if 6 is a possible dose for expansion. If it's up to five and we end up selecting five in the expansion dose, I would say the data, what was presented today, will be largely the data they see. If it's a scenario that we decide to escalate into cohort 7 and we clear that cohort, obviously that cohort will be included as well. I would say at this point, the baseline working assumption that we are internally utilizing for planning for this next phase of development is that the potential to expand at this current cohort we're rolling, which is cohort 6. Got it. That's very helpful. Also just wanted to check to see if you're seeing anything additional on impact on bilirubin, and you've mentioned the UGT1A1 biomarker in the past. I'm just wondering if you can remind me if you've assessed that in the clinic and if you're seeing any differences versus AG-270 on those measures. Sure. Matt, do you wanna answer that in terms of, liver safety profile to date, versus AG-270 in our clinical experience there? Yeah. We don't have the liability on the liver enzyme. You know, and we have not seen any significant liver toxicity to date. You know, we're encouraged by that. Got it. Okay. Thanks for taking my questions. Great. Thanks, Maury. We will take our next question from Charles Zhu with Guggenheim Securities. Good morning, everyone. Thanks for hosting this event, and thanks for taking my questions. My first one, I want to ask on the tumor SDMA down modulation signals that you've disclosed so far. I guess in addition to potentially looking at it from the perspective of percent tumor SDMA reduction, how should we also think about these tumor SDMA levels, you know, not only as a percent reduction, but also on an absolute level? For example, the cohort four pancreatic cancer patients you have showed some level of knockdown, but post-treatment, it looks like the absolute amount could still be, you know, perhaps comparable to what some other tumors may be on a pretreatment perspective. I guess could you provide some thoughts on that front as well? You know, not only on the percent knockdown, but also on absolute amounts post-treatment. Thanks. Mike, do you wanna take that? Yeah, absolutely. Thank you for that question. With respect to the absolute SDMA signal, when we look at that signal, we are really looking at the proteins that have been modified by that symmetric dimethylarginine, and our therapeutic mechanism of action requires that dimethylation to occur in order to support the pre-mRNA splicing that will allow the tumor to thrive. In terms of absolute concentrations of SDMA in the tumor, preclinically, we find that the better you suppress those absolute values of SDMA, the better response you have with respect to tumor shrinkage. In terms of what the absolute values are in the clinical arena and whether or not there's going to be indication-specific thresholds for efficacy remains to be seen. From the preclinical studies, we do know that the more we can suppress tumor SDMA, the better efficacy we see in those preclinical models, both the CDX and the PDX. Got it. Understood. Excuse me. I'm also curious then, you know, what are the potential implications on a pretreatment H-score impact? And, you know, could we still potentially expect to see efficacy in a low baseline H-score tumors? You want me to take that, Yujiro Hata? Sure. Yeah. Yeah. From what we have seen on the preclinical side, when we have a response to the MAT2A inhibitor, we have a suppression of the tumor SDMA. We have found tumors that have H-score of 80-100 that grow well and become suppressed, and we have tumor control with the MAT2A inhibitor treatment. I showed you an example of that with one of those lung cancer, squamous cell lung cancer samples. We also have tumors that have H-score close to 300, which is the maximum H-score that you can have. We find that we can suppress that all the way down to single or low double digits, and that corresponds to efficacy. The absolute concentration of SDMA in any given sample, we think, is going to be variable. It's going to be based on a snapshot in time with respect to the turnover rate of the proteins that are methylated, as well as the activity of the enzymes involved. It's going to be related to the speed of the growth of the tumor. We do find that we see efficacy, irrespective of the starting point of the SDMA signal, as long as we are able to suppress that with sufficient exposure to IDE397. Got it. Thanks for providing that level of color and detail. Maybe just one last one, if I could squeeze it in. I may have missed it, but what's the potential significance of observing what appears to be 100% knockdown of cytoplasmic SDMA while also knocking down 12% of the nuclear SDMA in that cohort 4 patient? Thanks. Mike, want to take that again? Sure. I'll take that one too. What we're seeing in that patient is signs of activity of IDE397 in the tumor that is indicated by a reduction in the signal of the cytosol and a little bit in the nucleus. We don't understand the mechanistic relationship there with respect to whether a tumor has a cytosolic signal or not. What we can say at this point is in that cohort four patient, we are seeing emerging signs of productive pharmacology vis-a-vis the drug is getting to the site of action for the intended therapeutic mechanism, is engaging the target, and is having a consequence on the pharmacology. That's the extent of the conclusion that we wish to draw. Got it. Thanks for taking all my questions. Great. Thanks for the question, Charles. Our next question comes from Joel Beatty with RW Baird. Please go ahead. Hi. Thanks for the presentation. First question is for the five SAEs and the grade three AE. Can you share what doses they occurred at? Sure. Matt, do you wanna take that? Yeah. The all-cause SAEs occurred across doses and are generally related to complications of you know their malignancies and progression of their malignancies. I think the one was also the one grade three. Oh, I see. The Grade three asthenia was seen at dose level four. Got it. I appreciate that. Could you confirm whether GSK will take response data and progression data at all into consideration when they make their opt-in decision? Yeah. I think at this point, Joel, the schedule of the option data package requirement is the data that we've provided around the categories including pharmacodynamic data. At this point, those are the contents of the actual option data package. Obviously, the two organizations are in regular communication, you know, through both the joint development committee of MAT2A as well as the joint steering committee. Just to be clear, the actual schedule for the option decision, the data requirements, ends with the pharmacodynamic tumor pharmacodynamic data. Great. Thank you. Sure. Once again, if you would like to ask a question, please press star one. Our next question comes from Benjamin Burnett with Stifel. Please go ahead. Hey, thank you very much for taking our question. I guess based on what you're seeing thus far, what's your current expectation for how long SDMA and SAM levels need to be reduced before seeing a clinical response? Yeah. Great question, Joel. Mike, do you wanna take a stab at that one? I can. One of the things that is an important mechanism of action for us is perturbation of splicing, which then has a consequence on the protein milieu within the tumor that is supporting the disease state. Our mechanism of action requires inhibiting the enzyme that modulates the splicing factors that causes the splicing perturbation that interferes with protein function. It's a multi-step process and will create a situation where some time is required in order to be able to have sufficient suppression of tumor-selected proteins that are supporting tumorigenesis. When we look at the preclinical models, sometimes we see situations where upon dosing, the tumor continues to grow and then turns over and is controlled. In other models, we see control from the beginning. There may be indication-specific differences in the timing. There may be indication-specific rather differences with respect to how fast we see a consequence of these effects based on the turnover rate of the splicing factors that are methylated. There are a lot of factors at play here that could affect the timing at which the therapeutic mechanism is engaged. From our preclinical studies, what we do know is that we need to stay on the target in order to be able to maintain control of the tumor, and we need to be able to suppress the target strongly to be able to evoke a productive pharmacological response continuously over time. Maybe just, Ben, I just would add to Mike's. I think really, you know, in addition to duration to your question, as Mike noted, I think here the importance of continuous dosing, you know, without having dose holidays, dose reductions, and that's why we, you know, did the comparative at the end of the presentation versus some of the historical. Because as we've seen some of that pharmacodynamic data, but, you know, based on the AE profiles, obviously I think, you know, the continuous dosing, lack of dose holidays and dose reductions obviously have been challenging for some of these past molecules. Understood. Okay, that's super helpful. Just one quick kind of clarification question. You mentioned some higher dose cohorts. Is there a goal or is there an appetite to go up until you hit an MTD? Or Yeah, no- Do you plan on stopping at a certain dose cohort? Yeah, I think that's a great question, Ben. You know, I think we are having that discussion internally and we'll be, you know, continuing the communication with GSK. You know, we do think now in cohort 6, you know, based on the PK/PD data that Mike and the human PK data that Matt walked through, you know, we do think we're at that dose range where, you know, we believe we're in the efficacious range. I think there is a very likely scenario that if we clear this cohort 6, that we would initiate the monotherapy expansion at that dose, and then, for example, start the combination at dose minus 1. While we do that, we could in parallel continue the dose escalation to cohort seven. I think these are all discussions that are occurring real time, but I think that's a, you know, potential scenario. Okay. Okay, that makes sense. Thanks very much. Sure. Thanks for the question, Ben. The next question comes from Timothy Chiang with Northland Securities. Please go ahead. Hi. Thanks. Yujiro, just going back to the GSK opt-in decision, is there any requirement actually for you to show a maximum tolerated dose before they opt in? I'm just sort of wondering, you know, do you have enough data to show to GSK such that, you know, GSK would opt in? You know, what do you think the likelihood of that is at this point? Tim, the way the schedule is written for the option, it's the expansion dose selected for this next phase of development or MTD. Really it's based on the decision we make for initiating the monotherapy expansion. I think separately to the question that Ben asked earlier, you know, I think there is a scenario that we would pick a dose, for example, cohort six, as the expansion dose, as we continue to dose escalate to define MTD. But that, you know, that's not a requirement for the option package delivery. It's really more based on the dose selection for the next phase. Then that could be either a lower dose or an MTD dose. I see. Okay. Maybe just one follow-up, and it's really on darovasertib. I mean, I guess you just announced an expansion of that collaboration with Pfizer. Could you just talk a little bit about what that entails? You know, is Pfizer going to supply you more product, more active product? Or are they, you know, also gonna devote some resources to the studies going forward? Yeah, no, you know, we were very excited to be able to make that announcement yesterday on darovasertib with Pfizer. There were two new agreements that were put into place. First, for metastatic uveal melanoma, you know, in our earlier agreement with Pfizer, it was very specific that it would not include work for a registrational trial. So the new agreement that was put in place was specifically to enable a potential registration-enabling trial. I think part of that is because, you know, it does require more just engagement, interaction with Pfizer, both from a regulatory perspective, and Tim, as you can appreciate, you know, if approved, obviously would be a label changing event as well. In terms of the setup, for that, it is similar in terms of supply. There is a joint steering committee. The two organizations do meet fairly regularly. In addition, obviously their involvement both in terms of certain specific regulatory documents and communication with the FDA, obviously the development of the clinical protocol. There are also specific provisions around joint intellectual property of which, joint IP has been filed here, already, as well as joint publication rights. The second agreement is separate, and that is to explore this combination of darovasertib with crizotinib in additional c-Met-driven tumors, including, as was noted, hepatocellular carcinoma and, you know, we believe, another indication, non-small cell lung cancer, which, you know, it appears Pfizer has interest to explore this combination in. That as well, the design, the protocol in conjunction with Pfizer has been developed. In parallel, we are also doing some preclinical validation work, as was noted in our earnings update today. That setup basically mirrors what I noted for the registrational one as well, except that it's not for registrational supply. That would be a next step pending this initial signal-seeking study. Okay. Yeah, that's good details. Thanks, Yujiro. Yep, absolutely, Tim. Thanks for the question. We will now take our last question in queue today coming from Zegbeh Jallah with Roth Capital Partners. Please go ahead. Good morning. Thanks for the update. I think I just have two quick ones. The first one is a follow-up to a question that was asked earlier about SDMA and the absolute percentage change. I just kinda wanna get a sense of, you know, how strong the correlation is between that and tumor reduction and based on the data that you have so far. I guess another thing I wanted to ask was, you know, perhaps some variability that you may be seeing and what might be driving that. Is this just the tumor type? You know, what are some of the variabilities that you're seeing, and how do you plan to tackle that? Yeah. I think first on the clinical side, you know, we've already shown earlier, Zegbeh, as you know, you know, CT scans, human CT scans of tumor shrinkage and I believe several of those patients and I also know we commented on a thymic patient I believe was on study at that point of the disclosure about six months earlier in the cohort dose escalation and we did not have tumor biopsies for those patients. I would say we're somewhat dealing with a limited N number in terms of at least currently you know the phase I dose escalation on that specific question. I think we have a lot of data pre-clinically on that association between SDMA reduction and tumor growth inhibition or regression pre-clinically. Mike, any additional comments there you wanna make? Yeah. Thanks, Yujiro. Thanks for the question. Yeah, that was great. Just as a little bit of a follow-up from a pre-clinical standpoint, Zegbeh, what we're really looking at here is not the delta so much as getting below a threshold. So, everything that we've seen so far suggests that you need to get below a threshold of SDMA to have a response. You're not always necessarily going to get a response. There is in some models required, but not sufficient in a pre-clinical setting. But we're looking at a situation where we want to get below a threshold of SDMA in the tumor to be able to have efficacy. Thanks. In terms of the variability, I guess, in patients getting below that threshold versus those that are not, are you seeing anything there in terms of nuances in baseline characteristics? Yeah. I would say, Zegbeh, in terms of our clinical data, you know, I think at this point the pharmacodynamic data that we have on every patient is plasma. There it's a fairly consistent and robust reduction of the pharmacodynamic marker. In terms of tumor PD, you know, it's in a smaller subset of patients. I think it's a bit hard to say at least at this point right now. We did show pancreatic as well as lung cancer, you know, at least in the figures today. You know, I think we just need a larger data set to comment on that specific question clinically at this point. Thanks, Yujiro. Sure. The last one here is I know that the combo data is not required for the package that will be submitted to GSK. I was just wondering, in terms of when GSK has to make the decision relative to when you'll have the combo data. Is it likely that you'll have the combo data before GSK has to make their opt-in decision? Just kinda wondering about how the combo data might help influence some of that decision making. Yeah. In terms of combination data, Zegbeh, there is no requirement for us to have clinical combination data. We have been working very much in a highly collaborative fashion. You know, GSK is, from our perspective, has added a tremendous amount of value on the pre-clinical combination evaluation, both in terms of GSK running a diagnostic screen, as well as helping IDEAYA think through, you know, really the scientific rationale and basis for a lot of these combinations. I think there we are on very solid footing, at least from our perspective, and we do have three combination arms that have been submitted as part of this protocol amendment with the FDA. Just to be clear, that is not the clinical portion, at least is not required as part of the option package. Thanks, Yujiro. Great. Thanks so much, Zegbeh, for the questions. Operator, are there any more questions in the queue? Nope. There are no further questions. Great. With that, we'll conclude the IDE397 phase I update as well as your Q1 2022 earnings update. Again, thank you very much for the time. Operator, thank you so much for hosting the Q&A session today. This concludes today's call. 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