All right, well, welcome everybody to our afternoon session with IDEAYA. We've got Yujiro here with us. Thank you so much for taking the time. Thanks for coming down to Miami, which I know is a chore for everybody, but appreciate you being here. Yeah, no, thanks so much, John, for the kind introduction, and thank you so much to Evercore for the opportunity to participate this year. Look forward to the conversation. Great. Well, let's jump right in. Obviously, we should start with Daro in uveal melanoma. Your data so far there have been really quite phenomenal. The update at ESMO showed some great initial PFS, well on your way in a first-line trial. That study is expected to read out later next year, but obviously you haven't committed to that in formal guidance. So maybe can you talk a little bit about the pushes and pulls on that expected date for data in first line? Yeah, no, for sure, so for those that may not be as familiar, so Darovasertib, John, as you just referenced, has been in a front-line potential registration trial in metastatic uveal melanoma. We've recently updated that we've exceeded over 150 patients in enrollment. The initial target for accelerated approval, the enrollment target is roughly 230 patients, perhaps slightly above that number, and there, the primary endpoint would be median progression-free survival, so it will be largely dictated by the cadence of enrollment. We're getting near that 200 number now already, so we're at a very rapid clip, and we are ahead of schedule, so based on that, as you noted, we have not given formal guidance. Some of it will just depend as we get closer to that date where enrollment is complete. But we do anticipate if this enrollment pace continues, that end of next year could be a viable scenario in terms of that readout for potential accelerated approval. Okay, makes sense. The comp arm in that first-line trial is physician's choice. That often indicates there's no good options for patients, as I think we're aware here, but it also sometimes leads to data heterogeneity, some unexpected results sometimes. So how much wiggle room is built into the trial from a stats perspective, maybe, if one of those comp options outperforms their historic benchmarks? Yeah, no, interesting question, John. Yeah, so for the listeners here, what we anticipate will be in the comparator arm are the following: DTIC, which is a chemotherapy here, PFS has been reported roughly two to three months, PD-1, PD-1 plus CTLA-4, both as well. We anticipate PFS roughly in that three-month range. So that's. Let's really read through from the non-uveal melanoma. That's actually been on various trials that have been done across the board in metastatic uveal melanoma where that roughly three-month PFS has been reported. So even for the approved agent that we have in HLA-A2 positive, that PFS is roughly in that three-month range. So there has been also large meta-analysis done in this indication. Now you're talking about a much larger denominator and dataset. Well, we do have some sense of at least where historical both PFS and OS is. So we do feel fairly confident that we're not going to see a PFS much different than what's been reported in the past, at least of what's going to be in the comparator arm. Right. Now you mentioned the approved agent there. That's Kimmtrak in the HLA-A2 positive patient population, not where your current first-line trial is running. You're running a phase 2 in the positives where they are approved currently, but what's your path to market there where there is an approved agent to go against? Sure. Yeah, so John, thanks for the question. So here for the listeners, we did have an oral presentation at ESMO last year where we did present both response rate PFS data. And really the quick summary is irrespective of HLA-A2 status, the efficacy data is pretty much the same. Probably what we would expect given that. Exactly, exactly. So based on the mechanism of action, which is specifically around an activating mutation of GNAQ/GNA11, which we believe 95% of these patients have this mutation, in either in each of those scenarios, whether it's HLA-A2 positive or negative, because of the GNAQ, that PKC signaling pathway we believe is activated. And all of our clinical data supports that notion. So as you mentioned, assuming we get approval in our registrational trial in front-line HLA-A2 negative, we will plan to continue to publish data in the A2 positive setting as we've already done at ESMO. Here we're targeting to enroll just over 50 patients in A2 positive. Assume that data remains to be consistent, at least based on the feedback we've gotten from our regulatory group. We believe the opportunity to get on compendia for pricing reimbursement is a viable path forward. Again, this assumes. As opposed to running an independent study to get registration. Correct, correct. Makes sense. All right. So the market in first-line setting isn't necessarily straightforward given the different ways that patients get stratified here. So what do you expect commercial landscape to look like as you head toward launch in a year or two? Will some fraction of the market be more difficult to penetrate even if you end up on compendia for the positives? Even just thinking about the negatives, there's certain different populations there. What should we expect from the commercial landscape as you head towards launch? Yeah, look, you know, based on the feedback we've gotten from various key opinion leaders that treat patients very regularly that have utilized our agent in the metastatic setting, at least the feedback we've gotten is a view that all patients with metastatic uveal melanoma will eventually see this agent. Whether that says, of course, in the front-line setting in A2 negative because there's no other approved therapies there, so that's pretty straightforward. In A2 positive, we're already seeing in our clinical trial, we're getting front-line patients, right? Even with an agent approved in front-line with randomized OS data, there's still situations where both the patient and the physician are opting to come on our trial as a front-line patient. So I think that says a lot. Obviously, if we have approval with randomized data in A2 negative, we have supportive data in A2 positive, whether it's before or after what's approved currently in front-line, ultimately we think patients will see this agent. Great. It seems like the market expectation is to comp a launch to Immunocore, which I understand given its positioning in the space, but there are some pretty substantial differences between your two drugs. We sort of alluded to that a little bit already. But do you think that is a good comp? Do you think it's a reasonable comp to think about launch cadence like Immunocore's has been? Yeah. Yeah, no, great, great, great question, John. So the short answer is yes. I mean, it's the only comp we have, right? So we believe the pricing and the trajectory of that launch has been largely driven by several things. First is that's one of the advantages of getting front-line approval, right? That you are the front-line treatment care, especially when you go into a setting where there are no other available options to that patient. So I think that's significant. The other, obviously, as it relates to pricing, and ultimately that's still very far away, or not very far away, but that's the next piece that we'll have to think through. We recently hired a Chief Commercial Officer. Ultimately, we think it's going to be dependent on the quality of our data, right? What does the PFS OS ultimately look like? Just as a reminder here, unfortunately, metastatic uveal melanoma is one of the most lethal solid tumors that are out there, right? Historical survival here is roughly a year. Moving beyond the metastatic setting, maybe, obviously you're looking at both adjuvant and neoadjuvant setting in a variety of different contexts. I've been really interested in that neoadjuvant setting, especially the enucleation studies that you've done sparing vision, sparing surgery. Can we maybe give a little context to us about what those different populations are and what those different contexts are in the neoadjuvant setting where the bars are set? Sure. Yeah, so as you mentioned, John, the neoadjuvant uveal melanoma setting, at least we believe, is an extremely exciting opportunity for the company and this program specifically, and that's for several reasons. This is an extraordinarily high amount of medical need, so there's nothing approved today in the pre-metastatic uveal melanoma, whether that's in the neoadjuvant setting or the adjuvant setting. Second, in terms of the two patient populations within neoadjuvant that you want to think about here, first, as you said, are patients with ocular tumors of the size and location of which their eye unfortunately has to be removed, so as you can imagine, a highly invasive procedure, and if you can really provide benefit and get those patients off of the enucleation track, we believe we would have delivered significant benefit to those patients. We believe that population is roughly 20%, slightly varied depending if it's in U.S. or Europe. Here we had a Type C meeting with the FDA, and the guidance that we were provided is that they accepted eye preservation, which in our briefing book, we noted exceeding a lower band of 10%. John, as you know, our current data is well over 50%. So we're well north of that type of threshold would be acceptable as a primary endpoint for full approval. So that's terrific. And we did, as you know, present data in a peer-reviewed setting, including an oral presentation at ASCO just a few months ago. The second group here is called plaque therapy. So these are patients that are getting basically radiation exposure to the eye vis-à-vis a plaque that's stitched onto their eye. Unfortunately, for a large portion of these patients from that radiation exposure to the eye, many of these patients will ultimately lose their vision. Second, they'll get something, what's called macular edema. So this is inflammation vasculature that occurs in the macula due to the radiation, which also causes complications, including impact to eyesight. So what we've seen with our therapy, we showed a fairly small dataset of 10 patients, but we have more now. We have 20 patients with over six months of follow-up, over 30 patients with four months of follow-up that we do believe we have the ability to positively impact vision by shrinking these tumors. Therefore, they have less radiation exposure. In addition, we believe we can prevent a lot of these patients from getting macular edema. So the majority of these patients end up getting macular edema from the radiation exposure. So ultimately, after the discussion with the FDA, where we landed is that we could use, if we hit either of those two endpoints, we would be able to get full approval. So that's been the back and forth with the dialogue with the FDA. We're about to submit that final protocol for the registrational trial. For both cohorts, there's a final secondary endpoint, which is event-free survival or EFS. Here, I think what's critical to highlight, the threshold that the FDA gave us for full approval is all we need to establish is no detriment to EFS. Typically, in a neoadjuvant approval trial, you need to show superiority, as you know, typically. If you're already showing benefit on enucleation or on vision sparing or macular edema, then even a wash on EFS would be acceptable. That's basically what they're noting with the no detriment, as long as we're not doing harm to that patient. Excellent. Makes sense. All right. Now, one of the things that we discussed a little while ago and sort of surprised me is the duration of therapy in the neoadjuvant setting versus the adjuvant one. Now, we're used to neoadjuvant treatment being relatively modest in duration. Patients slated for surgery, you want to get there as soon as possible and not have your patients progress. But in your case, that's a little bit reversed where you're treating pretty substantially before a surgical intervention. So can you put that into context for me here? How do you dial in the right duration of therapy for a patient who may or may not still be slated for surgery at the end of your intervention? Yeah, no, great, great and critical question, John. So when we started on this journey initially for the protocol, the period we were treating in the neoadjuvant setting was one month. We modified that based on the investigator feedback. We need to keep going longer. So we modified that to three months, then we modified that to six months. And most recently, we just modified that up to 12 months. So I think ultimately where that's going to land, we just need to generate more data with a larger denominator to really have a sense of duration. Like personally, because it is the neoadjuvant setting you said, at least my anticipation, likely in that six-month range where if you're seeing benefit, that's a half a year, which I think is a healthy amount. There may be situations for certain patients will extend beyond that, perhaps start approaching a year as well. For a patient who's slated for enucleation and you treat and suppose you're successful, what sort of intervention does that patient then get? If you've spared them full enucleation, where do those people end up? Yeah. So it's really one of two scenarios. It's either now the tumor's to the size where the eye does not need to be removed, but then they will ultimately place a plaque. And obviously, if that tumor continues to shrink, ideally, obviously the smaller the plaque, the better, because not only did you save the eye, you could also perhaps preserve the patient's vision. And we've done that with patients that were on enucleation where not only did we preserve their eye, but we had the ability to also preserve their vision. So that's one. The second is, is there a scenario, and this is we just don't have enough data or enough longitudinal data yet. Is there a situation where that patient could continue to get benefit where you don't even need plaque therapy? You could use less invasive procedures. I think that story has just not been written yet. We anticipate that probably will be a small proportion of patients, but obviously we would hope possible. Okay. That's very interesting in a neoadjuvant setting. The other place that you are looking is in the adjuvant setting. You've discussed in the past those trials take much, much longer to run or potentially a little bit more challenging to get on label for. So what is your current plan there compared to all the other places that you're looking? As you said, presumably most of these patients at some point in their journey are going to see Daro. How aggressively do you want to pursue adjuvant and where does it make best sense to drive value there? Yeah, look, you know, obviously having worked in oncology since the '90s, and I think, John, I know you cover very extensively oncology. Anytime you're talking about adjuvant setting, there's nothing more important, right? You're really focused on hopefully truly impacting these patients' survival in a profound fashion. And we believe we have the opportunity to have a therapy that could have potentially a key role in that setting. I think the key challenge for us here is, you just said earlier, that's going to be a very large, long study. We've run the stats on what that would look like, both in terms of how many patients we would have to enroll. In this case, we would anticipate the primary endpoint would be RFS, where you would have to show superiority, the time to get that readout. You're talking probably about a study that may take 10 years. And that's why for us, when we think about neoadjuvant, getting data in a randomized fashion where we're actually getting a survival readout such as EFS, although the FDA has said to us, all you need is no detriment to get full approval, we don't know. It's possible that we may have a much better hazard ratio, right? And now you've demonstrated in a randomized fashion, you've hopefully had the chance to potentially even positively impact survival. Then in our sort of clinical team scenario, have we sort of gotten both opportunities in one trial, which is going to be more efficient, faster to read out? So I think that's our current thinking is to focus on the neoadjuvant because we believe the path to commercialization will be much faster. There's really just no way around RFS endpoint for an adjuvant setting. With a superiority requirement. Yeah. Correct. In our remaining couple of minutes, maybe a couple of minutes to spend beyond Daro, as interesting as it is. Most of the focus on your MAT2A program, the MTAP-deleted tumors. So the first-line combos with synergistic agent like PRMT5, that's what's capturing most folks' attention. So maybe let's start there. You're headed to expansion cohorts around year-end here, presumably focused in lung cancer for obvious reasons with Amgen. But there are still multiple settings very relevant given these MTAP-deleted tumors. So can you talk a little bit about the settings you see the most potential in beyond lung? Yeah, let's start there. Yeah. No, look, MTAP is obviously a subject very critical to us. And for the listeners here, MTAP deletion is perhaps one of the largest patient selection biomarkers being evaluated by the industry in cancer, next to RAS. So it's been reported to roughly 15% of all solid tumors. And that ranges in tumor types like lung cancer, which is a high priority, 15%-20%, as high as 30% in urothelial cancer, similar range of pancreatic cancer as well as others. So by every measure, a significant opportunity and a high unmet need because there are no approved therapies. Within that framework, we had presented in Barcelona a few months ago as a late breaker oral presentation. We were alongside a few other companies where we reported a confirmed overall response rate of roughly 30% depending on the tumor type. Here we believe in order. I'll tell you here, John, is lung cancer our number one priority. Second is urothelial cancer. Next, I would say, is gastric and esophageal cancer. We, as an organization, have less interest in tumor types like GBM or cholangio or mesothelioma or pancreatic cancer, and that's really based on the basic biology of this pathway. In addition to monotherapy, which we're going to continue to evaluate with IDE3 97, as you mentioned, we're very interested in the PRMT5 combination, which we're exploring with Amgen. In particular, in the tumor type of lung cancer, you may know we also recently announced we have our own PRMT5 candidate that we'll be formally announcing here shortly. I'll ask you more about that. Okay. No, absolutely. And then second is we have a very key combination ongoing with Gilead with their Trop-2 ADC Trodelvy in urothelial cancer. We have seen early activity there, including a response we reported at Barcelona. Now, speaking of the Barcelona data, one of the things that sort of pops out is there is a big difference, squamous versus non-squamous there. Is that something that you have planned to carve out in further development? The studies are obviously in Amgen's hands right now for that combination. But where are you viewing the easiest development track there in the most relevant combos? Yeah, for monotherapy, I think that decision has not yet been made. But we do anticipate we should see greater activity in squamous lung cancer. For a combination, our anticipation is we would evaluate all the lung cancer, both squamous as well as adeno. All right. Well, let's talk about the internal PRMT5 then. What are the differences with your internal program versus some of the other PRMT5s in development, obviously Amgen being the combo that you're running right now? Yeah. So first, I would just emphasize the chemistry is novel. We've been doing work in this arena for well over five years. Basically, the key product profile we felt was ideal for this target. First, we believe brain penetrance is more a liability than a benefit. And that's based on the very specific biology of the targeted PRMT5. Second, we believe there's an importance between the balance between potency and selectivity. Our perspective, based on all the chemistry we've evaluated, is that you don't want to just keep driving the potency down, down, down, down, down, that there is a point at which you start breaking the selectivity barrier. So I would say in that context, our molecule is most likely closest to the BMS compound. Second is around ADME DMPK properties. As you know, there may be some molecules that are dosing quite high. We believe we have a much more favorable ADME DMPK profile. And then lastly, our core objective here is we believe we've identified a molecule that's fit for purpose to be able to create a best-in-class combination with our phase 2 MAT2A inhibitor IDE 397. Now, obviously, it's still early with the internal program, but given the learnings that you're already generating from the Amgen combo, I expect you'd be able to advance that relatively rapidly. Can you talk a little bit about some of those learnings you're getting from Amgen and how rapidly you could move your own program into combos in clinic? Yeah, no, exactly. I mean, the reality is our plan is to have this in the clinic by middle of next year, so only in a few quarters. We have a really good understanding of this combination, the dosing, the optimal dosing for moving forward. So I think we're going to be very well equipped to push this forward. And for us, it's always been a core strategic objective for us to have the ability to have a wholly owned combination. And for us now, we believe we have a best-in-class and first-in-class MAT2A inhibitor. And at least we believe we have the opportunity to have a best-in-class PRMT5 inhibitor. All right. Now, I plan to ask you about the Trodelvy combination as well, but we are running out of time, so I'm not going to. Instead, I'd love to give you the chance to talk a little bit about some of the downstream agents. You've got a PARG, Pol Theta, Werner helicase. Broadly speaking, these targets are sort of familiar to a lot of us, but not fully developed and clearly not had all their value unlocked. Especially Werner, as we discussed recently, seems to be developing as a real focus for a lot of folks. So can we start there? Yeah. Tell us about your program relative to everybody else's? Yeah, I think I would say beyond Daro and MTAP, for the listeners here, the target I would emphasize that we think is one of the more important targets in precision oncology that's been discovered in the last 10 years is Werner helicase. Here, I would just mention that we are in good company. Novartis and Roche have entered early phase one trials, but we are the first biotech company to enter the clinic. Next, and this is with our partner GSK, we do believe we have a differentiated molecule. We have committed with the support of GSK to be able to publicly communicate that we will be presenting that differentiation profile versus the existing Werner inhibitors in the clinic at a medical conference. So here, stay tuned for that. We're excited to share that information. This is obviously now a clinical stage asset. We believe clearly has significant market potential. Here, the patient selection biomarker is high microsatellite instability, which, as you know, John, is roughly a third of endometrial cancer, roughly 20% of colorectal cancer. Here, also not only an opportunity to develop it as a monotherapy agent, which we fully anticipate we will be able to, but as well as in combination with PD-1. Yeah, makes sense. PARG also on the cusp of data. You suggested we might see more there at an upcoming R&D day, which I think we're all looking forward to. But as we get prepped for that, what are the sorts of things that we should be paying attention to? What are the clinical differentiators, the clinical characteristics that you think would be differentiating for that sort of a program? Yeah. So for those that may not be familiar with PARG, it's a first-in-class agent that we have in the clinic. It's in the same pathway as PARP. Here, the primary difference is really the role that PARG has within this pathway as it relates to replication stress. Here, we are preparing to start the expansion phase as monotherapy in a specific solid tumor type. We'll likely not announce what that tumor type is, mainly for competitive reasons. And then second, we recently launched a new partnership with Merck, where we're looking at in combination with Keytruda, both in the high microsatellite instability as well as microsatellite stable setting in endometrial cancer. And then lastly, I would be remiss not to mention one of our core focuses for this is we believe the PARG mechanism has the ability, potential ability to enhance the efficacy of Topo ADC-based agents. All right. Well, we're well over time and into the passing period. So thank you very much for joining us, Yujiro. And we look forward to seeing more data on all of this at the R&D day and as we get into even further clinical updates next year. Great.