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. And 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 pre-clinical programs in PARG and PARP data. As part of this key advancement across our portfolio, today we'll be giving an additional update on the IDE397 Phase 1 dose escalation program. Before we begin, I wanted to thank all of the employees of IDEAYA and our partner GSK for their 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 we will 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 pre-clinical pharmacodynamic data, clinical PK, clinical adverse events, and clinical plasma and tumor pharmacodynamic data. At the end of this 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 within the data categories and what's enclosed in this presentation. And 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 by providing a high-level profile on the GSK option data package requirements and a high-level overview of the collaboration economics. Next, Dr. Matt Maurer, Head of Clinical Oncology will provide a walkthrough on the Phase 1/2 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 referred to today. 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 pre-clinical tumor pharmacodynamic data, as well as the clinical plasma and tumor pharmacodynamic data. And then lastly, a PK/PD analysis, as well as projected clinical efficacy time, the pre-clinical projections to our clinical, both pharmacodynamic pulmonary data. And then at the end, I will provide a summary of the presentation today as well as next steps for this program. And then we'll transition to the next phase of the presentation. You can get 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 3. 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. And 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 option data package of 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 we are currently enrolling Cohort 6, 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 through GSK, we also anticipate that we will deliver the option data package to GSK mid-year 2022. If GSK exercises its option, there will be a $50 million option exercise fee due subject to HSR clearance. If GSK likes 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 will 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 US profit splits, as well as ex-US high single-digit to sub-teen double-digit percentage royalty. We believe this partnership structure with GSK in this scenario of opt-in is highly value accretive for our shareholders and enables a very cost-efficient fashion to advance this program in the clinic. So 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 this presentation. Matt, I will pass on to you.

Yeah. Thanks, Yujiro. So in this slide, you can see the sketch of the 397 development plan showing a comprehensive approach to proof-of-concept evaluation of both monotherapy and combinations that are supported by our preclinical evaluations. This strategy provides multiple shots on goal and optimizes their 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 Esophagogastric carcinomas for both monetary 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 MTAP deleted cancers have a relatively poor prognosis and do not respond well to immunotherapy, given that they're generally cold tumors and thus require novel therapies. You can see that for each tumor type we are combining with the standard of care Taxane, Docetaxel for lung and Paclitaxel for Esophagogastric. We and others have validated preclinical combinatorial activity with MEK 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 lots 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 5, which is in our target range, has been cleared in preliminary tolerability and we are currently enrolling into Cohort 6 where the first patient has cleared the DLT period. You can see the normalized relative fold increase in exposures across a 20-fold range. IDE397 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 accrued 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 events 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 3 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 lipitor toxicities. So 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. Good 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 this 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 dimethylarginine modification (SDMA), that's hit two. So 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 a synthetically lethal mechanism. The same can't be said for the PRMT5 inhibitor, which strongly perturbs mRNA splicing in all cells. So given this mechanism of action in patients on trial, we follow drug-dependent methionine inhibition by measuring the concentration of SAM in plasma, that's our peripheral PD. And 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. So on the next slide, please you draw. In Slide 8, 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 methionine inhibition is sufficient to block PRMT5 activity in MTAP-deleted tumors in vivo. Nine of the 12 MTAP deleted models evaluated showed 80% to 100% reduction of tumor SDMA as compared to time-matched vehicle controls. We will give you two vignettes from one of our key indications of interest on the next couple of slides. On slide 9, 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 in this study. With respect to the PD, the vehicle arm middle panel showed extensive SDMA standing with an H-score of 85. The tumor SDMA H-score was reduced to zero by IDE397 treatment, as shown on the right, indicating 100% suppression of the production of SDMA in the tumor. On slide 10. 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 and control animals saw quite high the max is 300, as you can see in the middle panel. Ninety-five percent 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 1 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 1 through Cohort 5 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 5 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 modulation. So 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 4, shown on the far left and displayed little detectable modulation of tumor SDMA treatment. Cohort 4 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 exposure is about 2.5-fold higher than the pancreas cancer patient in Cohort 3. Notably, the cytoplasmic staining is absent on treatment with also a detectable, although modest reduction in nuclear SDMA staining, middle and 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 5. The plasma drug exposure in this patient is almost 6-fold higher than what we saw in Cohort 3 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 deletion lung cancer model. This patient was on the high side of exposures observed in Cohort 5 and the plasma SAM reduction is also on the high end at 79%. The central lab pathologist 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 standing intensity, receiving scores of 3 plus. In contrast, the on-treatment biopsy score 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. The 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 tumor SDMA is detectable at 3 milligrams per kilogram and is maximally suppressed by 30 milligrams per kilogram. We've plotted those exposure response details for the MTAP lung cancer model H838, on the right. Clinically, IDE397 achieved plasma SAM reduction of 60% or more across cohort 1 through 5 in the Phase 1. 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 a 95% reduction of tumor SDMA in cohort 5. Based on these observations, cohort 5 is in the target exposure range for efficacy and we are currently exploring a higher dose in cohort 5. So with that I'll hand the presentation back to Yujiro.

Thank you, Mike, for the overview, and thank you, Matt, for explaining the clinical data. Regarding the key next milestones for IDE397, our first goal is to deliver the GSK option package by mid-2022, followed by the initiation of both the monotherapy expansion and combination studies around the same time. We have submitted the protocol amendment to the FDA to facilitate the next phase of the clinical program. To summarize today's presentation, we believe IDE397 demonstrates strong tumor pharmacodynamic suppression in various MTAP-deleted PDX models, with a 100% reduction of tumor SDMA. We have completed the preclinical package for the option data, which has been uploaded to the data room. IDE397 also shows a favorable human pharmacokinetic profile that supports once-daily dosing, as noted on clinicaltrials.gov. Additionally, the drug has shown robust clinical plasma pharmacodynamics across all cohorts and exposure-dependent tumor pharmacodynamics. We have observed a favorable human adverse events profile, with no serious adverse events reported, and the maximum tolerated dose has not yet been attained. Importantly, we believe this data indicates an emerging risk-benefit profile in comparison to historical data. On the benefits side, we have observed clinical activity, robust plasma and tumor pharmacodynamics, and tumor shrinkage in multiple patients. From the risk perspective, we maintain a favorable adverse events profile, with no serious adverse events and no maximum tolerated dose achieved. To put this risk-benefit profile into context, we want to mention two additional molecules in this pathway: GSK’s PRMT5 inhibitor, which saw an expansion dose of 400 mg once a day with approximately 26% serious adverse events and 53% Grade 3 or 4 adverse events. For 8270 at the 200 mg once daily expansion dose, we observed just under 20% Grade 3 or higher adverse events, and at the next higher dose of 200 mg twice daily, there were 67% Grade 3 or higher adverse events. IDEAYA believes it is developing a molecule with adequate exposure that delivers robust pharmacodynamic modulation and a superior adverse events profile compared to earlier compounds, providing a unique opportunity for targeting MTAP-deletion. We are confident that this interim clinical data positions the molecule favorably for the next development phase, and we believe the positive risk-benefit profile will allow IDE397 to consider unique combinations and explore earlier lines of treatment as a monotherapy. This concludes the prepared remarks about the IDE397 Phase 1 clinical program update, and I will now hand it over to Paul Stone, our Chief Financial Officer, for an update on the portfolio and our financials related to our Q1 2022 earnings release.

Hi. Good morning, everyone. I'm Paul Stone, Chief Financial Officer of IDEAYA. I’m going to report on our financial results for the full-year 2021, as well as the 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 plant operations into 2025. From a program perspective, our Darovasertib Phase 2 clinical and our preclinical programs are each maturing. Starting with Darovasertib, we are currently enrolling patients in a Phase 2 clinical evaluation of Darovasertib in combination with crizotinib in collaboration with Pfizer, and their clinical collaboration and supply arrangement. We are evaluating that combination in both metastatic uveal melanoma as well as GNAQ/11 mutant skin melanoma. We also opened recently a monotherapy evaluation of Darovasertib in primary uveal melanoma and we are considering and evaluating expansion opportunities preclinically both with KRAS inhibitors in KRAS-driven tumors and in combination with crizotinib, potentially with other cMET inhibitors in cMET-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 part of a Phase 1 clinical evaluation of the combination in cMET-driven tumors subjected to preclinical validation. Finally, for this program, we are targeting FDA guidance, as well as the clinical data update in mid-year 2022. Our next most advanced program is IDE161, which is a wholly-owned program targeting PARG 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 aggressions in multiple niraparib resistant models, which is a PARP inhibitor. We're targeting an IND in Q4 of this year. In our Pol Theta, also partner with GSK, we’ve demonstrated in vivo efficacy in combination with niraparib, which is GSK's PARP inhibitor, and we are in IND-enabled settings for the 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 to early Phase 1. Finally, on Werner Helicase, we are targeting a development candidate with GSK in collaboration with them in 2023. And similarly for this program, we have the potential for up to $20 million aggregate milestone payments from preclinical to early Phase 1. We're excited to see these programs mature.

Great. And Paul, anything additional for the financial results or is that the conclusion?

I think that – I think we covered the financial results, as I said, $78 million of operating expenses for 2021 cash into 2025 with $360 million on the balance sheet for this year.

Okay, great. Thank you, Paul, for that summary. And this will be the end of our prepared remarks and with that the operator will open up for the analysts Q&A session.

We will take our first question from Anupam Rama with JPMorgan. Please go ahead.

Hey, guys. Thanks so much for taking the question. Just a logistical question for me, can you remind us when sort of the data upload is complete to GSK by midyear? How long GSK has to make a formal opt-in decision? And will you be disclosing when the package is delivered or just ultimately the GSK decision? Thanks so much.

Yeah. Yeah, Anupam, so the timeframe for GSK's review period has not been disclosed. But I would say that, we've been in very close communication with GSK towards the end of last year. 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. So our view is that one the doses selected for the expansion phase of this trial. It will be an incremental review, which we would hope, would enable an efficient, time-efficient decision by GSK on the opt-in. In terms of, would we provide guidance and when the option package is delivered? Relative to the decision by GSK, we have not made a decision on that point at this point. But I think our hope is that those two events may be in fairly close proximity. And based on that, I think it may not be a bad baseline assumption that we would make an announcement as part of an actual GSK decision on the option.

Thanks so much for taking my question.

Sure.

And 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 going to 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. And so just wanted to see if we can talk more about what else could still impact or be included in the GSK data package. And will you include any data from Cohort 6 in the package?

Yeah, so I think in terms of data categories that will be provided in the option package that's noted in the schedule and 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 6 goes. So we are currently in that Cohort, as I believe is noted in the print materials. We have cleared the first patient on the DLT window. My understanding is that second patient will likely clear sometime next week, if they get through next week. And so it depends on if 6 is a possible dose for its reaction. If it's up to five then we end up selecting five in expansion dose, I would say the data that was presented today will be largely the same. 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 that this current cohort, we're rolling which is Cohort 6.

Got it. That’s very helpful. And 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've assessed that in the clinic, and if you're seeing any differences versus AG-270 on those measures?

Sure. Matt, do you want to answer that in terms of liver safety profile today versus AG-270 and our clinical experience there?

Yes, so we don't have the liability on the liver enzyme. So, and we have not seen any significant liver toxicity to date. So, we're encouraged by that.

Got it. Okay, thanks for taking my questions.

Great. Thanks, Maury.

And we'll 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 downmodulation 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? Not only as a percent reduction, but also on an absolute level of, for example, the Cohort 4 pancreatic cancer patients who have showed some level of knockdown, but post-treatment, it looks like the absolute amount could still be perhaps comparable to what some other tumors may be on the pretreatment perspective. So, I guess could you provide thoughts on that front as well, not only on the percent knockdown, but also on absolute amounts post-treatment? Thanks.

Mike, do you want to take that?

Yes, 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 dimethyl arginine and our therapeutic mechanism of action requires that demethylation to occur in order to support the pre-mRNA splicing that will allow the tumor to thrive. So, 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. So, in terms of what the absolute values are in the clinical arena, and whether or not there's going to be indications-specific thresholds for efficacy remains to be seen, but 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, and I'm also curious about the potential implications on pre-treatment H score impact. Could we still expect to see efficacy in tumors with low baseline H scores?

Do you want me to take that, Yujiro?

Sure. Yes.

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-scores of 80 to 100 that grow well and become suppressed and we have tumor control with SDMA 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-scores of close to 300, which is the maximum H-score that you can have and we find that we can suppress that all the way down to single or low double digits and that corresponds to efficacy. So the absolute concentration of SDMA in any given sample, we think is going to be variable. It's going to be based on the snapshot in time with respect to the turnover rate of the proteins that are methylated, as well as the activity of the enzymes involved is going to be related to the speed of the growth of the tumor. But 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 and maybe just one last one, I’d like to 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 new nuclear SDMA in that cohort for patients next?

Matt, you wanted to add 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. So what we can say at this point is, in that cohort 4 patient, we are seeing emerging signs of productive pharmacology vis-à-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.

And our next question comes from Joel Beatty with RW Baird. Please go ahead.

Hi, thanks for the presentation. First question is for the size SAEs and the Grade 3 AE, can you share what doses they occurred at?

Sure, Matt, do you want to take that?

Yes, so the SAEs occurred across doses and are generally related to complications of their malignancies and progression of their malignancies.

And I think the one was also the one Grade 3.

I see the Grade 3 Avastin at dose level four.

Got it. I appreciate that. And then also, could you confirm whether GSK will take response data and progression data at all into consideration when they make their opt-in decision?

Yes, I believe that at this time the schedule for the option data package requirement includes the data we have provided across various categories, such as pharmacodynamic data. Therefore, those are the components of the option data package. The two organizations are maintaining regular communication through both the joint development committee of MAT2A and the joint steering committee. To clarify, the schedule for the option decision and the data requirements conclude with the pharmacodynamic tumor data.

Great. Thank you.

Sure.

Our next question comes from Ben Burnett with Stifel. Please go ahead.

Hi. 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 how long SAM levels need to be reduced before seeing a clinical response?

Yes. Great question, Joel. Mike, do you want to take a stab at that one?

One important mechanism of action for us is the alteration of splicing, which impacts the protein environment within the tumor that supports the disease state. Our mechanism involves inhibiting the enzyme that modifies the splicing factors, leading to splicing changes that disrupt protein function. This is a multi-step process, and it requires time to sufficiently suppress tumor-specific proteins that contribute to tumor development. In our pre-clinical models, we sometimes observe that after dosing, the tumor continues to grow before we can control it, while in other models, we see control from the outset. Therefore, there may be differences based on the specific indication and the timing effects depending on the turnover rate of the methylated splicing factors. There are multiple factors that could influence when the therapeutic mechanism begins to take effect. From our preclinical studies, we have found that it is crucial to stay focused on the target to maintain tumor control, and we must suppress the target effectively to achieve a sustained pharmacological response over time.

I would like to add to Mike's point regarding the importance of continuous dosing without interruptions or reductions. This is why we presented a comparison at the end of our presentation against some historical data. We have observed the pharmacodynamic effects, and it is clear that the challenges with previous treatments stemmed from their inability to maintain continuous dosing without breaks or reductions.

Understood. That's really helpful. Just to clarify, you mentioned some higher dose cohorts. Is there a goal to increase the dose until you reach a maximum tolerated dose, or do you plan to stop at a certain dose cohort?

Yes, that's a great question, Ben. We are having that discussion internally and will continue communicating with GSK. Based on the PK/PD data and the human PK data, we believe we are in the effective dose range for Cohort 6. If we successfully complete this cohort, we are likely to initiate the monotherapy expansion at that dose and consider starting the combination at a slightly lower dose. During this process, we can also continue escalating the dose to Cohort 7. These discussions are happening in real-time, and this is a potential scenario we're considering.

Okay, okay, that makes sense. Thanks very much.

Sure. Thanks for the question Ben.

And the next question comes from Tim Chiang with Northland Securities. Please go ahead.

Hi, thanks. Yujiro, regarding the GSK opt-in decision, is there a requirement for you to demonstrate a maximum tolerated dose before they opt in? I'm curious if you have enough data to present to GSK that would encourage them to opt in, and what do you think the chances of that happening are at this point?

The schedule for the option reflects the expansion dose chosen for the next phase of development or maximum tolerated dose. It really hinges on our decision to start the monotherapy expansion. In response to Ben's earlier question, there is a possibility that we could choose a dose, like Cohort 6, as the expansion dose while we continue to escalate dosing to determine the maximum tolerated dose. However, selecting the expansion dose is not mandatory for the option package delivery; it's more about what dose we choose for the next phase, which could be either a lower dose or a maximum tolerated dose.

I understand. And just one follow-up regarding darovasertib. You recently announced the expansion of the collaboration with Pfizer. Can you explain what this involves? Will Pfizer provide more active product or allocate resources to support this study moving forward?

Yeah, we're very excited to be able to make that announcement yesterday on Darovasertib with Pfizer, and there were two agreements or two new agreements that were put into place. And so first for metastatic uveal melanoma, in our earlier agreement with Pfizer, it was a 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. And I think part of that is because it does require more just engagement interaction with Pfizer, both from a regulatory perspective, and Tim, as you can appreciate, if approved, obviously would be a label changing of that 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 and additional cMET driven tumors, including as was noted hepatocellular carcinoma. And we believe another indication non-small cell lung cancer which it appears Pfizer has interest to explore this combination. So that as well, the design, the protocol, in conjunction with Pfizer has been developed. And in parallel, we are also doing some preclinical validation work as was noted in our earnings update today. And that setup is basically mirrors what I noted for the registration MUM as well except that it's not for registration and supply that would be a next step pending this initial signal-seeking study.

Okay. Yeah, that's good details. Thanks, Yujiro.

Yeah. Absolutely, Tim. Thanks for the question.

And we will take her 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 the question that was asked earlier by SDMA and the absolute versus percentage change. And so, I just kind of want to get into, how strong the correlation is between that and tumor reduction and based on the data that you have so far? And then, I guess another thing I wanted to ask was, perhaps some variability that you may be seeing what might be driving us, is it the tumor type, what are some of the variabilities that you're seeing, and how do you plan to tackle that?

I think first on the clinical side, we've shown earlier that CT scans indicate tumor shrinkage in several patients. We commented on a thymic patient who was part of the study disclosed about six months ago in the Cohort where we escalated the dose, and at that time, we did not have tumor biopsies for those patients. So, we are somewhat limited in the number of patients in the Phase 1 dose escalation related to that specific question. However, we do have substantial preclinical data on the relationship between SDMA reduction and tumor growth inhibition or regression. Mike, do you have any additional comments on this?

Yeah. Thanks, Yujiro. Thanks for the question. That was great. Just as a little bit of a follow-up from a preclinical 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 the preclinical 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.

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 and baseline characteristics?

I would say that regarding our clinical data, we currently have plasma pharmacodynamic data for every patient, and it shows a consistent and significant reduction in the pharmacodynamic marker. As for tumor pharmacodynamics, the data is available for a smaller group of patients. Therefore, it's challenging to make definitive statements at this time. We did present findings for both pancreatic and lung cancer today, but we need a larger data set to address that specific clinical question further.

Thanks, Yujiro. And then the math, I know that the combo data is not required for the package that will be submitted to GSK. But I was just wondering, in terms of when GSK has to make the decision, relative to when you will have the combo data, is it likely that you will have the combo data before GSK has to make their opt-in decisions, just kind of 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. GSK from our perspective has added a tremendous amount of value on the preclinical combination evaluation, both in terms of GSK running agnostic screens, as well as helping IDEAYA think through really the scientific rationale and basis for a lot of these combinations. And I think there, we are in 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. But just to be clear, that is not the clinical portion, at least it's not required as part of the option package.

Thanks, Yujiro.

Great. Thanks so much, Zegbeh for your questions. Operator, are there any more questions on queue?

No, there are no further questions.

Great. So with that, we'll conclude the IDE397 Phase 1 update as well as Q1 22 earnings update and again, thank you very much for the time and operator, thank you so much for hosting the Q&A session.

This concludes today's call. Thank you for your participation. You may now disconnect.