A great good morning everyone. Hope everyone had a great long weekend. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for attending TD Cowen's seventh annual Oncology Innovation Summit. For our next session, we're very excited to have a fireside chat with the IDEAYA management team, and it's my pleasure to introduce Yujiro Hata, the CEO, Joshua Bleharski, the Chief Financial Officer, and Michael White, the Chief Scientific Officer. Yujiro, Josh, Michael, pleasure to have you here. Thank you very much for joining me. Great. Well, Tyler, thank you for the kind introduction, and thank you to TD Cowen for hosting this fireside chat with the team today. I know Mike, Josh, and I will tag team here. We very much look forward to the discussion. Perfect. For those of you in the audience, if you have questions, you can go ahead and submit them through the portal. I've got a little dashboard here where I'll see your questions, and we'll do our best to get them answered, although we have a lot to cover. Before we get started, as you all may know, Extel voting kicks off today, and the TD Cowen Biotech team would appreciate your support if you feel that we've earned it. With that, we'll go ahead and get into the questions. Naturally, we'll start with darovasertib. The recent phase II/III results of darocriz certainly hit the mark and continued to confirm the impressive clinical profile. It would be great if you could start by briefly recapping the results in HLA-negative uveal melanoma patients for those who are not familiar. Yeah, no, sounds great, Tyler. Darovasertib, it's in a randomized registrational phase II/III study in HLA-A*02-negative frontline metastatic uveal melanoma. We recently read out top-line results for this study. The primary endpoint for accelerated approval is median progression-free survival, and for full approval, overall survival. What we noted was a hazard ratio of 0.42 and a p- value of less than 0.0001. Clearly hits that sig. In the treatment arm, we saw a median PFS of 6.9 months. In the control arm, the PFS was 3.1 months. In the control arm, it was largely ipi/nivo, and I would say that PFS came in exactly as we had anticipated. Tyler, as you know, we've been communicating, we had anticipated it was going to come in at three months. That sets us up great. I think just the other, in terms of secondary endpoint, probably worth noting is response rate. Really, we were very excited to see the response rate. By central review, we were trending towards 40% confirmed response rate. I think really just a fantastic result. Sadly for the control arm, came in at single-digit percent. I think clear benefit. We will be having a late breaker oral presentation on Monday, June 1st, in the morning, where we'll be giving the full results. That's great. Thanks for that. During that late breaker oral presentation, could we expect to see more data or results or details during that as well? There will be more data, Tyler. In terms of the actual figures we provided, partly because we were under embargo with ASCO, and we had to have some back and forth on what we could share. We did share a PFS Kaplan-Meier curve, but that was essentially all we had shared from figures and tables. We will have a CT scan waterfall for both the treatment and control arm, both by independent central review as well as investigator assessment. We will also have full safety AE tables here as well. We just had a several line summary. What we did emphasize as part of at least the safety portion is the data's been consistent with what we've reported in the past. We've had past oral presentations at medical conferences, including Society of Melanoma Research, fall of last year, including ESMO as well. We feel that the data's been very consistent with what's been reported for darocrizo. Sorry, just crizotinib independently. Great. I know the waterfall will be particularly important for these patients in addition to the PFS. On the topic of OS, the confirmatory endpoint, can you just discuss your confidence in eventually hitting that and over what timeframe we may get those results as well? Look, I think, Tyler, we do have quite a bit of confidence on OS, and what that really resides from is the data we publish. As you know, Tyler, here, when you have a situation where treatment arm response rate's trending towards 40%, control arm is, you're talking mid-single digit percent response rate, PFS, essentially, we're more than doubling PFS as well. We think that sets us up very well for a potential OS readout. Lastly, we did report survival data fall of last year. In that report, we reported an OS just over 21 months. This is across HLA-A*02- negative and positive in the frontline setting. Based on reported ipi/nivo OS, which the paper that we do reference or point people to is that Piulats paper, because it was a multi-site study, over 50 patients in frontline, all ipi/nivo. In that study, the OS came in at 12.5 months. Obviously, 12.5 versus over 21, that's just the data that's out there. The last part I will highlight also, Tyler, is that we also have visibility into a fairly sizable data set in HLA-A*02 positive. That data has been submitted for a major medical conference. That's going to be roughly 100 patients where we'll report response rate PFS and OS. This will be the first time we'll share specifically OS data in HLA-A*02 positive. We have a subset of patients that are also treatment naive. We also know what that data looks like. I think that as well is just another data point for us of why at least right now, we feel confident about OS. Okay, that's helpful. Since you touched on the positives and the ongoing phase II, can you just, I guess maybe provide more details or recap how the data compared across positive versus negative, and how many additional patients you plan to enroll in the positive cohort? Yeah. In terms of the data that we've seen across HLA-A2- negative and positive, the data's been very consistent, whether that's response rate, PFS, OS. I think here, which is not surprising, because the mechanism of action is not based on specifically an HLA-A2 allele, like other MOAs are. This is specifically around targeting the GNAQ/11 activating mutation, which activates the PKC signaling pathway. From a biological perspective, we shouldn't see differences, and we believe the data we've seen supports that. In terms of our focus on enrollment for A2- positive at this point, Tyler, we're essentially done. That's the good news. The target was to enroll just about 100 patients for A2- positive. That effort is now done. People will now get to see that data in a peer-reviewed setting at a major medical conference, as noted. We will plan to submit this data as part of our NDA submission. Just to be clear, this is not base case, but as potential upside to see if we can get A2- positive on the label, and base case would be pursue a compendia NCCN guideline strategy, and this would be based on this roughly 100-patient data set in A2- positive. Got it. Have you had any sort of discussions with the regulators regarding that 100-patient kind of sample size for positives? We've had conversations with the FDA, Tyler, and we don't want to get into too many specifics of sort of dialogue with the FDA, U.S. FDA. Big picture is we have had discussion just on this specific topic around A2- negative versus positive. As you appreciate, these will most likely be largely review type issue situations. That's why, just so it's clear, we're not communicating this as base case. Understood. All right, the darocriz NDA submission in the second half. It almost sounds like the positive data might be the gating item. Is that fair to say to get the filing in? Are you guys highly confident that that's going to occur by the end of the year? How do you think about how long it will take once it's submitted to get a potential approval? Yeah, we'll have that as a trailing submission, Tyler. We don't believe it's going to be a gating item. You may know that we recently announced we did get Real-Time Oncology Review, RTOR, from the Center of Excellence from the U.S. FDA, that's great, which allows us to submit the NDA as part of three pre-submission modules, for which the first has already been submitted. Yeah, for the A2- positive, we anticipate that's going to be staggered. Okay, great. Just to follow up on the RTOR, that should allow for priority review, hopefully. That's correct. We already have Fast Track designation, so we anticipate we'll have expedited review. Our timelines anticipate that. Typically, RTOR obviously depends on all of the facts of the program, but I would say historically, the hope through RTOR, you could expedite that review process by even a few months in certain cases. We're preparing for that. We're obviously thrilled that we've been able to get RTOR. Hopefully, it demonstrates the alignment with the FDA on the study, gives us more interaction, and obviously allows us this sort of rolling review through these pre-submission modules. Great. Let's move to the neoadjuvant uveal melanoma setting in darov monotherapy, which you guys are definitely not getting any credit for at this valuation. Can you discuss what your expectations are for the updated phase II OptimUM-09 data in the second half of the year, and should we expect additional patients, analyses, longer-term follow-up, et cetera? I would say all of the above, Tyler. The single-arm neoadjuvant study OptimUM-09, that abstract has also been submitted for a major medical conference. As you know, the data has been very robust. Just for folks on the line, we did receive FDA Breakthrough Therapy designation specifically in this indication last spring. We will have more patients, more follow-up, specifically for the enucleation cohort as well as the plaque therapy cohort. Hopefully it will just continue to support why we are enthusiastic about this indication. As you know, these patients have no systemic treatment alternatives at this time. Great. Discussing or moving to adjuvant as well, maybe can you discuss why you all chose to pursue this, and what the ultimate goal in this setting is for darocriz and how you think about duration of treatment? Yeah, I would say, Tyler, the adjuvant study is aligned with our longer-term corporate strategy and vision as a company, specifically in the area of precision oncology, and our belief that one of the greatest areas of patient impact that we can deliver is in the early-stage disease setting. We think there's no greater setting to deliver that type of patient value than the adjuvant setting. We also believe that the adjuvant setting in uveal melanoma is likely to be the largest market opportunity, both in terms of annual incidence. Right now, you start going to 10,000 to 12,000 patients a year. Prevalence should be multiples of that. The treatment duration is going to be the longest. For the study specifically, which we work together with Servier, our partner, in collaboration with the FDA, where the treatment duration will be 12 months. As you know, in adjuvant setting, patients can be on treatment for as long as they can. We think really a big market opportunity. Lastly, I would mention several points on the study specifically. Roughly about 450 patients will be randomized one-on-one, randomized against observation. Here, again, highlighting the unmet need. We're not randomizing against anything at this point. A typical, I would say gold standard adjuvant randomized study, where the primary endpoint is superiority for relapse-free survival. We anticipate we'll hopefully enroll that study as fast as we can, HLA agnostic. That readout will likely mature in sort of that three to three and a half year timeframe. Got it. That's helpful. Hard to imagine darocriz will not succeed with that design. All right. We have a question here from a client in the audience. In HLA negatives, does investigator-assessed PFS Kaplan-Meier allow the additional ability to speak to duration therapy, willingness of the docs to treat longer versus the BICR Sorry, just make sure I got that one, Tyler. This is treatment beyond progression. Is that correct? Yeah, that sounds like what they're getting to, yeah. Sure. Yeah. Maybe I'll tack in here with Josh. Josh, do you want to take that in terms of the treatment beyond? Yeah. Does the investigator-assessed PFS Kaplan-Meier kind of speak to that? Yeah. I don't know about that, but what we've seen historically is about 10 months of duration in our trials. That's what we're seeing. It's a few months beyond what we've shown for PFS. I think that's in the clinical setting. It's also consistent with what we're hearing about in the commercial setting as well with one of our competitors. Look, I think the bottom line is for patients that have no alternatives, physicians will have to make that determination on whether the patient is still benefiting and whether there's anything else to switch them to. In the HLA negative setting where we're focused, there really aren't any alternatives, and historically what patients see is checkpoint inhibitors, which is what we randomized against in our O2 study. It's clear there's really a lot more benefit or almost no benefit in terms of PFS with the checkpoint inhibitor based on our data. I think there is a scenario where in the real world, a physician may choose to keep a patient on darovocriz for beyond that seven-month PFS or even beyond the 10 months that we've seen in our clinical trials, depending on the patient, depending on the disease and how they're tolerating the therapy. Time will tell, but I do think that there is a credible path for that playing out in the real world. Yep, that makes sense, and there's also very clear precedents already set in the setting, which is advantageous. To wrap up the darocriz conversation before we get to ADCs, just you've got obviously metastatic, neo-adjuvant setting. Just to, I guess, reiterate or reinforce, can a patient receive daro in every single one of those settings if they continue to progress? How big do you believe the combined market opportunity is across the three different settings in uveal melanoma? Yeah. I'll take the first part, and then on the market, I'll pass it to Josh. The short answer there is yes, Tyler. With neo-adjuvant, remember here, the primary endpoints for the neo-adjuvant portion is around ocular endpoints, right? Preserve the eye, preserve vision. As you go into the adjuvant phase, now that transitions to relapse-free survival or preventing metastatic disease for these patients. Ultimately, once that occurs, typically, as you know, as long as there's some kind of washout period, which there typically is, to rechallenge in that metastatic setting. We've seen this before, right, Tyler? Whether it's checkpoint therapy, other agents in breast cancer and others, where that occurs. We think there's precedents for that, and we think once you really compile each of these, which I'll let Josh talk through, we believe it's a very sizable opportunity. I think on the commercial point, we think there's a credible path to darovacriz being a blockbuster across UM, even a multi-billion dollar blockbuster. Just thinking about the metastatic opportunity, sort of the first to come online. I think we think the negative population is the majority of those patients in the metastatic setting. There's an analog or a competitor out there that I think has eclipsed about $400 million in annual sales, servicing the positive subset. That's one benchmark you could point to. I think the real drivers of the opportunity are going to be ultimately pricing and duration of therapy, right? That I think will contribute to what we see in the metastatic setting, along with any ability to penetrate the HLA-A*02- positive patient population, which we've talked about here. I think we have reason to believe that there is potential for that to have a meaningful impact on those patients as well, just given the mechanism of our drug. When you start to get beyond that in the primary setting, that's where you see more patients and longer follow-up or longer time on therapy. In addition to the HLA agnostic feature of the drug, that's where the opportunity really starts to multiply in our mind. As you start to stack those opportunities across uveal melanoma, I think we find a path to that multi-billion dollar zip code being potentially possible, if the drug plays out the way we think it will in the commercial setting. Right. That makes sense. Yep. Yeah. Maybe, Tyler, also just on that point with Josh, I think there's also a component of patients we think that have not been typed specifically for their HLA-A*02 allele. We think that could be even around that 20% range, especially when you start going into the community. If we're able to get on the NCCN guidelines without a specific reference to HLA-A status as well, obviously, that becomes an attractive opportunity there as well. Okay. That's a good add. Thanks for that. Let's move to ADCs, beginning with IDE849, of course, your DLL3 ADC. Maybe you could just talk about, at a high level, how it's differentiated versus the other ADCs, given the increasing competition, as well as the clinical data that you expect to update later in the year and what we should expect from that. Yeah. No. First, within the ADC area, maybe here, Tyler, sort of zero- in on small cell lung cancer, obviously, we think there's also an application neuroendocrine carcinoma. There are different antigens that are pursuing small cell from TROP-2 to B7-H3. Within that, we do believe DLL3 is the most optimal target. Perhaps the analogy I'll give is in many ways HER2 for breast cancer for ADCs because it's directly connected to this survival oncogene of ASCL1 and its direct expression impact on DLL3. We just got disconnected for a second there. I apologize. No problem. The second aspect is the linker. Here, ours is a tetrapeptide cleavable linker. Only cleaves once it's internalized. There's another set of linkers that's related to what's called the tumor microenvironment cleavable, which is specifically designed also to cleave extracellularly. We do believe that's making an impact in terms of AEs and safety. You may know that there is an asset where once you go above a certain dose, specifically 1.6 mg / kg, higher grade ILD has been observed. We think that's our window of differentiation. Can we dose higher than 1.6 mg/kg? We already know that our partner Hengrui Pharma is expanding at 2.4 mg/kg. It appears we're seeing perhaps even better tolerability outside of China. We're also targeting higher doses and expansion. If we can, our view is can we deliver a higher confirmed response rate, PFS, and ultimately OS? We'll have two large data sets, Tyler, to hopefully support all of the comments or statements I just made. It'll be over 100 patients across small cell neuroendocrine carcinoma. We will have both response rate PFS and for the first time, landmark 12-month OS data. We will also have our data, which we anticipate will likely be over 30 patients in the U.S., Europe, other parts of Asia. Right now, our view is we believe we have a potential best-in-class asset, not just within DLL3 topo ADCs, but across all DLL3 modalities. The last point of, I think, differentiation, two parts I'd highlight to you. First is we have PARG IDE161, and that is one of the key reasons we are actually pursuing this asset because we believe with that proprietary combination, we can enhance the durability of this asset. That could give us a significant competitive advantage versus our peers. As you know, a lot of this is going to be ultimately how you implement your clinical strategy to differentiate. I know I covered a lot there, but hopefully that's a useful summary. No, that's great. A lot of follow-ups to that potentially, but we've got to move on given that you guys have many other programs in the pipeline. IDE034, maybe kind of a similar question, the B7-H3/PTK7 bispecific. Why are you guys so excited about this program? Why does combining these two targets make sense? What could we see from the early data that could be released later in the year as well for this program? Sure. Mike, do you want to take that? Absolutely. This is a very exciting asset for us, B7-H3/PTK7. The representation of those two antigens on tumor cells that we have assessed by surface proteomics, a very broad opportunity in indications with a lot of unmet need. We showed that at AACR this year. The important thing for a bispecific, an appropriately designed bispecific, has an avidity advantage for binding double positive tumor cells versus single positive internalization delivery of the payload to the tumor. This is great because single positive B7-H3, single positive PTK7, we show less binding, less internalization than the monospecifics. More binding, more internalization of the double positive tumor cells gives us a really nice therapeutic window because we have poorer internalization of normal tissue and better efficacy because we have better internalization in the tumor itself. As Yujiro noted, if you want an asset to combine with a PARG inhibitor, this is great because we won't get any collateral damage, we think, in normal tissues due to tumor-specific delivery of the payload. Big opportunity for us in monotherapy as well as in combination with PARG inhibitor. That's awesome. No collateral damage sounds great. I guess just to follow up on the early data release in the second half of the year, what should we expect from that? You're talking about for monotherapy here, Tyler, for the? Yeah Sorry, for the bispecific. Yeah, the bispecific, sorry. Yeah. Here, it's going to be fairly early data. What we can say is we believe we're already in an efficacious dose cohort based on the dose escalation. I would say a significant emphasis on different solid tumor indications, including colorectal cancer, non-small cell. We are seeing quite a few colorectal cancer, as you know, a very important indication in an area perhaps where ADCs historically have had not had success. I think probably too early for durability data, but I would say we provide response rate type numbers, and that's our hope. Okay. We're a minute over time, but I have to ask about MTAP and KAT6/7. Maybe at a high level with MTAP, you could help orient people there. You've got potentially multiple things ongoing, MAT2A, TRODELVY combo, PRMT5 is obviously a big target of interest among investors. I think you all said we could see something strategic on that front sometime soon, you all said the CDKN2A. Where are you guys prioritizing in the MTAP space among everything you have going on right now? Yeah. Look, Tyler, we think we are one of the industry leaders in MTAP deletion. We're one of the few companies that have two clinical stage assets in this MTAP deletion area against two independent targets. You also know we have a third program around CDKN2A that's now hopefully moving towards the clinic, which we're targeting first half of next year. What I would say is that our strategy really has revolved in two specific areas. One is opportunities to fully suppress the PRMT5 pathway by hitting both MAT2A PRMT5. There, we want to be mainly focused on non-small cell lung cancer. A second strategy, which I think Tyler is to your point around other key coalterations. That would include CDKN2A, that would also include RAS mutant. Here, as we know, big focus on pancreatic cancer and colorectal cancer. Maybe, Mike, do you want to maybe just map that out? I know because of time, maybe just on the co-alterations and what your mind makes sense from in terms of rational combination strategy here. That's a great point. I think it's really important to recognize that the coalteration frequency in pancreatic cancer, CDKN2A deficiency, is much higher than MTAP because you are actually covering mutations in CDKN2A as well as turning off CDKN2A by epigenetic mechanisms. Very high frequency of coalteration with KRAS in pancreas cancer. We think that there are mechanistic interactions there that we can take advantage of with respect to the asset that we have that attacks the CDKN2A deficiency setting. That's an important opportunity for us that we're prioritizing, and we have preclinical evidence that that interaction seems to be very effective in pancreatic tumor setting, both as a monotherapy for the CDKN2A deficiency as well as in combinations with assets that attack those coalterations. Okay, that's helpful. Maybe just for the final question, maybe staying with you, Michael, on KAT6/7. We're going to have updates from some programs at the upcoming ASCO in terms of KAT6, but maybe you can talk about why your asset is differentiated as a KAT6/7 dual antagonist and how you expect to show that clinically. Yeah, thanks for that question, Tyler. This is very, very important for patients in my opinion. The reason we have a KAT6/KAT7 dual inhibitor is because the ability to control chromatin that is being driven by oncogenic acetyltransferase activity is a combination of those two acetyltransferases, KAT6A/B, and KAT7. If you inhibit KAT6, it's not enough. You still have activity. You need a combination asset. If you hit KAT7, that is sufficient to close down lineage-specific transcription factor activity, so we get deeper and more durable responses. Also, bringing KAT7 on board allows us to intercept resistance mechanisms that are due to drug-tolerant persister cell evolution, as well as tumor-initiating cell self-renewal of two features that allow for adaptive resistance on therapy. Very exciting for us to have an asset that as a monotherapy, will deliver deep and durable responses that we have validated in preclinical studies that you cannot achieve with KAT6 inhibition alone. We're in dose escalation studies right now in the tumor types where we see the biggest opportunity for this asset, lung cancer, colorectal cancer, and hormone-positive breast cancer, as well as prostate cancer. Awesome. Michael, maybe just a 30-second on just combinations on ESR1 mutant and RAS there. I know some of the data we just published is here. Yeah, we have seen from an empirical evaluation, a really spectacular synergy with RAS inhibitors with KAT6/7. Perhaps that's not so surprising because we think it's a double mechanistic pincer move where inhibiting the RAS pathway inhibits MAP kinase-dependent activation of the transcription factors that drive the oncogenic transition, and the KAT6/7 closes down the chromatin that the transcription factors need to bind. We essentially extinguish those tumorigenic programs when we put these assets in combination preclinically. That's a very exciting opportunity that we would like to pursue, particularly in the setting of colorectal cancer, where you have lots of KRAS mutations, lots of heterogeneity, lots of adaptive resistance. We think we can directly help KRAS or a RAS inhibitor in that setting, as well as deal with the heterogeneity, the mechanistic and adaptive heterogeneity that you see in colorectal cancer that's making it kind of a beast with respect to monotherapy RAS inhibition. Very, very interesting. Look forward to seeing more on that front. You too, Josh. Michael, thank you so much for your time. For everyone in the audience, we've got Crescent Biopharma that just started. Thanks for attending. Thank you, Tyler. Thank you. Thank you to the TD Cowen team.