All right, great. Hopefully everyone's connected. Yigal Nahumovitz, biotech analyst here at Citi in New York City. It is my pleasure to introduce the next iteration in our virtual C-suite fireside chat series with Yujiro Hata, who, of course, needs no introduction, the CEO of IDEAYA Biosciences. If you guys have questions for Yujiro during the course of the conversation, please email me, yigal.nahumovitz@citi.com, and I will hopefully see those and relay them over to Yujiro. Yujiro, welcome. Thank you. A lot has been happening. You had a great R&D day right after Labor Day. A lot of activity at several medical meetings, as we well know. Maybe it would be helpful if you could just kind of review maybe some of those key milestone markers with the pipeline. Then we will move into a discussion across all of the programs. That would be a good place to start, I think. Yeah. First, Yigal, thank you so much for hosting this fireside chat. Thank you to Citi as well. Yigal, as you mentioned, this past quarter probably has been one of our most productive quarters that we've had since the company's founding. As you noted, we had several updates at major medical conferences, including at the World Conference on Lung Cancer for DLL3 in Barcelona. We also had an oral presentation at ESMO for darovasertib in adjuvant. We also had the Society of Melanoma Research oral presentation in Amsterdam, where we reported our first survival results. As you know, our lead program is getting closer to our objective around the randomized PFS results to hopefully enable our first accelerated approval filing in the U.S., which right now is guided from year end. We're getting about a month to December to Q1. We are getting closer and closer to that. Enrollment is going great. We're almost finished with full enrollment. That study is also in the process of getting wound down. I would say we're probably going to be done with full enrollment for the OS, randomized OS as well portion, in about a week or so. Beyond that, we're firing on all cylinders, which is a continuing to be a growing pipeline, DLL3. We did dose our first patient in the U.S. We're ramping up sites globally to accelerate that. Obviously, a big focus in small cell neuroendocrine tumors as well. MTAP as well here with our partner Gilead on Trodelvy. We picked an expansion dose recently in urothelial cancer. We've dosed several patients already in lung cancer, and that enrollment has been extremely robust. Just as a reminder, as part of our earnings, we did note a confirmed 57% response rate in the MTAP urothelial cancer setting. Beyond that, our PRMT5 asset is now in phase one. We got IND clearance. We also filed an IND on our B7H3 PTK7 bispecific ADC as well. A lot is happening. We expect, hopefully, a very catalyst-rich next several quarters. Okay. That's a good start. Maybe if we could just kind of go big picture first and go through what you sort of see as the opportunity across the uveal melanoma landscape, because as you pointed out, we're looking at metastatic, neoadjuvant, adjuvant. If you could kind of just outline the scope of those opportunities and how crowded or not crowded each of those are. Yeah. One of the areas that we're very focused on is to ensure that darovasertib has the opportunity to be the standard of care across the uveal melanoma patient journey. As Yigal, as we just talked about. We're getting close to hopefully our randomized PFS results for frontline metastatic uveal melanoma. As you know, we launched a second registrational study in neoadjuvant uveal melanoma. Now we're guiding with our partner Servier to launch a phase three randomized study in adjuvant in the first half of next year. In terms of metastatic annual incidence, we believe this is about 4,000-5,000 patients. Prevalence would be higher than that. We're seeking approval in the A2 negative population where there's nothing approved. We would be a frontline treatment in the scenario we make it to market. We also believe the agent is going to be equally active in the A2 positive setting. We do believe we will capture market share in that segment. For neoadjuvant, that number of annual incidents goes up substantially from 4,000-5,000 to at least double that. We think that's more in the 10,000-12,000 range. Here, average treatment duration in neoadjuvant, roughly in that six-month range. In adjuvant, same thing, 10,000-12,000 patients. Their treatment duration we're anticipating or we're discussing with Servier is a 12-month treatment duration. In the adjuvant setting, we anticipate we'll pursue that with our partner as a darovasertib-crizotinib combination as well. In adjuvant, there's nothing approved, as you know, Yigal. Here, we would anticipate that we'll be randomizing against placebo in the adjuvant setting. Okay. I think it would be helpful if you could kind of walk through the neoadjuvant data that you showed at ESML, because there were two cohorts, obviously the enucleation and the plaque brachytherapy. What were the key conclusions in each of those? Did they meet or exceed your expectations as far as the endpoints that you were aiming for there? Yeah. So maybe just a table set here, Yigal. We received Breakthrough Therapy Designation from the FDA in the spring based on a good portion of the data that we just shared at ESML, in particular in the enucleation cohort. We shared about 95 patients' worth of data. Roughly 60% of that was from the enucleation cohort, the remainder in the plaque therapy. In terms of eye preservation rate, what's in our current phase three clinical protocol, which we had alignment with the FDA, was we needed to exceed or we need to exceed a 10% eye preservation rate with a 95% confidence interval to receive full approval. So that's our primary endpoint for the enucleation cohort. What we demonstrated is the majority of patients, we are preserving their eyes and getting them off of the enucleation track. So we are obviously well above that 10% threshold for full approval. For the plaque therapy cohort, the primary endpoint here is around visual acuity, which is a 15-letter BCVA vision test. Here, I would say several pieces of information that were new. First is that we are seeing what we think is very meaningful vision improvement during neoadjuvant treatment before the plaque therapy. Yigal, you may recall at our R&D day, we noted a median letter improvement during neoadjuvant treatment of seven letters at R&D day. At ESML, with a larger data set, more follow-up, if you pool both of those two cohorts, we saw on average roughly a 14-letter vision gain. That is a fairly significant jump from 7 to 14 as we went into more patients with more follow-up. Lastly. Based on the level of consistent and robust ocular tumor shrinkage we're seeing, at least based on visual radiation prediction tools and visual prediction tools, we believe the amount of predicted vision loss is going to be substantially less in the treatment arm versus the control arm. That is the setup. As you know, there is also a no detriment requirement of event-free survival, which is going to be a pooled analysis across both cohorts. There is no specific hazard ratio we need to hit. All we've said with the FDA is that they need to be overlapping confidence intervals that we're not doing harm to the patient. We have publicly noted, Yigal, here that so far we've seen very few events in the single-arm phase two studies. We feel good about that no detriment EFS requirement as well. Okay. And then given the 10% level that you mentioned with regard to eye preservation and then the 10-17% range on the improvement in letters, how are the phase threes, the pivotals structured such that you're well positioned to be better than those, or at least in that range for the vision, and I presume much better on the eye preservation? Just if you could just review the cushion you have on the phase three to get to that type of efficacy. Yeah. So on the eye preservation one, Yigal, I think that one's pretty straightforward, right? Where it's a 10% threshold, 95% confidence interval, which means you want to ideally be at a 15% eye preservation rate or higher. Here, we're already multiples north of that. I think that one should be relatively straightforward. For the plaque therapy, the way this is going to work is the treatment versus the control arm. We want to be able to demonstrate 20% of patients or greater are passing that 15-letter BCVA vision test in the treatment arm versus the control arm. That's what we need to show to hit our primary endpoint. The reason why we feel good about this endpoint is because, as I just noted, Yigal, during the neoadjuvant treatment, the treatment arm patients should have better vision because during neoadjuvant treatment, we're seeing this vision gain that's occurring, which in the control arm, that shouldn't occur. Second, the patients of the treatment arm should have much smaller ocular tumors because Darovasertib is shrinking those tumors and therefore getting less radiation to the critical eye structures and therefore less vision loss. You have two stacking events, right, that should hopefully push it in our favor to be able to hit that primary endpoint. Okay. I mean, visual acuity is obviously kind of a gold standard measure. Are you looking at anything else in terms of position of the tumor in the eye or anything related to center versus non-center lesions, looking at retinal imaging, for example, or is that all secondary? Yeah, those are secondary. The primary endpoint is around this BCVA 15-letter vision test. We have other secondary endpoints, including response, prevention of macular edema, as well as others. The primary endpoint is this 15-letter BCVA test. Okay. You also reported that apparently a certain percentage of patients had gained over five letters consecutively. Consecutive visits. Why is that important for people to understand as opposed to not consecutive or over a longer period of time? Yeah, great question, Yigal. I know you also track the ocular space. At least from what we understand, the consecutive visit readout is actually quite important. In the setting of just sort of a visual improvement, that it's not just at one time point, but through multiple consecutive visits, that you're seeing this sort of consistent, maintained visual improvement. I think that data also improved since our R&D day. We're excited to see that as well. Okay. Just again, on neoadjuvant, the timelines are. For data. What is the latest statement on that? Yeah. So the way. Yeah. So you may have seen that the plaque therapy cohort, we've reduced the number of patients we need to enroll from 400 to -330. That was based on FDA feedback around the statistical plan. We didn't need to split the alpha between the two cohorts. That's great for us. It makes the trial size smaller, which means we can enroll it faster. Right now, what we've said is that our target, at least, is to try to enroll this study in roughly five quarters. The first data we'll likely see, it will be the eye preservation data from the enucleation cohort. The second data set would most likely be the no detriment to EFS. Because of that no detriment threshold, we believe with about 35-40% of the events, we'll know that answer. The last one is the visual acuity results from the plaque therapy cohort. That first analysis will be approximately 18 months from the last patient enrolled. That is the sequence. When did this clock start on these five quarters? We are right now in that process of the study has just launched. Essentially, right around now. Okay. All right. Got it. Usually when companies talk about changes to power, usually the press release says that they had to raise things, right? In this case, interestingly, could go in the other direction. Was that—clearly you had the buy-in from FDA and you did it. Was that controversial or not? I mean, you could have kept it, I suppose, and had more of a cushion, but it sounds like in this case, it simply was not necessary and not a wise use of R&D capital. Yeah, exactly. No, look, I think the FDA collaboration has been great. We're obviously very grateful for them to provide us that feedback that we didn't need to split the alpha between those two endpoints. Yeah, sort of simple statistics and not needing to split that alpha enabled us to reduce the patient enrollment number. Okay. So that's neoadjuvant. And then adjuvant, anything else you want to—you briefly mentioned the design there. Can you just go into a little bit more detail, perhaps, on the timeline? Yeah. So here, Yigal, it's going to likely be in that 400-450 patient enrollment range. We want to ensure that this study has sufficient power. Second, with our partner Servier, we did discuss, do we do it as a company sponsor versus a cooperative group? We decided we're going to be able to move a lot faster to do it as a company-sponsored study with Servier. Second, our partner will be side by side with us in terms of to ensure rapid enrollment for this trial. Next is that the patient population will be HLA-A2 agnostic. So. We're not going to have any kind of HLA-A2 requirement here. In terms of the metastatic risk population, we haven't made the final decision there, but it's most likely going to be the high risk and the high medium risk group. So that's the setup. In terms of the control arm, as you know, Yigal, there's nothing approved here. We believe the control arm will be essentially placebo. This will likely be a superiority endpoint around relapse-free survival. Okay. So then sort of in the marketplace, if people get Darovasertib neoadjuvant. I assume they would not be eligible in the adjuvant to get it again? Or how does that whole logic work? Yeah. Once commercialized, one is, as you know, for the neoadjuvant, it's monotherapy. There'll be likely some clear-out period, which there typically is anyway. Between neoadjuvant, you have the primary procedure before you start adjuvant care. For adjuvant, it would be as a combination. For the actual trial, I would assume here that we will not let patients that were on the neoadjuvant portion flow into the adjuvant, especially on the control arm side, as you can imagine. Okay. Makes sense. Then, of course, let's talk about the metastatic MUM, which we're getting very close, as you pointed out. I think everyone is very familiar, but just to remind everyone, maybe what is the expectation for control and active for PFS? You mentioned you're very close to finishing on the OS enrollment. Can you just talk about when that might potentially be available and whether there would be any commentary on OS towards the end of the year or if that would be a future update? Yeah. So for the PFS here, at least we feel based on historical data, the control arm is going to come in somewhere between two to three months. We feel the treatment arm, as we reported most recently, ESMO. Sorry, Sorry, SMR, as well as ESMO earlier, was a seven-month PFS. I would hope that it's going to land in that seven to eight-month range, which would put us in a solid position to hit stat SIG for accelerator approval. In terms of OS, Yigal, as you know, there, we feel the historical data and treatment naive has been in that 12- 13-month range. At SMR, we reported a 21-plus month OS. I think as long as we're in that range or obviously above, we should be in good shape for the full approval OS as well. Okay. At this point, are you, I mean, it's November 6th, so are you kind of getting, are you in the database lock portion of this right now? Or are you still, that is yet to occur? That has yet to occur. The events are continuing. Yeah, that's still ongoing in terms of the collection of the events. The database lock has not occurred. Okay. The data from Society of Melanoma Research, which was a very good number, the 2021 and change. How does that, in terms of thinking about how that would work in translating to the phase three of those patient populations, very similar that that's a good translatability? Can you make that statement with high confidence that that over 20 months is a good proxy for what could occur in the phase three? Yeah, look, it's a frontline patient population. I think, Yigal, if I were to sort of highlight one patient baseline characteristic where maybe we might see some improvement was around the ECOG performance status. As you may recall from the SMR data we presented, the ECOG performance one percentage of patients was about 40%. ECOG zero was 60%. In the peer company of ours, randomized phase three, both in their treatment and control arm, the ECOG performance status percent was about half of that. ECOG one was 20% versus 40%. I think there the question is, if we had that type of population, might we see some additional benefit in survival? As you know, Yigal, there is published data on how ECOG performance status does impact things like survival. That's one for us to watch. Yeah, otherwise, it's a frontline patient population. Otherwise, I would say the patient baseline characteristics are going to be similar. Okay. It sounds like you're not speaking about OS for the MUM study. That's not going to be something you're ready to talk about until sometime in 2026. Is that? Yes. When the IDMC looks at the PFS, randomized PFS, Yigal, they will look at OS, but our anticipation is that it's going to be too early. Okay. Okay. That makes sense. All right. Let's move on then to talk about some of the other topics. IDE 397. Maybe to start out with just, that MTAP deletion market is a very interesting market. What is the commentary there in terms of the opportunity set? Yeah. For MTAP deletion, this is an indication where there's multiple tumor types that are relevant here. I would say for us, the tumor types of greatest priority for us is lung cancer is one, urothelial cancer, and I would say PDAC. There are other tumor types as well that we're evaluating, but I would say those are going to be the highest three priorities. Obviously here, Yigal, as you know, we're one of only two companies that we're aware of that have two clinical assets in the MTAP space. Obviously, MAT2A. And our MTAP cooperative PRMT5 is now in phase one as well. Okay. If you could just kind of give us a quick synopsis of what you've seen so far with 397 in both the monotherapy, and you've shown some combo data as well. What is the go-forward strategy there for both monotherapy and combo? Yeah. So for ID 397 monotherapy, we've seen a confirmed response rate in that 25-30% range. The expansion initiatives have been largely focused on lung cancer and urothelial cancer. Now we've shifted the focus to the Trodelvy combination, which is data that we shared at our R&D day recently. There, as I noted, at the expansion dose that was selected for urothelial cancer, which is 30 mg once a day with ID 397, that's our monotherapy expansion dose, and Trodelvy at 7.5 mg per kg. That is an infusion once every three weeks. As you know, Yigal, Trodelvy is approved at 10 mg per kg, so it's below the approved dose. At that dose in urothelial cancer, or at least right now, it's a small data set, but we're observing a confirmed response rate that's in the 50% range. That's good to see. We're still monitoring durability, but so far, I would say we've continued to see not just confirmation scans, but continued confirmation even post the confirmation scan. I think that's encouraging to see. We're now expanding that work in lung cancer as we've already dosed several patients there. Of course, now our PRMT5 asset is in the clinic. Our plan is to launch that combination work as fast as we can. Based on the starting dose, the FDA agreed with us on our PRMT5 molecule. We believe by the second cohort, we should be at an efficacious dose. We have, based on the protocol, had the ability to enable that combination once we're in that second dose cohort. We'll get that moving rapidly. I would say our number one priority for that combination will be in lung cancer. We have other, I would just say, strategies here around co-alterations without getting into too many specifics, including in our internal pipeline, which is our third MTAP program, which is targeting, we believe, the largest co-alteration of MTAP. That would give us three potential clinical assets in MTAP, and we would be very unique in that regard. All I could say is we're having other conversations about enabling other co-alteration combinations in the MTAP arena at this time. Okay. For lung cancer, is it going to be the same dose with Trodelvy? Or is that unclear at this point? Right now, that expansion dose should be very viable in lung cancer. That is our focus. I think the question is, can we dose Trodelvy a bit higher in lung cancer? Yigal, you may know that urothelial cancer patients, I would say, I am going to make a general statement here, but are sort of viewed to be typically a bit more fragile than lung cancer patients. You may have the ability to dose a bit higher. We may explore that, but we do feel very good about this dose that we have. Okay. What type of a response rate would it also be in the 50s that you got for urothelial? What are you looking for in the lung cancer to go forward? I think for both urothelial and lung, Yigal, that I think as long as we're sort of 40 and above with good durability, I think we're going to be in good shape. Obviously, if we can be 50s and above, even better, of course, but in terms of kind of a go, no go, and that's what we've publicly communicated, I would say ideally 40s and above. Right now in urothelial, we're north of that. Obviously, we want to build more data, a larger data set, and obviously more follow-up. You're keeping the 397 dose the same in lung and it's just Trodelvy that you think you can go higher with in lung. Is that correct? Potentially. Yeah. Potentially. That we may interrogate to see if we might even drive greater efficacy. Obviously, the balance between safety and efficacy is obviously important anytime you're doing ADC combination. We know at that 37.5, at least right now, based on the data we have, which is growing, we feel really good about what we're seeing from a safety perspective. Yeah, could we go higher in lung and move that to 10? I think that's still an open question. Okay. And then what is the next decision? If these look good, what is the decision point after this? Do you go into late-stage studies in one or both of these, or are you going to sort of determine which is the better place to start a pivotal urothelial or lung with your partner? Yeah, that is the next step, Yigal. Once we have a larger data set, more follow-up, we'll likely give that guidance perhaps in January for next year, but at least in my mind, the next step is a registrational study. Here, yeah, that's going to be the decision matrix. Do you go forward in lung only? Do you do both lung and urothelial? Obviously, lung is the larger market. I think the part in urothelial that we're monitoring that we think could actually expand this market quite significantly. Yigal, I'm sure you saw the PATS PD-1 data in urothelial that's potentially moving even before metastatic into the pre-metastatic setting. That data looked quite encouraging. If that happens, we believe the frontline metastatic setting in urothelial could really open up. If we can capture that portion, this market would get much larger. Okay. For the combo with PRMT5, now, obviously, it's your own molecule. How are you feeling about this combo given some of the past attempts with other partners with PRMT5? How is this looking? You know, look, Yigal, for us. To really make a run at frontline lung cancer for MTAP, this is our focus. Based on all the data we have, the preclinical data, we feel that's the best opportunity to really deliver, hopefully, an exciting result. We know others have launched a PRMT5 combo with chemo. I think that's with a checkpoint inhibitor. We think that's fine. That wouldn't be our preference. We think if we can deliver something exciting with a chemo-free regimen, with a checkpoint inhibitor, would really position us in a unique way in frontline lung. That is going to be our focus. We obviously have to start generating data now, but we feel very good about our MTAP cooperative PRMT5 molecule. We do believe it has a potential best-in-class profile. I'm sure we won't have time to go through that now. This molecule was made fit for purpose to combine with ID 397. That is going to be our strategy and focus in lung cancer. Okay. Have you talked? Right. Have you talked about the doses? You said you're in the second cohort, looks like a good place to be. Can you be more specific there about what the doses are? Or that's not? Yeah, for ID 397, we're fairly confident we know what that dose needs to be in combination with a clinical stage PRMT5 inhibitor. We have that data, so we know what that dose should be. Then it's about as we dose escalate with the MTAP cooperative PRMT5 inhibitor. Based on our preclinical evaluation, we believe by the time we've cleared that first cohort in combo with a set dose we know with ID 397, we should be in an efficacious range. We should be in an efficacious range essentially right out of the gates because we're not going to start the combo work until we get to the second cohort. Right. Okay. In terms of what would you be watching for in terms of possible combo talks that need to be monitored? Is there anything specific that just needs to be kept in mind or you would not expect any additional talks on combo because of the combo? I think in this pathway in general, right, for PRMT5, I think probably the main one people have been looking at in terms of target-related is really myelosuppression. I think that's what we'll be looking at. Based on prior work we've done here, at least our perspective is we should have several cohorts hopefully available to us that we can move forward with that should be efficacious. That's what we'll prosecute in the clinic and make that determination. Okay. Someone was just asking me if you could expand a little bit on, you mentioned these co-alterations in MTAP. Can you just expand on that so everyone is clear on what you mean? Yeah. So we know that MTAP has genetic co-alterations with other key mutations, including RAS, right? In PDAC, for example, if you said pan-RAS, RAS more broadly, so KRAS, HRAS, NRAS. You're going to have most of those patients will overlap with MTAP, at least in certain tumors like PDAC. Depends on the tumor type, they vary. The other beyond RAS, I would say people have been looking at, which is CDK N2A. You may know that CDK N2A and MTAP are very often co-deleted because the proximity of those genes are very actually close. When MTAP is deleted, CDK N2A is often co-deleted. We've been having a drug discovery program on this for probably four or five years now. We've been kind of all over this for a long time that this could be a great combination opportunity. For us, we were very focused and we wanted to wholly own this. What we're doing, I can tell you, is the chemistry has been very, very complicated. We're very much nearing a candidate now. If we can deliver that, that would be our wholly owned strategy around taking that coal alteration approach. Hopefully with that, we would have sort of covered our full basis on at least what we think are the most exciting rational combinations. In that case, we would wholly own three sort of pieces of this lever that would position us very uniquely in the market. Okay. So you're not ready to talk about an IND on that yet, I guess? Candidate this year, yeah, I would hope sometime next year, maybe towards the end of the year. For co-alterations, PDAC is one, an obvious one, maybe lung cancer, although I think we'll prioritize the MTAP PRMT5, but probably for the PDAC one, the co-alteration strategy for us is one we want to consider. Ideally with an internal asset as well. Okay. I want to make sure we get to DLL3. So 849, obviously a lot of interest in this. Asset you got from Hengrui. Just essentially tell us what is the thesis on your construct. You have competitors, as you know, but what makes yours stand out? Look, we feel that our ADC on DLL3 with Topo1, it is from a very battle-tested platform from Hengrui. They have been in several thousand patients across multiple clinical stage programs that have been presented in many major medical conferences. We know that this platform, in particular around the payload linker system, which is a tetrapeptide cleavable linker, is sort of your classic linker system, which cleaves once it is internalized in the cell from lysosomal degradation. Here, things are similar to the Daiichi platform that was developed. We feel really good about that platform and its level of validation in patients across many, many studies. We feel we are positioned to have a potential best-in-class molecule based on what was presented at the World Conference on Lung Cancer recently in Barcelona. Just quick snapshot, at least at the 2.4 mg per kg expansion dose, which is likely going to be one of our expansion doses we'll be focused on. Just so you know, that's the starting dose the FDA has let us begin our US trial with. Our first patient that was dosed was at that dose. We saw a confirmed response rate by RECIST of 70% in the second line setting. We feel really good about that number. We've seen a lot more data since the World Conference on Lung Cancer. I would say the data continues to remain to be robust. In addition, on the PFS side, across all lines, we reported a PFS of approximately 6.7 months, which, Yigal, as you know, is a very good number in relation to other reporting of PFS, including in Delta where they got accelerated approval. It was four months and change. We are obviously north of that. We want to build that data set, build it with a global data set, and that is what we are doing right now. I think we are in a good spot, and now it is going to be about speed as well as what is our clinical strategy. We are not prepared to disclose at this time all the specifics for competitive reasons, but we would like to launch ideally two registrational trials here. One in small cell. I would say another in another tumor indication. We do believe, based on the data we are seeing, we should have some monotherapy accelerated approval path available to us. Oh, interesting. So you're thinking monotherapy accelerated approval because, as you know, some of the competitors are talking about comparator arms and talking about needing to enroll in Deltra in those arms, which obviously raises the bar for a randomized trial. Any comments you want to offer on that discussion? I mean, you can still have an accelerated approval path as a randomized study, right? I think there, Yigal, and that's the part we just haven't disclosed yet what our strategy is. What I can say is we're thinking about this very deeply. I know the clinical team, I know is even going to investigate or vet next week to kind of dig even deeper on this and get input on where to focus that monotherapy accelerated approval study. Hopefully we'll be able to share that publicly here not too far in the distant future. The only other part I should have mentioned to Yigal was at that expansion dose I mentioned because I think maybe there was maybe some lack of clarity on this. We are seeing what we think is a very viable AE profile. Where the grade 3 or higher AE rate at that dose, at least right now, was observed at less than 20%. We think we can go even higher than that based on that because, as you know, with ADCs, it's very common to have grade 3 or higher that's in the 30-40% range, including very well-known ADCs like Enhertu. That's still kind of being determined. 2.4 is not necessary. You say starting dose, but there could be potential for going higher. We could potentially go higher. I think right now we're very focused on that 2.4 dose. We will be doing some dose evaluation, but we feel good about that dose. That is, we think it's a very viable dose at this time. Any thoughts you want to offer on activity in the CNS tissue for your construct? The data that was presented at the World Conference on Lung Cancer is a response waterfall in patients that had brain metastasis. What we could say is we're seeing very robust activity there. We do not see any diminishing of response in that setting. We feel good about that. Obviously, brain metastasis is something you have to think about in that indication specifically. Right. Okay. In the final few minutes here, you have a lot of other assets earlier stage or some that are earlier stage, some that are maybe getting close to mid-stage. Can we kind of walk through those in a little bit more rapid fire, maybe? I mean, which of those would you like to highlight? Poltheta, the PARG. Obviously, you have the CAT6 as well. There's a B7H3, PTK7, bispecific ADC. We talked a little bit about 892. Of those other ones, can we just kind of quickly run through those and where do you see the most opportunities? Sure. Yeah. I can do more rapid fire here, Yigal. Maybe quickly with poltheta, for the listeners here, this is partnered with GSK. Focus is combination with niraparib. Specifically in patients with BRCA. That escalation has been going well. It has entered the combination phase with niraparib. We do anticipate an expansion dose being selected here relatively soon on that combination, which would trigger an expansion milestone payment. I think that's all going as planned. For WRN helicase, as you know, Yigal, we feel we have a truly differentiated best-in-class molecule based on the way it binds to the D1D2 domain and does not bind with that key cysteine 727 interaction, which both the Novartis and Oric molecule do. Our hypothesis on this is that that should lead to greater efficacy. That escalation is also going well. Hopefully we'll be able to give some disclosure update on that with GSK over the next couple of quarters. There we do plan to have, I would say, an important focus on gynecological cancers as well as combination with GSK's checkpoint inhibitor, dostarlimab. The next two programs here, Yigal, I think that at least I'm excited about. We're quite excited about what we're seeing preclinically with our B7H3 PTK7 bispecific. It's very active preclinically. We do see enhanced efficacy versus B7H3 alone or PTK7 alone, based on the data we have. The co-expression population is large, which is why we pursued this bispecific, in particular in indications like non-small cell lung cancer and CRC, which are two very high priority areas for us. Now that IND is in file, it's essentially now a clinical stage asset. We will be very focused, I didn't mention it for DLL3, on the combination with PARG ID 161, which is our other phase one asset to enhance the durability of topo ADCs. That preclinical data, which we shared R&D data, looks great. We've demonstrated this with multiple ADCs now. That is going to be a really key strategy and lever for us for both DLL3 and the bispecific. CAT67, we're tracking towards that IND next month. A first-in-class dual inhibitor. One of these have not entered in the clinic, is similar to our bispecific. No bispecific of that format has entered the clinic yet. Clearly, we believe based on the preclinical data we're seeing with that dual inhibitor, we should be able to drive greater efficacy. We are going to be very focused on that asset as well. Breast cancer, lung cancer, obviously big opportunities. As you can imagine, Yigal, we're not going to be able to do all of this on our own. We are having a lot of different conversations, a lot of interest across the portfolio. We are trying to build a world-class precision oncology company. We are thrilled to really be able to get these next set of assets into the clinic and to move them forward. I mean, there's been a lot of excitement around the WRN helicase, and I was tracking it for a long time. Is that a week close to getting an initial readout there? I know you showed the biomarker data, I believe it was earlier this year, if I'm not mistaken. What is the timeline there and what would be a good result that would be compelling? Yeah. So yes, we need to be in coordination with GSK, Yigal, on that and kind of the timing of that disclosure. Ideally, it's when we sort of have an expansion dose and we have a decent amount of data there. We will be in coordination. In terms of response rate, I think there. It will be about, at least in my mind, what do you see in the setting of gynecological cancers? Here in this case, specifically, indications like ovarian and endometrial cancer. I would say the second area is most likely around CRC, which we know MSI high is very prevalent in both of those settings. You may see different response rates depending on which of those two indications or general indications that you're focused on. What would we like to see? I mean, Yigal, I think for a monotherapy, ideally, right, you're above 30% or higher, with good durability. This will be the first time, again, a molecule is going to be tested in the clinic without this cysteine binding interaction. We know in the MSI high setting in particular, you have to be very thoughtful about point mutations because it's a very rapid point mutation clinical setting. You're doing high MSI for Warner. I guess, say solid tumors, but I guess, as you point out, endometrial would be important. Then you're also doing that with PARG with Keytruda. I mean, that's a different partner, obviously. When you think about those two programs, they could both proceed together, right? I mean, how do you think about that? Is one going to win, or is it not like that? Yeah. With PARG ID 161, our focus here, Yigal, is around enabling the topo ADCs. The reason why we've been evaluating the Keytruda combo, which we're done with that dose evaluation, is really to answer the question around safety. Could we generate that safety data? We've done that now. The reason why we did that was as we enable the ADCs now. With the ADCs with PARG, right, as you can imagine in lung cancer, non-small cell lung cancer in particular, you're going to likely want to do that with a checkpoint inhibitor. That's why we have that data to enable as we think forward about the PARG checkpoint ADC combination. That's where our focus is for that program, versus sort of competing with Warner independently in the endometrial setting. Hopefully that makes sense. That's our current focus right now. Okay. The CAT67 axis is also heating up. There are several other players in the space. You have a dual, or, I guess, it targets both six and seven. What is the rationale for that versus just one of them? What does that get you in having the dual targeting? Yeah. Our CSO, Michael White, we think is one of the world experts in this arena. Really, the shortened version of it, Yigal, is we believe seven is a key potential bypass mechanism for CAT6. We have a lot of preclinical data to support that statement, including data we've presented publicly. Essentially, we feel by hitting these two together, which I would call for now paralogs, we feel we can drive much greater efficacy and durability, as well as expand the opportunity into other indications beyond breast cancer, including indications like non-small cell lung cancer. The chemistry was very complicated. Our team is obviously first rate, and we were able to figure that out. We'll be in patients here shortly. I should have mentioned also the GLP toxin both species is done. Everything's behind us now. It's really just about IND assembly, some of the final CMC pieces. Essentially, we have the data we need to file that IND. I was always impressed with some of your more technical slides where you talked about advanced physics concepts like free energy perturbation, which does not come up much, obviously. To say the least. But really, the question is, with the obvious acceleration in machine learning and LLMs and everything and AI and AGI, how much more is that helping you in the very early innings when you are designing molecules? Are you leveraging that even more? Because you do have a platform, which I am sure you are working on all sorts of other things you have not talked about at all. But how much more is that technology advancement helping you? Yeah, Yigal, you know, look, it's been an amazing voyage because we began investment in this area several years ago. We began applying it to several programs like CAT67 as well as others. Now it's essentially integrated across all of our direct discovery programs. I would say it's been a really great surprise how much more efficient it's made us in terms of optimization of certain parameters of lead optimizations. We found that it's not great for certain areas of lead optimization, but extremely effective in others. I think here it's really about knowing where to apply it. I would say what makes us unique versus some of the other players here is that we're applying it to first-in-class targets, right? We also have a machine learning process and system that's becoming more and more sophisticated because we're actually feeding the results into the next programs. We probably have one of the largest WRN helicase databases, polymerase databases of chemistry, and we're feeding that into the machine learning system. It's actually getting more and more effective and sophisticated in what it's doing. Look for us to double down in that area, Yigal. That's why we highlighted it at our R&D day. I know for our CSO or our Chief Technology Officer, it's definitely very much of a high priority. Our hope longer term, it should just essentially accelerate our time to IND, right? By how much? Right now, we're probably seeing about a 30% acceleration, which is big, right? Now the question is, can we even enhance it beyond that? Before it took us five years to get WRN, if you could do that in three, that's big, right? If you could even reduce it more than that, that's a game changer for us. Without giving away the house secrets, so to speak, I mean, you mentioned areas where it's more effective and less effective. Just generally speaking, how do you characterize that? Where is it? Where are the pitfalls? Where do you know that it's just not going to do a good job? And where is it really, really, really helping you? Yeah, that I can't tell you, Yigal. I'd get in trouble if I told you that. I do know the answer. Yeah, there are definitely really areas. We actually have great data on it, which I've seen just how predictive AI has been for certain parameters of lead optimization. Where in other parameters, it just does not do a very good job. You do need to know where to apply it effectively. As companies get more sophisticated and build their own databases, I think companies will get better and better at this, which is great for the whole sector. Okay, great. Thank you. Very interesting for sure. We will be watching for the MUM data any day now or in the next few weeks, I guess. Thank you. Congratulations on very strong progress over the last six months. Yep. No, great, Yigal. Thank you so much for the time and really appreciate the chance to talk today. Okay, absolutely. Take care. Bye for now.