Great. Good morning and good afternoon, everyone, and welcome back to the 2025 RBC Capital Markets Ophthalmology Conference and our annual conference this year. For the next session, we're pleased to have IDEAYA Biosciences. Joining us from the company is Yujiro S. Hata, the President and CEO, as well as Dr. Darrin M. Beaupre, who's the Chief Medical Officer. We look forward to really nice discussions. A great time for IDEAYA with respect to their lead candidate, darovasertib, but also a really nice diversified pipeline that is emerging. With that, Yujiro, over to you for a brief overview of the company. If I have my math right, I think we're coming on a 10-year anniversary for IDEAYA, so I think that's quite a milestone that's worth appreciating here as well. Yeah, that's right. Thank you first, Greg, so much for the kind introduction. Thank you to RBC for the opportunity to participate this year. As you mentioned, Dr. Darrin M. Beaupre, our Chief Medical Officer, will join us today for the fireside chat. Amazingly, we're approaching our 10th year anniversary coming this summer. It has gone very, very quickly, but very excited about what we're building and what's to come over the next couple of years. Maybe here, Greg, really quickly, as you mentioned, darovasertib, our lead program, we're in a registrational study, which is a frontline study of metastatic uveal melanoma. We are guiding towards before year-end, potentially our first readout to hopefully enable accelerated approval. This primary endpoint is median progression-free survival. We have several other updates, which I'm sure we'll talk about today on the darovasertib program that we're guiding for this year. As you know, on Monday, we also announced getting Breakthrough Therapy Designation in the neoadjuvant setting, which we're thrilled about, which I'm sure Darrin will walk through as well. Beyond that, in aggregate, we have six clinical programs. I think we'll hopefully get to some of that. In the second area, a big focus on MTAP deletion. Obviously, as you know, IDE397, MAT2A, potential first-in-class asset. We anticipate we'll have our second clinical program in MTAP by the middle of the year. I would say the third focus area is in the areas of our topo ADC and PARG assets, where we're looking at key combinations with a topo ADC class. Greg, as you know, here with DLL3, we're also guiding towards a data readout at a medical conference in 2025. We did recently just submit the IND in the U.S. Once we get that clearance, we'll target to give more guidance on when that data update will come, how large that data set will be. We do anticipate we'll have data at multiple expansion doses for that program. The next one is Werner Helicase. Here, Werner, as you know, we have an oral presentation at AACR upcoming here in a couple of weeks. We're excited to share the story on Werner. We know that there's another company, a major pharma, that looks like they're going to present their first clinical data on Werner. It will be exciting to see the first data on what we think is an extremely high-value target. Beyond that, we have Pol Theta in the clinic. As I mentioned, PRMT5 coming in. We have a bispecific ADC we're looking to follow an IND on, as well as our KAT6 program. As you can see, we're keeping Darrin very busy. He's going to have a lot to do in 2025. Yeah, that's great. Maybe before we dig into uveal melanoma and darovasertib, maybe, Yujiro, just a comment on what has enabled all of these development programs as you think about IDEAYA's precision medicine platform, the drug discovery capabilities, integrated nature, just that focus on tumor heterogeneity, which is obviously complex, rational combinations. Maybe just comment a bit about what kind of ties that together, what underlies the development of all these assets. Yeah, for sure. We have several key pillars that have really driven the company over the last 10 years. They include a significant focus on first-in-class opportunities, which several of our programs, including darovasertib, represent. Second is the importance of having a key patient selection biomarker. As you know, in the area of uveal melanoma, GNAQ/GNA11 is that predominant genetic mutation that we've been targeting. Third, as you mentioned, around addressing what we believe is one of the key challenges of treating patients with cancer, which is tumor heterogeneity. We believe really our core ability to address tumor heterogeneity is through rational combinations. We've implemented that clinically across many, many programs and many situations. We were the first to enable those. For darovasertib, as you know, PKC and c-MET with crizotinib, obviously MAT2A in PRMT5 and MTAP deletion, Pol theta and PARG in the area of homologous recombination. Now we'll be implementing with GSK, Werner with PD1, and MSI high. That list is going to continue to grow. What I would say supports all of this is what we think is an extraordinary R&D engine that spans basic cancer biology, significant focus on translational medicine, and a big focus on, in particular, computational and structural biology-based drug discovery. That's great. Thank you for that. Let's talk uveal melanoma and darovasertib and the programs. Maybe just walk us through how darovasertib fits into the current treatment paradigm and maybe talk a bit about some of those assumptions when we think about a high opportunity, but small market, but certainly very opportunistic here. Yeah. Darrin, do you want to take that one? Yeah, I can take a little, give a little bit of background of why we're in such exciting space with darovasertib and uveal melanoma. It's obvious, first of all, the biology takes front and center stage. You can't actually develop uveal melanoma without a mutation in one of the genes that activate the protein kinase C pathway. That's sort of the harbinger of the disease. It is the key trigger. It is the key driver of growth and survival of the tumor. That's why we're seeing such exciting data with darovasertib as a protein kinase C inhibitor. The key here is we think because of this important node in the development of the disease, we actually have the potential to cut across the entire patient journey of patients with uveal melanoma. Now, we've obviously started in the metastatic setting. We did so with a combination of Crizotinib. Why? Because it turns out that when you're in the metastatic setting, not only do uveal melanoma depend upon protein kinase C signaling, but they also depend on MET signaling. In fact, the little interesting factoid that maybe some of your folks don't know is uveal melanoma loves to metastasize to the liver. Once you know it, the ligand for CMET is hepatocyte growth factor, which is so the liver is a really nice source of that ligand. By going after both protein kinase C and MET with the Darovasertib-Crizotinib combination, that's why we've seen such profound activity in the metastatic setting, both in HLA-A2 positives and negatives. We can get into the details of that trial. Ultimately, by the end of this year, we're going to have a good view of what kind of activity we have relative to your standard treatment in this setting. Thinking about what happens before that, you have, okay, what about primary uveal melanoma? Wouldn't it be great if you could do something for patients who develop the disease, have it in their eye? Now they can be managed, but a lot of them are either going to lose their eye or lose their vision. Again, because we go after the key driver of this disease, even single-agent darovasertib has a profound anti-tumor activity. We've already presented some data to show that a significant proportion of patients get their eyes saved because of this treatment. Even if you're a person who has a smaller tumor that gets plaque brachytherapy, not only can we shrink the tumor, but we've provided evidence that we've been able to reduce the radiation dose and improve their vision based on a vision prognostic tool that can tell you how patients are going to do three years down the road. Lastly, this entire patient journey we're talking about is now, what about preventing metastases altogether? There is an opportunity to use darovasertib or darovasertib-crizotinib in the adjuvant setting, which is another focus that we may have in the future. To line it all up, if you're looking at the disease as a whole in the entire patient journey, you got a tumor in the eye needed to be taken care of, darovasertib can get involved. If you have, okay, now you have a high-risk patient who's had their eye removed or they've had their plaque brachytherapy and there's a high risk of metastases, there's the potential for Darovasertib to have an impact. Lastly, the metastatic trial is ongoing where we've shown that we have activity that's clearly superior, at least based on phase two data, than anything out there in this setting. We are looking at a very active combination regimen that we think is going to help patients a lot. That gives just sort of a high-level overview of why Darovasertib, why is it important in uveal melanoma, what is the patient's journey, and how can Darovasertib fit in? That's really helpful. I like, Darrin, how you reflect on that patient journey to just put, I think, a real-world nature in the context of Darovasertib. Maybe just keeping with the metastatic in that first-line setting, you alluded to the standards of care and also your phase one-two data that you have. We're going to see some more data later this year. I want to get to that. As we put the study and what you've shown already into context in first-line metastatic uveal melanoma with Darovasertib and Crizotinib, just talk about how you look at that with respect to the standard of care with the available agents that are used today. Sure. Okay. What is the standard of care? If you have metastatic uveal melanoma, what do people do? If you have metastatic disease requiring systemic therapy, what are your options? If you're in the United States, we're probably talking about an Ipi -Nivo mbination, so an immunotherapy type approach with a combination, which obviously carries some toxicity with it. If you're in Europe, we're talking about using single-agent checkpoint inhibitors because they're typically what is the first-line therapy for that region. Why? I think there's some debate about whether the combination of checkpoint inhibitors is better than single-agent. There's some controversy there. The only approved therapy for patients who are HLA-A2 positive, which, by the way, only makes up about at most 30% of patients in this setting, is Tebentafusp. I want to say two things. Number one is uveal melanoma is not like skin melanoma in that it doesn't have a high mutation burden. It's not immunotherapy sensitive. It's a different disease. Therefore, you might expect that these therapies that I've just described may not be as effective as you'd hope. Now getting into the numbers, what can we expect when you get this kind of therapy? On the average, the response rate is somewhere around 10% or so, plus or minus. Progression-free survival is about two to three months. Very, very limited with respect to response and progression-free survival. That's obviously a problem. Patients need more. We've presented data. We presented an oral presentation at ESMO that showed that in patients in the first-line setting have a response rate of 40%. Our progression-free survival was seven-plus months. We had half of patients on study for over a year, maybe 30% two years. If you look at our PFS curve, there's a tail on that curve that makes it look like 20% of patients two years out are still continuing on therapy. We are advancing the field significantly, we believe, with the darovasertib-crizotinib combination. That's why we're so bullish in looking at our data and what we can deliver at the end of this year. If we think we're in line with the kind of numbers that I've just described that we've seen in our phase two trial, we're going to beat standard of care pretty handily, but obviously, we need the data to read out. Certainly alluding to the end of the year with the data for the registrational trial. Before that, it looks like there's a plan to show the OS data for the phase one-two coming this year. Maybe talk a little bit about that. What should investors look at as sort of that clinically meaningful benchmark on the OS that, frankly, would give you and us greater confidence in the trial that's underway now? Darrin, do you want to take that? Yeah. We have maturing data, obviously, coming out with the study that you've alluded to here. You'll get an update on the overall response rate, the progression-free survival. Importantly, we haven't presented in the past overall survival data. Let me put this into context for you. If you went and you looked at meta-analyses, you look at a large number of patients and how they've done with standard of care therapy, in the metastatic setting, you're probably looking at an overall survival median of approximately 12-13 months. That's kind of what you're looking at. Any therapy that can prolong survival six months relative to standard treatment, standard of care would be considered a win, right? I think what you're going to see at the end of this year, now, admittedly, it is from a single-arm phase two trial. It has its limitations. There's this thing about cross-study comparisons, etc. It does give a guidepost of what you might expect the overall survival could look like in a registration trial. I think as we unveil that data later this year, I think it'll help folks understand why we really feel like we're as best positioned as you can be in terms of response, PFS, and OS that tells you that not only was this trial that we've designed well conceived, but you'd have to think that the probability of success to phase two data tells you everything you want to know. You'd have to say that you're leaning on the, "I'm very excited" side. Yeah. Also, Greg, in addition to the OS, Greg, you may know, we haven't reported median duration of response before. That data has been immature. We'll provide that number as well. I think people will be enthusiastic when they see also just more color on where we are with MDOR. Great. Great. That update will give way to the year-end PFS update for the registrational enabling phase three. Maybe just talk about how that's enrolling, how that's progressing, and just how you're tracking to that year-end update. Yeah. We're doing great there. We're at the terminal phases of the phase two enrollment. That'll continue to roll. That's great. In terms of the phase three portion, again, if everything stays the way it is currently, we're on track that by the end of this year, as early as the end of this year, we could complete enrollment for the phase three portion. It'll just be a matter of waiting for things to read out. What would be the current assumption on approvability based on PFS? We have talked to the FDA before about the trial design and its execution and how it was a seamless phase two-three design. Obviously, they felt that if the results were significant, as we've pointed out, and they maintain what we've seen thus far relative to the phase two, they would certainly entertain a discussion about an accelerated approval. Full approval would be dependent upon the OS readout. We will get an OS readout at the time of the PFS readout to get a sense of where we are. At that stage, if we read out with PFS, we could talk to the FDA about accelerated approval. If the OS data continues to be immature because remember, if we're doing a great job helping people, there may not be that many events, right? We may have to wait a little bit, but we will have another look in the middle of next year to look at more mature data and see at that point, have we reached a level where the number of events is appropriate that the FDA can buy into? Fantastic. Just remind us, Darrin, just investigator choice in terms of the control, maybe what are the assumptions there on performance in? Yeah, that's a great question, Greg. In this particular trial, we've done something that other people haven't done. The Kimmtrak didn't do this in their registration trial. They didn't have IPI-NIVO as a comparator, right? We are going to convince people based on this trial, there is nothing out there in the HLA-A2 negative patients that is better than darovasertib-crizotinib. How are we doing that? Again, you can get IPI-NIVO as a treatment. You can get single-agent checkpoint inhibitor as a treatment. People are eligible for those, and it should be very few, less than 5% of patients who can't get a checkpoint inhibitor for some other comorbidity. For example, let's say they have bad rheumatoid arthritis, something like that. You can get dacarbazine, which is chemotherapy. We expect very, very few people to be in that bucket. It's really darovasertib-crizotinib versus the best of immunotherapy that you can deliver. Our expectation is we're going to see a lot of IPI-NIVO in the US. We're going to see maybe less of it in Europe. It's basically, this is it. Nobody can run, nobody can hide. Nobody can say IPI-NIVO is better than single-agent checkpoint inhibitor. We'll be able to compare the control arm data. We'll be able to compare it to the treatment arm data. We're going to get a lot of answers that are not only going to help patients, but it's going to help the field understand where all of these different therapies sit. Excellent. You discussed earlier just the SKU on the HLA negative versus HLA positive. This study is designed to support approval in the negative mom. Just remind us of that strategy of opening up to positive, how you think about either potential listings, how Darrow-Crizzo can be used in the broader population. Right. Great question. We haven't forgotten about the HLA-A2 positive patients. I want folks to know that very, very clearly. They're top of the mind. It is sort of the minority of the patients, but still, it's very, very important. Based on the biology and based on what we've seen clinically, there's no reason to think that HLA-A2 positive patients won't benefit similarly to HLA-A2 negative patients. We have opened up our phase two trial to enroll more HLA-A2 positive patients, which is underway now. We're looking to enroll up to 70-75 patients or perhaps slightly more that are HLA-A2 positive. The base case is what we hope to do is publish a very nice publication that shows that when that phase three data reads out, we'll have an overall response. We'll have a progression-free survival and maybe some early survival data. We'll be able to show that in the HLA-A2 positives that, you know what, the response rate, the progression-free survival are very, very similar. Again, that'll be a cross-study comparison. Get that data published. I hope the folks that review the guidelines for treatment of uveal melanoma will see this. If it becomes a standard of care for HLA-A2 positive patients based on the NCCN guidelines, patients would be allowed access through compendia use. You'd have the registration trial that would read out hopefully positive and HLA-A2 negatives. They'd get full access. Then you'd have compendia used through the NCCN guidelines. Now, there is another thing that we're doing in order to up the ante here, which is we're looking at opportunities to collect real-world data, looking at patients who are HLA-A2 positive, getting standard of care therapy, and maybe use that as a comparator arm to that single-arm phase two. It is very possible that we could sit down with the FDA at the time that we're thinking about the HLA-A2 negatives and say, "Hey, listen, we have this data from HLA-A2 positives. The biology says there shouldn't be any difference. The clinical data shows that there isn't any difference. We've compared this to real-world data. Look at how exciting it looks relative to real-world data. Would you be open to talking about the potential for a broad label?" That is still on our mind. We know it's a long shot, and it's not the base case, but it's not a crazy idea in a disease that doesn't have any good treatments. It's not like there's a lot of good things people have waiting for them. This is probably the best thing out there, at least in our mind. I think in addition, Greg, I think another concept we're talking about as part of that submission is we're also going to have a lot more neoadjuvant data in uveal. Again, there we have HLA-A2 positive and negative. Could we also submit that data just as tumor shrinkage and that we're seeing consistent tumor shrinkage also in the pre-metastatic setting that I think would just support this sort of broader theme that the drug is active irrespective of HLA-A2 status? Yeah. That's helpful. Also reminding, we tend to overlook that Darovasertib is an oral option versus some of the others. I want to take the conversation earlier in that patient journey to the neoadjuvant setting and certainly some meaningful updates this week, Yujiro, just on your FDA engagement. Just walk us through, and Darrin, you spoke about the rationale, which is super helpful, but just walk us through some of those updates that you've received this week, the breakthrough, and just how that's fitting into the updates that are coming this year. Yeah. Maybe I'll start, and I'll hand it to Darrin here. I think first, Greg, I think I know we had caught up earlier, and at least we had our regulatory team fact-check this. We believe we're correct on this, but we think we're the only second company that's gotten Breakthrough Therapy Designation in oncology for the neoadjuvant setting. The other is Keytruda here. I think we're in pretty good company from that regard. I think it's a testament to, obviously, at least the preliminary value we're seeing for this agent in the neoadjuvant setting and obviously phenomenal work that Darrin's clinical and regulatory team has done. Maybe with that, Darrin, do you want to give some of what data we provided, what people should expect? Also, we are also focusing on the plaque brachytherapy data set, which we're equally excited about, but Darrin, why don't you take this on? Right. We were able to share with the FDA some of the emerging data that we had from the OM trial. Remember now, that particular trial is patients who come in with either two types of uveal melanomas. One, the very large one for which the doctor says, "Listen, I'm sorry, but this tumor is too big. We're going to have to take your eye." There are patients who have smaller tumors where the doctor says, "Okay, now I need to sew a plaque onto your eye. I'm going to radiate that tumor." Although I have to tell you that if we do that, there's a reasonable chance that you're going to lose your vision. You get to save the eye, but your vision preservation is in question. That is the patient population that we're talking about. The idea here was to look at, did we have an ability to shrink those tumors? Because if you shrunk those tumors, in the large ones, you could actually save the eye, right? In the plaque brachytherapy group, if you could shrink that tumor, you could reduce the amount of radiation, which then translates into vision preservation. We have been able to show, based on data that we've provided previously, that we are able to save a significant number of eyes. About 60% of eyes are saved simply because patients got darovasertib. By the way, the vast majority of patients who get this treatment have tumor shrinkage. You've probably seen that in our waterfall plots. In addition, 60% of those is enough where the eye can be saved. On the plaque brachytherapy side, the data is less mature there, to be quite honest. As the trial opened, the vast majority of patients who came on initially were enucleation patients where shorter-term follow-up is required to actually know if you've saved the eye or not. With the plaque brachytherapy group, they came on a bit later. You have to simulate them pre and post treatment to actually look at radiation that they would have received if they hadn't got Darovasertib and compare it to what you think that they'll get after they get the Darovasertib treatment. Long and short of it, in the plaque brachytherapy group, we saw almost universal tumor shrinkage. We saw radiation reduction, vision preservation based on a vision prognostic tool. That was presented to the FDA. Again, a data set that was fairly mature for enucleation, still in progress for the plaque brachytherapy group. They clearly felt that this was a remarkable effect and that Breakthrough Therapy Designation was completely appropriate for the enucleation patients. The plaque brachytherapy folks just need more follow-up and more time to simulate more data. This is what you're going to be seeing more of as the data matures over the next year. Our initial plans are to look for an ophthalmologic conference at the middle of this year to present specifically the plaque brachytherapy group, not in its entirety, but to give you more data than you've seen in the past. What should you expect there? You're going to see evidence of tumor shrinkage with darovasertib in the neoadjuvant setting for these patients, how that translates into radiation reduction, how that translates into vision preservation. Most importantly, one of the things that we haven't really talked much about, folks, is what actually happens during the neoadjuvant therapy. You know what? Based on feedback from investigators, what have we heard? We've heard things that people like Carol Shields would say, "This is incredible. I've never seen anything like this before." People come in with retinal detachment. The retinal detachment gets better. People come in with subretinal fluid or subfoveal edema, and that gets better. It used to be when you had those two things, your visual outcome was bad. I mean, really bad. Now they're actually seeing it reversed on therapy. We've had even a few patients who've come in with 2,200 vision or worse. That is legally blind. They end up on darovasertib therapy, and their vision gets into the range of many of us at my age who, if you wear glasses and you take your glasses off, their vision is better than yours. Okay? We have those examples. This year coming, at that mid-stage, you're going to see some of that. What our plan is by the end of the year at a large scientific conference is you're going to see even a larger sample set which will encompass both the enucleation patients and the plaque brachytherapy patients so you can get a holistic view. Mid-year, you're going to get a teaser, an appetizer on more data than you've seen before with the plaque group. That should stimulate your interest even greater. At the end of the year, you're going to see it all in combination. If you were to ask me, "Greg, how is this going to translate for people looking at us from the outside?" To me, it's like, "Okay, metastatic disease in a relatively rare tumor, really exciting." You're obviously making all you have to do is look at the waterfall to recognize you're making a big difference in this disease. Now, in addition, in the neoadjuvant setting where the patient population is bigger, we're talking about a large opportunity now for patients across the spectrum of uveal melanoma having similarly profound effects. I think people are going to really be really excited about the opportunity that we have for patients after seeing this data. That's great, Darrin. Thank you for that overview. Maybe, Yujiro, just to close, and you touched on this a bit at the top, but beyond the ocular malignancies, there's so much more for IDEAYA and even what we discussed today. You mentioned AACR and Werner Helicase. Maybe just close with some of the other programs that you think could drive that increased and continued interest in the pipeline, starting with AACR and Werner Helicase and maybe some of the other programs. Yeah. I think here, Greg, what we would just emphasize is we have a lot of confidence in darovasertib. I think that message is palpable from Darrin and his enthusiasm for that program. A core objective for us is to continue to drive IDEAYA forward as a significant growth story with multiple clinical programs following darovasertib with large data sets that have the opportunity to be first in class. That is where MTAP fits, Werner Helicase. I think Werner is a situation where we do believe it is one of the highest value targets in precision medicine oncology. We are the first biotech company to have a Werner Helicase inhibitor in the clinic. We believe it has a best-in-class profile. Pre-clinically, we believe, based on the pre-clinical data, that there should be a monotherapy path forward. This is a large patient selection biomarker opportunity with high microsatellite instability. I think AACR is going to be really exciting because I think in a lot of ways, this is where Werner could get unveiled with two oral presentations now set up for that conference. I think a lot of people have been waiting for this time for Werner finally to show its first data. Beyond that, I would say is around DLL3. I think here, Greg, as you know, that ADC area with DLL3 specifically has come into focus. It sounds like there's going to be another oral presentation. Sounds like most likely at ASCO, there's already been data presented here. I think the part where people perhaps don't fully appreciate, which is our program is getting quite mature. When we do present this data at a medical conference, it's going to be a fairly sizable data set. is why I mentioned people should expect a sizable data set with data at multiple expansion doses. As I noted, we have already filed our IND. We are going to be gearing up to get that global study going as well as to enable combinations in the second half. That's great. Yujiro, Darrin, thank you so much. It's a great place to leave it. A lot going on, as always, with you and IDEAYA, even after 10 years of being a company. Congratulations. We look forward to all the updates. Thanks for joining us, guys. Thanks so much. Yeah, great to see you, Greg. Thank you. All right. Thanks so much.