Biosciences, we're a leading precision medicine oncology company. We have nine programs in the clinic, so a very deep and diversified portfolio. Umar, as you know, our most advanced program is darovasertib, which is now currently in two phase III randomized studies, one in the first-line metastatic uveal melanoma indication. Next, in the neoadjuvant indication, we're looking to launch our third phase III study this half. Obviously, very much in focus is our upcoming guidance around our top-line results for the first-line metastatic uveal melanoma setting here. The primary endpoint is median progression-free survival, I'm sure we'll talk more about that today. Beyond that, we have a very deep pipeline. I would say next is a portfolio of assets in the ADC space. I would say probably most attention is to our DLL3 Topo ADC IDE-849. We are guiding towards a clinical data update on that program by the end of the year, and we believe this molecule does have the potential to be a best-in-class asset. As both you, Umar, and John know, we did present a very robust single-agent activity as an oral presentation at the World Conference on Lung Cancer last September. Beyond that, we also have a deep pipeline in MTAP deletion. We have two clinical assets here, both PRMT5 and MAT2A. We think a lot of interesting opportunities, both as monotherapy as well as combination. Also, as I think both of you have been following, a lot of interesting intersections between RAS and MTAP as well. Lastly, KAT6/7. IDE-574 has now entered phase I. We think a really unique opportunity, and perhaps one of the largest addressable patient populations, including in breast cancer, and colorectal cancer. Mick White, our CSO, is here, and we can definitely dive into the science of that as well. I think that's a, hopefully, a good summary and encapsulation of the company. Got it. Okay, great. Fantastic. Maybe just as we begin, could you just remind us, sort of the timing and the expectation for this upcoming readout? Yeah, the timing is gonna be in the next couple of weeks. We've now guided on or around the very end of March, so we're obviously going towards March now. The data update is in the near term. In terms of sort of table setting on expectations, Umar, here, our perspective is what we believe we'll see in the control arm is gonna be consistent with what's been published in large meta-analysis before. I know there's been some questions about ipi/nivo in the control arm, and I think here, probably the most, at least we feel, reliable paper there is the Piulats paper, which was a multi-center study. There, we believe the PFS is gonna come in roughly 2-3- months. In the treatment arm, we've reported a 7-month PFS in two oral presentations, one at ESMO, several years ago and then most recently at the Society for Melanoma Research this past fall. That PFS has been solid, approximately seven months, including with roughly two years of follow-up. We feel good about that number. You know, if that's what we see, you know, we feel good about our prospects to hit stat sig as our primary endpoint. Got it. Can I, can I ask, before we, before we get too far off of what- Sure. ... the trial design is one of the things that I know we've spoken about in the past, and I am continually curious about, is given, you have a investigator's choice comp arm, ipi/Nivolumab, probably the most relevant thing that people are asking about. There are other options. You've got a combination on top of crizotinib, which is not available in the comp arm. Can you give us some of your thoughts about what the potential variability is in the comp arm, about what the contribution of parts is in the experimental arm, and how we should be balancing the, the expectations there? Yeah. Darrin, you wanna take that? Well, in terms of the contributions of the two components in the daro-crizo, that's pretty clear. I mean, darovasertib, we know what it does as a single agent. It's active. We've shown that in phase I. Crizotinib, however, has limited activity, at least at MET inhibitors in this space. They've been tested before in small numbers, in clinical trials. Really haven't shown much in the way of activity. It's very clear, at least pre-clinically, when you put the two together, and you impact both pathways, Protein Kinase C and cMET, you can see enhanced antitumor activity, and we've shown that pretty conclusively in the clinic, obviously, with the daro-crizo combination, relative to what either agent can deliver alone. Also, we've discussed this with the FDA. Contribution of components is pretty clear. We know that you need the MET inhibitor to enhance the activity in the metastatic setting. We also know in the neoadjuvant setting, you don't need the crizotinib. It doesn't seem to add. We already have profound activity in the neoadjuvant setting with darovasertib as a single agent, so our, our thoughts are we don't need the crizo in that setting. However, in the metastatic setting, different story. With respect to your other question about the control arm, to be quite honest, there's been at least two meta-analyses published, thousands of patients, and I think we feel very, very comfortable with where the control arm sits, whether it's ipi/nivo, whether it's ipilimumab, whether it's a single-agent checkpoint inhibitor like nivo or pembro. They all sit right around two or three months. With our long-term follow-up from the OptimUM-01 trial, two years of follow-up, where we maintain a rock-solid PFS of seven months, and we only need to hit maybe 5.5 in order to be, have a positive study. We think we have a great buffer zone. Again, I think we're just as well positioned as you possibly could be to beat the control arm in this particular situation. Our OS looks profound, too. I mean, that PFS translates into another metric, which is OS. We have 21 months of overall survival. Mm-hmm ... in the OptimUM-01 trial, and so those two things go hand in hand. If you combine that with the fact that we're tripling the response rate compared to standard of care, we have a really rock solid duration of response of nine months. You know, we just think we couldn't be better positioned to take on standard of care in this case. Well, since you brought up, OS, Darrin, that was gonna be my next question. John, can we maybe just 1 second? Can we just, like, set the trial? I wanna go through all the data very carefully, but maybe let's just set the trial. Can you remind us the design of the trial, just so we're all on the same page? Sure. What we're talking about now is metastatic uveal melanoma. Patients with uveal melanoma who have metastasized. They also have to be HLA-A2 negative, which is probably about 2/3 of the patients with uveal melanoma. It's a simple, randomized phase III comparison of either standard of care, which in this case is either single-agent checkpoint inhibitors, a combination of checkpoint inhibitors, plus other immunotherapy, like ipi-Nivolumab. You could, if you happen to be a patient who couldn't get immunotherapy for whatever reason, you could get chemotherapy, but we think that's gonna be a very small proportion of the patients treated. Of course, in the treatment arm, on the other side, is the darovasertib crizotinib combination, which we've tested extensively at the 300, 200 milligram dosing. Again, this is a study where the primary endpoint is progression-free survival, so that'll allow us to have a discussion with the FDA. Then, of course, that study will go on to read out for overall survival for full approval. What has happened so far in the trial? Has there been any interim looks so far? No. This is what's coming up now, our top line to look at our first, our first look at progression-free survival. How mature do you expect OS to be at the time of PFS maturity? Very good question. I think the maturity is one of those things where, you know, if when we talk about the, the outcome for this particular study, some of the things that we're likely to talk about is obviously the response in the two arms, the progression-free survival in the two arms, of course, maybe some durability, you know, with respect to duration of response. You know, survival at this stage may be relatively immature. If we don't say anything about it, it's not because it doesn't look good, it's because there may not be enough data- Mm ... to actually make a call on, on whether there's any trend, for example. Right. However, there, there will be opportunities down the road. You know, we'll be obviously filing, the NDA. We'll have the opportunity to once again provide the FDA, safety information and perhaps efficacy information during the filing period. Of course, our first interim analysis for OS comes up at the beginning of next year, or the first half of next year. That'll be a couple of opportunities to look at OS, and it, it's very possible that during that period of time, we'll have enough events. At the first look, it's uncertain at this time if that will be the case to really make a call. Right. So if I- Sorry, John, before we move on from the trial design, there's a phase II here, and there's a phase III here. Could you just remind us, have you guys spoken to any dynamics around the phase II data yet? No. At this point, again, this will be the first time that people have seen what we have evaluated with respect to progression-free survival, as well as safety, comparing the control to the treatment arms. We did have... You know, this was a sort of a 3-component study. We had a 2-A part, where we actually looked at dose optimization to show that the 300, 200 milligram dose going forward was the optimal dose, had the best benefit-risk profile for patients. Then the 2B3 is the part that we'll be reading out now, which now accumulates patients to be able to have enough data to show that the progression-free survival, how it compares between the two arms, and then we'll follow that up with overall survival. Okay. 3-component study, Part 2A completed, 2B getting... 2B3 getting ready to read out, and then the. How many, how many patients were in Part 2A? Part 2A was designed to look at the two doses, and without getting into dramatic detail, essentially, it was a 2-staged component, so it depends on how you define it. The long and short of it was approximately, you know, 80 or 90 subjects to be able to look, take that first look. Remember, they were randomized two- to- one, so two to the control arm, two to the treatment arm, one to the control arm. It took about 90 patients to figure out what was the right dose. We had additional patients that came on after that, you know, as we were continuing to enroll, that were part of the 2A, but they weren't part of the initial analyses. Right. Essentially, you know, that was around, you know, that 90 patients or so was all that was required to determine what was the optimal dose. Right. Then you move forward from there. Darren. The reason I. Those 90 patients, those were both A2 positive and negative. Those were- No, no, no. This study is only HLA-A2 negative, so it focused- In a pivotal. You did have a phase II that had all HLA subtypes. Yeah, that's a different component. We'll probably get to that later. That is a patient population that we haven't forgotten about, that's critically important to us. We think this treatment should work there, no different than it does in HLA-A2 negatives. However, we're evaluating that patient population in our 01 trial. We'll have nearly 100 patients' worth of data who are HLA-A2 positive. The objective would be the following: As this study reads out, our view is it'll show an improvement in progression-free survival, ultimately, an improvement in overall survival. In parallel, we'll be able to present data to the FDA, as well as the NCCN panel, that puts together the guidelines for treatment, that shows in 100 patients' worth of HLA-A*02 positive data from a phase II trial setting, that we have a similar overall response, progression-free survival, overall survival, durability of response that we do from our randomized phase III trial, and hopefully that will allow people to look favorably at that data set and utilize it as appropriate. There's no mechanistic reason to expect your drug to behave any differently in these two populations? Absolutely correct. Right, it's all about the, the mutations that drive the disease to begin with. These, these tumors, 95% of the time, have mutations in GNAQ, GNA11, G protein-coupled receptors that drive Protein Kinase C signaling, and that's why darovasertib is so effective in basically knocking the wheels out of the driver for the disease. Yeah, HLA-A*02 only matters because of Kimmtrak already approved in that. Exactly. Maybe just on the trial design again, because I just wanna make sure we. I wanna go through all those things, but just on trial design, there's a phase II and there's a phase III. Maybe let me just put up something that, that the reason I've, I'm just trying to go step by step on this. Here's something I was, I was looking at just for my own sort of understanding of the trial. We know there's, we know there's 440 patients that came in, and you said 80 of them were in phase II, so that's kind of, like, consistent with sort of- No, that's, that's not what I said exactly. What I said was. Yeah. Well, yeah. Maybe I could just- Yeah ... step in, sir. The number of patients, just to be really exact, the phase IIa portion is 124 patients. Okay. Okay. 2a, 124 patients. 124 patients, yeah. Yeah. Remember, the dose that's not moved forward gets dropped regardless, whether you, we included the 2a in the analysis or not. Yeah ... it turns out that roughly 75 patients were in the non-move-forward dose, would've been dropped regardless. Right. That leaves you. 360... Oh, sorry, go ahead. Yeah. How many get into phase III? What that leaves you is with 49 patients, with the move-forward dose, as well as the control arm. That's, was the question, should those 49 get included as part of the analysis or not? The decision ultimately that was made was that we were going to utilize that phase IIa for the Project Optimus dose optimization portion at the end. the phase IIb and phase III now are the same. It's because it's an ITT analysis, and because enrollment was ahead of schedule, when we do the analysis for the PFS, the full enrollment for the OS has also now been complete. the phase IIb and phase III are 313 patients. That's how you get to that 437 number. phase IIb and phase III is 313 patients, you said? Total, yeah. Total, right. That will be for both the PFS as well as OS analysis. 313 is the number we're going. Okay, got it. Exactly. That makes a lot of sense. The reason, that's why I was like, when John was sort of asking him those questions, the reason I kept coming back to the trial design is, I just wanted to be sure that I understood. PFS anal... 'Cause the way OS is being analyzed here, and I wanna get into the relevance and significance of that in a second as well, but this option 1, 2, 3 for OS analysis depends on what happened on PFS, right? What I wasn't sure about was, it kept saying PFS off of phase II, like, kept saying PFS in phase II. It's not phase II, it's PFS across the whole trial, phase II and phase III, all 313 patients, correct? Correct. Yeah, yeah. This sample, this sample size of 200, PEG 2.55 has ratio, so this is actually 313. You have more wiggle room, technically. That's correct. I see. You'll also have a subset of these patients that are substantially more mature than the bulk phase III, the patients that were enrolled later on in the study. That's correct. Yujiro, is it fair to say that, the interim is still being triggered by 130 events? That's correct. Right. Yeah. I see. It's gonna be the first 130 PFS events that will drive that analysis, and as you have there, the OS is 253 OS events. interim equals 130 events out of 313 patients. Exactly. Um, what was- Remember, the trial was designed, the 2a was for optimization, the 2b was for accelerated approval, and the 3 was for OS. Remember, as Yujiro pointed out, the 2b and the three collapsed together because the enrollment went so quickly. Yeah. And the- Yeah ... the additional patients that he mentioned in the phase IIa are simply because, you know, we over-enrolled the phase IIa to make sure we had enough patients to do the analysis. Makes a lot of sense. It does mean that your 130, 140 PFS events you need for the final read, almost half of those are coming from patients in the go-forward dose in the 2a, that are presumably more, much more advanced. Is that fair? No, no, no. 2a is only contributing 49 patients. 49- 2b and 2, 2b and 3 is really the trial. Yeah, if, if 49 patients, presumably, most of which, most of whom have progressed much well advanced of the other patients, that's, that's almost half. ITT, the way I understood it, was on Part 2b and Part 3. Am I mistaken there? Yeah, that's right. No, you've got it correct. Yeah. Yeah, it's the 2b, three that drives both the PFS and the OS analysis. Right, exactly. When- Yeah when did Part 2b start recruiting? We noted in December of 2024 that the IDMC selected the move forward dose. I would assume it's, you know, roughly, I don't know, roughly a month before. One time. Yeah. I see. So before- Over the course of 25, basically, you guys recruited it in about 14 months. 2-to-1 randomization, so 100 patients should all have had... I, I'll tell you what I'm really getting at. Of the 313, you've basically got, if I can have my thing here, you've basically got 100 versus 100 versus 200 type of randomization going on. All these 100 patients were presumably recruited in, over the course of 2025, and by now, almost everybody should have had an event, and almost feels like this PFS, the 130 events could have hit even sooner, or has it already happened? I don't know if, or maybe it's happened, and you guys are not unblinded to it yet. Yeah. We have said, Umar, as part of this most recent earnings, that the 130 PFS events has occurred with BICR. We're now in the data-cleaning process. Okay, that would be consistent. The reason, you know, you can imagine, the reason I was going down that path was if the if the under 30 has not been hit yet, it sounds like control arm might be outperforming by a little bit, but that's not, presumably that would... The treatment arm is doing better. treatment. No, I was- Yeah, there's. I was just going by- There's two in the treatment arm versus 1 in the control. Right, right, right. True. With 100 patients in the control arm, the treatment arm would have to be doing really spectacularly to not hit, not hit events at all. Right. The other reason that I wanted to. Hang on, John. Sorry. Hold, hold that thought for a second. Darren, let's just go with what you just said a little further. Wouldn't that also mean that if the active arm was, let's say, tracking more like a five month and compared to at three months, these interim would have happened back in, like, October, November. We can also rule out the scenario for a more narrow PFS benefit, or am I going to an extreme there? Well, listen, I don't wanna speculate, except to say I know that we've been rock solid seven months, you know, I'd be- Right I'd be shocked, you know, if we're way off on that, but, you know... Right the data's gonna speak for itself. Yujiro, do you disagree with my logic there? Say, repeat that one more time, Umar. My, my point was, if we know the comparator arm tracking at three months or so, and most of these 100 patients would've had a PFS event by late fall last year, let's say 75 out of them, or 80 out of them. In a scenario where the active arm was tracking at a slightly lower than expected PFS, let's just call it five months for a second, we would've seen perhaps a pretty meaningful number of PFS events in the active arm too, to the point where this interim would've gotten triggered by September, October last year, if the active arm was tracking a little lower than previously. The fact that this interim did not hit in September, October, doesn't that effectively become a validation for your prior efficacy got replicated? I mean, I think that's a logical conclusion, Umar. I mean, I think the key part here is what you mentioned earlier, is that it's a 2-to-1 randomization, right, from the treatment to the control arm. That control arm's gotta be pretty wide range to the right, if that's what's really driving the analysis, right? If it was flipped 2- to- 1 from control to treatment arm, again, you know, it's two to the treatment, one to the control arm. I think what you're saying, you know, just high level, makes sense to me. Right. Just factual point, 'cause the question around when did the 2B/3 portion start, I just was looking at my notes here. In that release, when we noted the 2B portion started, once the IDMC picked the move forward dose, we mentioned that 124 patients in the 2A portion, either way, 75 were gonna get dropped, 'cause it's not, that wasn't the move forward dose. We noted in that release there were 185 patients enrolled. To your question, even at that time, end of 2024, right, we were already roughly 60 some odd patients into the 2B/3 enrollment. Wait, there were 60 patients already enrolled? In the 2B3, yeah. In the December 24 release, we noted that there were 185 patients already enrolled. Yeah. We talked about 124 was in the 2A, so that, by default, that means- Makes sense. 61 or more patients were enrolled by the end of 2024. Yeah. Right. Yujiro, remind me, when did you guys say interim has happened? You guys never said that... You definitely never said that at our conference in December. That's correct. We did not. Yeah. Yes, we did-. It came in, it came in 26, whenever it did. Yeah, we clarified that the PFS events were not achieved through the end of last year, end of last year, we still had not achieved them. Yeah. I think, okay, that's, that's very helpful. That's very helpful. I mean, my understanding is there is an expectation for you to hit OS in this setting. Would you agree with that? Well, we wouldn't have done the study without it. Okay. Yeah, I mean- There you go. I think, yeah, I mean, I think all we can say there, Umar, is that we presented OS data at SMR, right? We showed, you know, roughly over a 21-month OS number, so... Yeah you know, we feel good about that. It's obviously a single-arm study, relatively small denominator, but, you know, we think it's an encouraging signal. Is it reasonable to assume that this is where you guys wanna be, in terms of the OS analysis? Like, the PFS comes in, I don't know, 0.55 or better, and then you preserve a lot of alpha for OS. That's correct. Okay. If you think about it, I mean, most people would argue that the therapies that are out there for HLA-A2 negatives right now are relatively ineffective, right? You're talking about therapy that doesn't do a whole heck of a lot, except for a few rare patients.... You're talking about a therapy that has, you know, tripled the response rate, you know, double at least the progression-free survival. Overall survival looks amazing. We, we, we should hit on overall survival, you know, you have to do the study. That's what we're doing. Got it. One last thing. One thing we were talking about OS earlier is about timing on that. So, you know, you're gonna file with the agency on the basis of PFS data, but you're gonna show them the OS data, presumably, there are probably multiple opportunities for the agency to see that. Is there a chance that there's enough follow-up on OS to get to full approval before people expect or, or on the same timeline as the initial submission? I'm glad you brought that up, because there's one thing here you have to know, is that there, there is no crossover permitted until the OS reads out. So I think that is very important, that we need to look at this data and just be aware that, you know, patients are gonna be looking for options. For HLA-A2 negative disease, there really aren't any good therapies. So if you're on the control arm and you got an ineffective immunotherapy, it would be really important to be able to offer what's going on in the treatment arm, if possible. We can't do that until we cross the threshold where everyone feels comfortable that, you know, we're looking at a PFS that's robust. We're looking at an OS that looks like there's a, a significant trend, that it's not unlikely to be reversed. Again, that'll be an FDA call-. Right We'll give them every opportunity to look at the data in order to make that assessment, along with the IDMC. Right. How long will it take...? Sorry, John, were you asking the same question? There was an investor question. Maybe. No, no, I was also gonna ask about the fate of the phase IIa data. Oh, yeah, maybe let's just ask the investor question just before we move on to that. The question was, 'How long would it take to get the independent review of PFS done? If you could remind us whether this is investigator-assessed or blinded.' Right. This is not a blinded study. However, we have blind, independent central review because of that, and so that's part of the analysis. They are obviously doing the imaging analysis to evaluate whether patients progress. We'll be looking at both investigator-assessed progression as well as independently assessed. Which is primary? Blind, independent central review. Okay. Okay, great. fantastic. Sorry, John, you were asking? Well, I was gonna say- So it would take you a few weeks, you said? Is that how long it would take? Well, it's all in the process of doing that now, right? We're in the process of evaluating, you know, getting the data into the database, cleaning the data, you know, producing queries. Ultimately, once the, you know, the database is locked, then basically the data between the blind, independent central review and the EDDC has to be merged, analyzed statistically, and that's when you'll get the output. That's what Yujiro was referring to when we're talking about targeting the end of March, is that's kind of what's going on at the moment. Makes sense. Sorry. Go ahead, John. I was gonna ask about the phase IIa, which obviously is, is in hand, and, admittedly, there's 75 of those patients that are not on the go-forward dose. You know, do you have plans to submit that as part of the same package to the agency? Have they seen that data already? When can we expect to see that data as well? The agency will see everything, because what they wanna know is what the safety is on every patient that was dosed. They haven't seen it yet. Mm ... see it as part of the- The independent data monitoring committee has seen it, and they're the ones that evaluated it, said it was still, the appropriate dose to go forward with was the 300, 200. They felt the safety profile was adequate and to go forward, and so we should let the study read out, and that's what's happening in the next month. Okay. Will you show that to investors ahead of time as well? I mean, the phase IIa data, I mean. Is it? It's, presumably, it's already mature. Remember, it's got much shorter it's similar data than you'd seen with the O1 trial, right? The O1 trial actually has two years of follow-up, so it's probably more of the same, except shorter follow-up. Okay. Fair enough. Okay. John, there were a few more questions from investors on these. Do you wanna go through those first, or you wanna go through your side first? Either way is fine. Sure. One of the other questions that just came up was more on that phase III expectations side. On the safety side, do we expect to see safety comparable versus phase I observations? What are the specific criteria for dose reduction and what the protocols are in the phase III part of the trial there? Well, you know, I'd say we've done a really good job. You know, investigators learned with OptimUM-01 how to manage, you know, the adverse events associated with the darovasertib crizotinib combination. We have a group of people that are familiar with its use, and so I think you'll see a safety profile that looks, you know, relatively similar to what you've seen before. I am pleased to say that because investigators, there's two things. People are very motivated to take the therapy, as you might imagine. Mm ... you know, when you have a disease where there's no good therapies, and the only good one is the one you're on. They really wanna stay on the treatment. Investigators are getting better at, you know, managing the adverse events associated with it. Because of that, I think you'll see at the end of this trial is a really relatively low dose discontinuation rate due to adverse events. It's gonna be more about keeping the patients on therapy. We know that's important, and the KOLs that we've worked with are getting really quite expert in how to manage that. I think you know, we'll be in good shape there. What about discontinuation? Not discontinuation, what about dose reductions? I would expect to see in later stage trials as, as docs get more familiar with the drug, you see fewer discontinuations. Do you have an expectation for the number of patients who are gonna down dose? We'll have to see about that, but, you know, I would say there's a few things that are going on here, and the reason why I can't give you a number is, you know, one, obviously we're talking about a trial that only a few people can see the raw data to, and two, talking about experience I've had with Deferiprone. There's two things that people do, and again, this is usually due to grade three toxicity, which isn't terribly common, right? But usually they do one of two things. They usually do a very short pause. We're being told by some that a one or two day pause is sometimes all it takes to get rid of some of the toxicity. The other thing they do is they typically lower, if they're gonna lower anything, they don't lower the crizo, they don't lower the daro. They'll lower the crizo dose slightly. Ah. Again, I, I think, you know, with those two moves, they're able to keep a motivated patient on therapy for most of the time. By the way, we have some data accumulating now that also implies that the toxicity happens mostly in the first two months of therapy, and thereafter kind of weans itself off, so it gets more easily tolerated, it seems, in later time points, and we'll be sharing some of that data as this data evolves. I think those are what I could say about, you know, managing the toxicity. Thus far, our, the people that are running the trials are getting quite good at it, and it's manageable. The dose reductions and discontinuation rates hasn't been high in Deferiprone. I don't think it'll be any different here. I think, you know, patients just wanna stay on the on the study because, you know, the therapy is just so good compared to what the options are. Makes sense. Umar, unless you've got more on OptimUM-02, should we-. Yeah, maybe just... I do wanna sort of over the, in the next 10 minutes or so, bring it back to the big picture and some of the other pipeline as well. Could you just remind us for the prior data? I was trying to find it. John, do you have the prior data? Because I couldn't find it in our folder. Yeah. I was- Yeah ... I was trying to understand, maybe, if you could remind us, what% of patients had liver mets? What% of patients had LDH disease? I just find that as we often try to translate from prior data to the new trials, sometimes we can lose track of the baseline. I just wanted to make sure I had it for my purposes. We have to remember, with uveal melanoma, virtually everybody has liver metastases, right? Mm. So that's- I was looking at these- That's where, that's where the disease goes, you know? It's actually to have, you know, extra hepatic disease only is pretty uncommon. If you have both, that's even worse. You know. Darren, I was looking at a couple of Nivolumab ipi references, like the GEM1402 trial. It says 80% liver mets, and 50% had non-extra liver mets. I was gonna ask- That's in addition to liver mets, mostly. Righ t. Yeah. Oh, sorry. You're saying everybody had liver mets in your trial? Well, the vast majority of patients will have liver mets with this disease, 'cause this is where- In. That's where, that's where the disease metastasizes to. Additionally, some will have disease beyond the liver. Right. That's why things like, you know, liver-directed therapies are so big, right? Because people think, "Well, I can go after the liver, and I can get a lot of it." You know, but eventually, if you go after the liver too much, it'll end up somewhere else. Right if you live long enough. Yeah, Umar, I've got the numbers here. Our frontline study that we've reported at SMR- The prior data? Yeah, the prior data. Over 90% of patients were either hepatic-only or had hepatic and extrahepatic. Only about 5% had non-liver. Right. The tebentafusp phase III study, very similar, so roughly 95%- Okay ... had either hepatic, extrahepatic, and about 4%, so very similar to what we reported, had non-liver disease. Right. In terms of upper, greater than upper limit or normal on LDH status, both our study, roughly a third of patients. Mm-hmm ... and the, the tebentafusp randomized phase III, very similar. It was, you know, roughly, a third of the patient. Got it. that, Fantastic ... you can find from their New England Journal paper. I'm looking at the Okay. Super helpful. Okay. And- It's fairly balanced. Before we move on, the one other thing that I wanna make sure we, we talk about on OptimUM-02 is when you- how long will it take you to prep the filing after the top line? Just so you know, you know, sort of we're going with sort of average metrics here, right? It's, we're talking about, you know, probably around that six-month time period in order to put the package together, and then, of course, the FDA has to review it. That's probably another six months, so that's sort of general guidepost, but we're obviously gonna try to do everything we can to expedite the process, for sure. That puts us to the first half. That's how we get to that first half 2027 expected. Yeah approval time. Makes sense. Okay. On, O-one and the, A2 positive patients, can you talk about when you'll have a breakout of that and how rapidly, NCCN guidelines could proceed after a potential approval next year? I can, I can sort of give you a high level of the entire package, since we're probably running a little limited on time, but there are multiple things we wanna do. We obviously wanna submit this, get it to the FDA, get it to the NCCN panel. In parallel, what we'd like to do is get the HLA-A2 positive data out, you know, that 100 patients, get it published so that the timing lines up, where we'll be able to again say something about, you know, the overall response rate, the progression-free survival, the overall survival. Talk to them about the biology, how it's no different when you're going after Protein Kinase C, and therefore, they'll have a couple of pieces of data. They'll have a randomized phase III, they'll have a single-arm phase II, both relatively good size. We'll show them that the data is very similar. The NCCN panel can decide what they want to do that. We suspect that they'll overwhelmingly welcome this treatment into both category of patients very robustly. In addition, we're gonna talk to the FDA about the opportunity to potentially get the HLA-A2 positive patients in the label. Could a real world data set help? Are there other things that we could do in order to make that happen? That's a discussion that has to happen. In addition, in parallel to all that, is the neoadjuvant trial, the OptimUM-09 study. Mm-hmm. Yeah. Mm-hmm. Yeah. We would like to get that published in parallel. You know, we've presented that data recently at ESMO, really exciting. Tumor shrinkage in the majority of patients, saving more than half of the eyes, improving vision, not only during the neoadjuvant period, but potentially long-term, based on a visual prognostication score. It would be great if they also had that body of data for published in, in their hands so that they can decide what they want to do with that, as our studies continue to evolve. On that neoadjuvant side, because that, it, as you say, very potentially very exciting. The data you showed at ESMO was, was excellent, but it's also, five or 6 x the size, patient population-wise, versus the metastatic setting. Can we talk a little bit about patient journey, into the neoadjuvant or adjuvant, into the surgical setting, when patients get diagnosed and, how, how physicians are choosing the enucleation versus brachytherapy and, and where daro would live? Just from a very high level, a patient walks in, says, "I have trouble seeing." Optometrist looks in their eye, they say, "Geez, we see something there, I don't like it. I'm gonna refer you to an ocular oncologist." They do a workup, a clinical workup, and they make the determination that the patient has a uveal melanoma. From there, in general, the movement is pretty rapid. Within weeks, the patient can be set up for either an enucleation, which is the removal of the eye, and those are tumors that are usually large and too large in order to be controlled by radiation. Or if the tumor is smaller and they can sew a plaque to the eye, which contains radiation, they can do that, and both of these things are typically happened with, happen within weeks of the diagnosis. Again, the problems that come downstream with that is obviously, if you lose your eye, you lose your vision. Then if, even if you get plaque brachytherapy, you may have saved your eye, but you may eventually lose your vision due to the radiation doses. Also there are toxicities that happen downstream of, of radiation, radiation retinopathy, toxicity, et cetera. What we hope to see is in the future, someday, a patient will come in and get the diagnosis, and instead of being sent off to having something sewed to their eye or having a surgical procedure that removes their eye, it'll be as simple as: "You know what? I'm gonna write you a prescription. You're gonna take pills for up to 6 months, and then we're gonna decide what we need to do." It'll be completely different, paradigm changing for this disease. Daro, is that- Where you get a prescription, you don't have to go directly into your primary local therapy. But most- Is that being done in the trial, though, daro? Yes, exactly. That's exactly what's being done in the trial. Yeah. Like, you know how it has the, a fourth of the patients are in enucleation and the other, three-fourths are not? Is it- is the active arm not removing the eye in the enucleation subset? Remember, it's almost like 2 studies in one. If we focus on the enucleation group. These are the guys with. Okay big tumors, they're gonna get their eye removed. Yeah. Basically, they get randomized. Either you go straightly to get your eye removed, or you, if you're randomized to the treatment arm, you get 6 months of neoadjuvant therapy. We try to save your eye. If we do what we've done in OptimUM-09, we're gonna save more than half of them, and they can be transferred to a less invasive or a less, surgically extreme kind of, treatment... You. plaque brachytherapy. You keep the eye even after that surgery in this group then? No. Well, that's a big- You don't have the surgery. Yeah. You- Well- You'll get the surgery, and then that's in the control arm, go straight to enucleation, or. Sure ... you don't have the surgery- Right ... you get neoadjuvant therapy instead, and if all goes well, you get maybe a plaque placed there instead. But the off- Obviously, there are some patients that'll have to have the surgery because perhaps the tumor didn't shrink. The off-ramp from enucleation is radiotherapy, and then in the radiotherapy cohort, where there may be the tumor is small enough, where enucleation wouldn't be the primary treatment option. No, you're mixing the cohorts again. That's the second trial, John. Yeah, just focus on enucleation. Okay. There's only two options: You're either gonna have your eye removed, or you're going to get neoadjuvant therapy, and then hopefully something else will happen. Right. Like, they'll get a plaque placed, or they'll get proton beam, or external beam radiation, or something. You're- That is getting radiation, so you're, you're moving from enucleation- Only in the treatment arm if the eye is saved. Right. Only in the treatment arm if the eye is saved. The enucleation group just gets their eye removed. That's the enucleation cohort. Daro, just let's, just, Sorry, before we go to the non-enucleation cohort, I guess this is a question both for you and Yujiro. Unlike a typical neoadjuvant study, because we're talking eye preservation here, could this form the basis of a very rapid filing in much more than the first line setting? The only limitation is, remember, another one of the important endpoints for the study is Event-Free Survival. Right. We have to show that we're not creating any detriment to delaying the primary local therapy. With that has to read out, but the fact that we'll have known about saving the eyes very early, as soon as we hit the EFS events, you're right, we could actually take that part of the study and go talk to the FDA. Very probably- Event defined by disease progression? What's that? Free loss. Event defined as- Yeah. Yeah, it's relapse. Yeah, Sumer, also I would just highlight, as you know, you know, typically a randomized phase III neoadjuvant study, right? You have to show superiority on EFS. Here, all the FDA's asked us is a no-detriment threshold, which. Mm you know, which is much lower. Because of that, you know, typically for an EFS readout on superiority, you gotta wait for most of those events to occur, right? Here, you know, we think with about a third or 40%, we'll be able to establish no detriment. It could be a, you know, just generally, as, as Darren said, especially if we try to submit that enucleation portion first, with the no detriment that's pooled across both cohorts for EFS, yeah, I think it would be faster than your typical neoadjuvant study, right? salvage alone is not sufficient. Correct. Yeah. Right. They, they wanna see no harm to EFS, which. Okay ... you know, at least based on our single-arm data neoadjuvant, we, we don't see evidence of that at this point, so. Right. Um- The definitions must be pretty well established for who counts as an enucleation-eligible patient? Yes. Correct. Exactly. It's all about size. You know, when your eyes- Size of tumor. ... because the radiation can only penetrate so far, so if the tumor is too big, you have to get enucleated. Wow! And when- Sorry, John. I guess, maybe I'm curious how you guys think about it. Six months of... The comparator arm will have 100% enucleation right away. Correct. How does the active arm get established versus comparator arm? You just have to go all 6 months to be able to do that? Could you just do it... No, no, you get randomized. ... within the first 3 months, let's say? once you have a tumor that requires- Right enucleation, you get randomized. Right. One group will go to get their surgery, the other group will get the neoadjuvant therapy. Right. How long are they supposed to stay on there to establish that, oh, there's a meaningful differentiation between the two arms? I'm not sure I understand you. How long are they- My point is. on therapy? Let's say, let's say we took, 120 patients, 60 got immediate enucleation. Mm-hmm. The other 60 now are on the drug. Right. They didn't get it enucleated for now, some of them are starting to. I guess, how much into that process on that other sort of on that, on that active arm, are you able to say, "Okay, we're now starting to see that there's a 50% reduction in enucleation?" That number itself would keep fading, right? It might start at 100 and it's fading. We typically know in about four to six months... Yeah whether that patient dies. Well, this is what's happening. They're getting a scan every month, ultrasound every month, and they're getting treated for six months. Right. As soon as the tumor shows maximal reduction in growth, that's when you take them to your, your primary doctor. Right. Which is to say, as soon as it starts to grow again, you sort of take them off neoadjuvant, go to the either enucleation or radiotherapy. Yes, that happens in a minority of patients. Most usually. Okay ... they drop down, they, they shrink, and then they kind of level off at the end, and that's when you take them. Right. there's no ipi/Nivolumab use in neoadjuvant? No. I mean, remember- Oh, it's all adjuvant. It's all adjuvant. if you're gonna do it in a neoadjuvant setting, you have to shrink the tumor. These treatments- Right don't treat the tumor. Right, right, right. That's right. Yeah, also remember, you know, it's not, you know, obviously, you know, the drug has gotta get to the eye, right? I mean, I think we're fortunate that, you know, clearly we're having an effect there, but I, I don't think that's a given. As Darren mentioned, IO therapies, here the objective is to shrink the tumor, and we know that's not. Yeah, IO, IOs get used in metastatic settings, presumably because they may be doing something against the metastases, but they're not gonna do a ton in the eye. Exactly. Yajira, wouldn't this recruit, like, right away? I mean, the phase II, 1, 2 single arm was extremely robust once we got the sites up. You know, that's our expectation. I mean, I know- There's a tremendous amount of scrutiny. ... the team is also, like, with less than six months to recruit. I guess, let me just push it to an extreme. You start the trial in early 2026, you could be fully recruited by ASCO, presumably, because people are getting their eyes removed. They'll probably say, "Let me try this out," presumably. It's only 120 patients, and you track them over 6 months. You could hit all the events by December, January. Is that too extreme a scenario? For the full trial, we're guiding towards first half of next year, but that includes the pilot cohort. Could the enucleation enroll you know, first, and we get that readout first? Yeah, yes, that's a possibility, I suppose. But- Okay As noted by Darren earlier, we still need to wait for the pooled analysis for the EFS, right? Okay. Also, sorry, my last one on this. I remember Bristol ran this study back when John and I were covering sort of all the ipi/nivo trial readouts. There was a trial called NADINA, I think, in stage III neoadjuvant. I thought that had become standard of care. Is that not the case? Like, you'd give ipi/nivo before resection. I realize it may not have much activity in uveal setting, but in general, isn't everybody supposed to be getting ipi/nivo? In melanoma. In neoadjuvant. Yeah, you're talking about skin melanoma, maybe. Yeah, different, different disease. Different. Oh, okay. This, that's why this disease is so unique. There were no uveal patients in those trials. No. Is that right? Basically, this is a treatment that doesn't work for... The biology is completely different. Right. Tumor mutation burden in this disease, low. RAS mutations, RAF mutations, low, if not at all. Mm. It's just a different disease. Just happens to be a, you know, it's a, it's a melanoma, of course, but they're driven-- ours is driven by a different set of mutations. It's wired differently. Yeah ... I just confirmed- Really respond. they excluded uveal. I mean, why do we give immunotherapy? Because we don't have anything else. Right. You know? No, they excluded uveal. You're, you're right. I just checked as well. Okay. Great. Wow, this neoadjuvant, usually I see neoadjuvant, I was like, "Okay, this is, like, five years away." That's not the case here. No. we're hoping we can do faster than that. Yeah. Okay, great. In the last 10 minutes then, I wanna do two things. A, I wanna make sure we take care of any investor questions there are, but also, just ahead of that, could you just sort of lay out for us sort of the size of commercial opportunity, as well as sort of the highest conviction programs beyond this? Because I feel like there's other things happening, which we usually catch up on. Sure. Josh, do you wanna take the commercial market piece? Yeah, sure. On the uveal melanoma side, so the metastatic setting, we think that's between 4,000 and 5,000 patients incident globally. That's really US, Europe, Australia, that's where those patients are concentrated. What's U.S.? U.S. is roughly 1,500 a year. US is $1,500. Okay. Great. You're thinking of pricing as orphan? I mean, look, we're, we're, we're big proponents of value-based pricing. It's gonna come down to the sort of benefit that the therapies can offer. I think one benchmark people point to is obviously the Tyvaso price, which is approaching $90,000 a month. We'll see what our data looks like, but that's one benchmark out there to consider. Okay. Ajit, from your perspective, this takes the company to profitability, this launch in metastatic alone? You know, we haven't put out that specific guidance on profitability, Umar, but, you know, obviously some of it will also be driven by our spend. You know, we have other registrational studies across other programs we're looking to launch. I think some of it will be, depending on how we, you know, ungate. Got it. ... upcoming studies. Yeah, look, we, we do think, depending on the trajectory of that launch, obviously, we have other readouts, including neoadjuvant, that will be trailing. You know, I think that's gonna be part of the conversation as, as we move forward. Absolutely. Makes sense. If you could remind us the cadence of readouts beyond this program, for some of the rest of the pipeline. Yeah, sure. I would say the next one, probably most in focus is our DLL3 Topo ADC. Their enrollment in the US and outside of Asia is starting to pick up, so we are targeting a clinical data update for that program, for monotherapy, by the end of the year. At least based on the monotherapy activity that we and our partner are seeing, you know, we do hope there is some monotherapy approval path that's gonna be available to us. In addition, we have current guidance around an MTAP clinical data update here with Trodelvy. We'll be pushing as hard as we can. You may know we have a PRMT5 inhibitor that's now in phase 1, and so we'll, we'll, we'll see how that develops as well. I would say those are, you know, several of the pieces. I know our bispecific ADC is also in phase 1, and, you know, that we anticipate that enrollment should also go quick. We'll be closely monitoring, the progress of that. But I would say that's probably another, possibility as well. One thing. Where do you? You didn't just mention that I, that I wanna make sure we touch on, something we talked about at JP Morgan that really fascinates me every time we talk about it, is the PARP, which I know is a potential combination agent for any of the Topo ADCs. You said you were gonna start those combinations with a DLL3 this year. You know, given how rapidly late-stage patients in small cell progress, fair to say that we could see those initial combination cohort early in the next year timeline, and we'll be able to look at them side by side with the DLL3 monotherapy data? Yeah, I mean, we're, we're planning, and Darren, you should comment here, but, we're, we're planning to dose that combination here very shortly, in about one month or so. I, I think we should be in good shape on that one, John. You know, we've done a lot of work on PARP dose optimization. At least my personal sense is I, I think we'll get a sense of where we are pretty quickly, right on that combination. You know, we, you know, we could have data fairly rapidly on that, and I, I know the team is, you know, I would say, very enthusiastic about that. Even ahead of next year? Could we have it, you know? It's possible. Yeah, it's possible. Okay. I think, I think it's gonna depend on how much follow-up- Mm-hmm ... we want and kind of the expectation around that, but there's obviously a durability piece, but there's also just around, you know, just pure response rate and do we. PD on PARP as the mechanism with topo, is that something that we could get ahead of durability? Yeah. That's the idea. Yeah. Yeah, that's the idea. I mean, that could be a differentiating factor for us, really, to, to put us above the rest, you know? You know, it could apply to other ADCs as well. I mean, that, that could be a, a unifying message that, you know, if you have a PARP inhibitor along with an appropriate ADC, good target that carries a topo payload, this could, this could make a difference. You know, we hope that'll be the first test, but it won't be the last in DLL3. Makes sense. Okay. Yeah. The last 2, couple investor questions. 1, expected timing of filing for accelerated approval after the March readout? Darrin, do you wanna hit that? I think you kind of spoke to that. I mean, given... Yeah. Yeah. Six- We kinda, we kind of basically spoke to that before, right? About six months to put the data together and then six months to... Something that's kind of where we're sitting. That six months is presumably also to get some OS looks. Is that right, Darrin? Yeah, yeah, absolutely. I mean, we'll, we'll share as much as we can. Again, we'll, we'll get some of that at the top line, but it may not be very mature. We'll probably get more of that during the filing period, and then, of course, the first interim will read out the first half of next year. You don't need to wait for first interim to file? Well, we will be providing follow-up data with the FDA. They're gonna wanna see follow-up safety data during... Once you initially file, they're gonna ask for, you know, 120-day follow-up information, and so, you know, that could be part of the package, potentially. ... you'll get what you have, presumably, at that point. The idea would be you file by August, September, and then the 120-day update allows you to get that first OS interim in there. Okay, makes sense. Well, I wouldn't call it a first interim. I would just call it, you know, an evaluation. The datum could be available for the FDA to review at that time. The official interim won't happen until the first half of next year. Per stats plan, the OS- Right, exactly. does happen. Per the statistical analysis plan. Right. Exactly. Okay. The last program I think we didn't touch on is KAT6/7, which obviously is, is getting started in phase I imminently. We saw Pfizer make their announcement on the dual inhibitor. Can you give us the, the, the two-minute-. Mm-hmm ... pitch on where your version of this inhibitor stacks up relative to some of the others we've seen in the clinic? Sure. Mike, you wanna take that? Yeah, absolutely delighted to talk about that program. This is potentially very meaningful for patients. It's part of our central strategy to address tumor heterogeneity. What we have found, what we've shown, is you want dual potency on KAT6 and KAT7 in order to be able to intercept these tumorigenic transcription factors that are present in breast cancer, lung cancer, colorectal cancer. Our asset with respect to the clinic is the only one that I'm aware of that has that profile. We have not profiled Pfizer's asset, but we do know that the other assets that are out there in the KAT6A, KAT6B space, we think do not have the capability to deliver that profile on KAT7. That is critical because KAT7 can substitute for KAT6A, KAT6B in the regulation of chromatin, and that's also critical because we and others have shown that KAT7 brings on a very meaningful biology that will intercept both intrinsic and acquired resistance, and those are two of the big conundrums facing precision medicine. KAT7 inhibition together with KAT6, that can kill tumor-resistant cells that are drug-tolerant persister cells, therapy-resistant, drug-tolerant persistence, so that's an intrinsic heterogeneity mechanism. Then also, KAT7 is required for the self-renewal of tumor-initiating progenitor-type tumor cells, these so-called cancer stem cells that are a wellspring of acquired resistance. Very exciting program. Large patient population's available to us based on intercepting lineage-specific transcription factor activity, as I noted, breast cancer, lung cancer, colorectal cancer. Mick White, the one thing that I wanna make sure we, we tease out of what you just said is the dual potency against KAT6 and KAT7. We've seen numbers from Pfizer's program, from some of the others, that suggest that you get, you know, good, nanomolar or sub-nanomolar potency against KAT6A, KAT6B, and then maybe you could have, in the order of 1.5-2 orders of magnitude before KAT7, and then three orders of magnitude before you're getting to KAT5 and KAT8, where you'll have the toxicity. When you say you wanna hit both at the same time, in your opinion, is getting 10x or 50x more selectivity for KAT6A, KAT6B, is that, like, enough hitting KAT7, or do you really need to be right on top as your curves look like that? I think that's a great question, and it's really important for people to be able to actually deeply evaluate the mechanism of action here. What we have seen is you want dual potency, you want low nanomolar potency on KAT6 A, B, and KAT7. I have seen a lot of data, our own data, other assets' data. When people are looking at a 10-50-fold window for biochemical activity, what we have seen is that translates to a 200-fold window or more, sometimes as much as a 1,000-fold window with respect to cellular target occupancy. Mm. Biochemical activity does not take into account the multivalent complexes that are controlling these enzymes and are making a big contribution to your ability to cover that enzyme in cells and compete with everything else that's going on in that setting. Super important to have a clean line of sight on your PD, to understand what your target coverage needs to be. We have shown empirically that this matters a ton. If you're looking at your preclinical models, PDX coming from patients that have progressed, for example, on Ibrance fulvestrant, you cannot cover these with the clinical KAT6 inhibitors. You can't even cover them in combination with palbociclib and fulvestrant, we can hit them with the KAT6/7 dual. Very, very clean, very, very robust demonstration of the exposure profiles that you need when you have a dual-potent KAT6/7 that you can't get, if you don't have that low nanomolar potency and that very small window between the two. You do have to stay away from, KAT5 and KAT8, as you noted. Yeah. Excellent. Well, I think we're, we're unfortunately out of time. I feel like we could get Mike, I'd love to have just you on the next webinar, so we can really get nerdy on the biochemistry there. No problem to have. Yeah. Mm-hmm. Fabulous. Obviously, a lot to talk about. We spent most of our time on daro today, but there's a whole ADC platform, PARP, MTAP, and KAT6/7 to talk about as well. Thank you guys so much for being on with us. We really, we really appreciate the time this afternoon. Thank you, guys. No problem. Thank you for having us. Thanks so much for the time today. Great. Thank you again. Bye for now. Bye-bye.