Kicking off the next fireside chat here. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and I'm really happy to welcome, Julie Eastland, President and CEO of Zentalis, and she's joined by, Ingmar Bruns, Chief Medical Officer. Welcome. Thanks for joining us. Thanks for having us, as always. We appreciate it. So, Julie, you've joined Zentalis—you and the team, actually, joined Zentalis now a little bit over a year ago. For those that are less familiar with our story, just remind us of the key strategic priorities and goals that you and the team implemented so far. Yeah. Yeah, thanks Mike. We certainly did want to bring a very focused strategy to Zentalis, and that strategy is to bring azenosertib to patients as quickly as possible. Our focus today is on patients in the platinum-resistant ovarian cancer space who have high expressions of a protein called cyclin E1, and we're running a registration trial called DENALI. It's a multi-part trial. We're running the second part of that trial, which is a potential accelerated approval pathway trial, in this population, and we plan in the first half of this year to also enroll our first patient in the confirmatory Phase 3 randomized trial called ASPENOVA, and provide a readout at the end of the year on the DENALI Part 2 trial. Great. So, good to hear that. Are we still tracking to that? I think you set out to that goal about a year ago. So nice to hear that this is all tracking well. Maybe just stepping back a sec, and the platinum-resistant ovarian cancer space has been getting more competitive in a way. So there's a lot of ADCs that are being pursued here. You know, how do you think about the overall opportunity for azenosertib as a small molecule, an oral drug in the category? Yeah, great, great question. And Ingmar certainly can chime in. But, you know, there is a lot of new agents coming. A lot of these agents in the ADC space, as you probably know, carry the same toxophore or the same payload. So we see that really as a great opportunity for patients to have multiple therapies in the space. But azenosertib really stands out in a differentiated way. Azenosertib is an oral agent, of which ADCs are not. They're infused. Azenosertib is also a non-chemo choice. And patients coming into this setting have had mostly chemo as choice and certainly all have seen chemo. And one of the benefits of azenosertib is to give patients an opportunity to have a chemo break. And then lastly, of course, azenosertib is focused on patients with high cyclin E1 protein expression. So you have an oral molecule that is a non-chemo option that is for a very specific population that is shown to benefit from azenosertib in this space. So we think quite differentiated. This isn't a question of will azenosertib or other therapies be important in the setting. It's really a question of and, and we believe azenosertib should be first and foremost for these patients to give them the maximum benefit. Makes sense. And then, yeah, remind us of how the clinical profile of azenosertib stacks up in the space. And, you know, what have we seen? I know historically there have been some, there has been some debate around tolerability of WEE1 inhibitors in general, especially the AstraZeneca molecule. And so what have learnings been so far on, on, azenosertib? Yeah, and I'll just do just quick, and then I'm going to hand it off to Ingmar. But we, we presented data in January of 2025 on the historical studies of azenosertib in monotherapy, at doses of 300 and 400 single daily doses, with a schedule of 5 days on and 2 days off. And what we saw there was a very manageable tolerability profile, one certainly that, that we think, is, even better than, other agents, WEE1 agents that have been in the space, adavo, as well as a differentiated profile and again, very manageable as compared to, other cytotoxic agents, whether those are, an ADC profile or a chemo profile. In terms of, how we see this going forward, Ingmar, do you want to add, to that in terms of, tolerability? Yeah. So we, we do actually think that it has a very favorable tolerability and safety profile. And, you know, of course, there's this history that we can't change. But, as a matter of fact, if you compare this to standard of care and even ADCs, I think we do look at a pretty positive profile here. Right. We're looking at 10% high-grade neutropenia. We're looking at overall, you know, good tolerability where, you know, most of the other groups of adverse events, GI fatigue is mostly low grade, and especially the GI portion of it is very well manageable, right, with pharmacologically manageable. We also think that you can during a trial, you know, get a lot of, make a lot of progress here with oversight and education, also really giving sites and investigators, you know, support. We've really, you know, implemented a very data-driven approach where the clinical organization, clinical sciences looks at data every day. And whenever there's a gap or there's, you know, a potential adverse event, then they proactively contact the site investigator and help manage. You know, over time, of course, this won't be necessary, right, as people learn to manage this drug as they did with others. Right. Comparable drugs, CDK4/6 inhibitor is a good example here. And, you know, as we go through launch commercialization, more and more prescribers, of course, become more confident in the management there. But during a trial, especially for a single asset company like ours, you know, we think it's very important. You make a huge difference by this very hands-on oversight. Yeah. And so obviously, since that update about a year ago, you have now been enrolling the DENALI study. I think there was still the question of which dose to move forward. The 300 or the 400 mg 5 days on, 2 days off. And so, yeah, remind us. I know you provided some updates recently where you stand with the dose selection. I think you're in Part 2 now. Yeah, is that correct? We actually, yeah, we guided that we've enrolled Part 2A, which is up to 60 patients, 30 patients in each dose cohort. So that is enrolled. Of course, we have a seamless design in the trial, which means that we will continue to enroll in both dose cohorts until we've followed patients and have selected a dose. Then at that selected dose, Part B is completing the enrollment to get to about 100 patients. So both Part A and B at the selected dose will be the data set for approval. We are done with enrolling Part A, but we'll continue to enroll both doses until we reach the threshold of data that we need to make a determination. We'll let the market know what that dose selection will be. We've given guidance. We expect to provide that in the first half of this year, and then, of course, we'll continue to enroll at the selected dose, and get to the trial readout, which we anticipate the top line of that will be at year-end 2026. And then remind me the target number of patients is 100? 100 patients in the selected dose approximately. Of course, all the patients in the unselected dose will be supportive data, obviously, for safety. Right. But efficacy will be based on the selected dose. Right. So the big question then obviously is what metrics will you use to determine which of the two doses to select for the registration cohort? Sure, sure. Ingmar, you want to talk about that? Yeah. So, I mean, it's the overall risk-benefit profile. Right. And, as I, you know, alluded to earlier, we think that both are very tolerable doses. And, the safety or tolerability is actually the preferred term here. You know, there's, there's probably not a lot of differentiation. Right. In the past, we've seen 400 to be a little bit more pronounced, but, you know, not materially different. So a lot of this will be around, overall response rate, you know, to determine it. We also do have, a PKPD model that we're building that's, you know, primarily for regulators, of course, but, you know, that might also provide additional information there. But, needless to say, the doses are not that far apart. It's an oral drug. Right. There's, you know, some, variability there and overlap, in, in exposure for sure. Will you be able to share any data, perhaps on the less, you know, the dose that's not been to be chosen to move forward? We don't anticipate to be able to share that again because the data will be part of the broader filing for the whole safety and tolerability database. Makes sense. Yeah. You know, if we can find a way to share, certainly we would love to do that. But I think, you know, importantly, the message around a go forward dose, completing enrollment and reading out the trial, you know, is an indication that we feel that we should march forward and continue to allocate capital here and complete the trial. Other than that, I'm not going to set an expectation for detailed data till we get to the study end. The risk there, if we do, could be that we have to stop and then re-enroll patients. That's a time, a commitment we don't want to take. Right. How do you expect patients in Part 2 to be different in any way compared to patients in Part 1? We've already seen data, obviously. Do you look for reproduction of that data? Will there be any changes that could implement outcomes that impact outcomes? You mean will we see differences in Part 2 of DENALI versus Part 1? Yeah. Yeah. You want to talk about the changes we've made? Yeah. So, I mean, there's a change in eligibility. Right. Because Part 1 was 1-5 prior lines. That's, probably the main difference. And, it wasn't, you know, a prospectively biomarker selected population. Now we're, prospectively selecting, based on cyclin E expression. And we limited the eligibility to 1-3 prior lines for those who are folate receptor alpha positive and where mirvetuximab soravtansine is available and reimbursed, can be up to 4 prior lines. So there is a little bit of a difference in that population. And, you know, we're, on average, you know, question is if, if the, median, line of prior treatment is, is materially different. Right. So, to be taken with a grain of salt, but the eligibility is different. Yeah. I mean, that's not just, you know, different from what other companies have done to limit, to slightly earlier stages. Right. Right. Yeah. And then remind us of the biomarker selection criteria and what have you done around developing a test for the cyclin E expression? Sure. So So we've developed an IHC assay. This assay was developed and looked at retrospectively across all the prior studies. So starting with the 001 dose escalation trial of azenosertib, patients' archived tumor tissue was analyzed for their correlation of a number of biomarkers, but in one, including, of course, cyclin E protein expression levels that continued through all the monotherapy arms. And the collection of data historically around the PROC population in monotherapy for doses 300 and 400 was certainly a substantial amount of data that was retrospectively then aligned to determine responses. And so the cutoff for cyclin E1 expression was based on this retrospective analysis across several hundred patients. That then cutoff is the same cutoff that will be used and is being used to prospectively screen patients for their enrollment in DENALI part 2 and for the phase 3 Aspenova trial. Quite a substantive amount of data, and one in which, of course, you know, has been discussed with the agency. We feel certainly confident in the development of that assay. These trials will validate that assay for commercial purposes of companion diagnostic. What percentage of patients are expected to be positive? We've seen pretty consistently across the prior trials, about 50% of the PROC patients, who meet the eligibility of our cutoff. And so we expect that to hold in the future. But again, of course, that's subject to what we see in the trials, but, pretty consistent, percentage of total patients, eligible at that level. Yeah. And then you said you're starting, you're enrolling now the ASPENOVA, the confirmatory phase 3 study. Can you discuss any differences in eligibility or design of this trial and how it compares to DENALI Part 2? Sure. Ingmar? Yeah. So it's the same eligibility. Right. We chose to do that for two reasons. I mean, it first enables the highest PTRS. Right. Because you're, you know, just relying on a comprehensive prior data set for that. And then regulators, especially the FDA, now have a clear preference for confirmatory trials in the same patient population. Right. And previously, sometimes you went to earlier lines of treatment, of course. Right. Different patient populations. That's, you know, a lot harder. And given where we at and, you know, Julie can talk more about that. But you know, the refitting of the clinical activities to the runway, etc. Right. This seemed to be the, you know, the certainly most appropriate choice. Okay. Yeah. It's, of course, the ASPENOVA trial, the phase 3 is a randomized controlled trial against standard-of-care. And DENALI is a single-arm trial for accelerated approval. But obviously, the agency has been fairly clear, I think, on their guidance around accelerated approval trials. And we've had conversations with them about DENALI standing for accelerated approval, in light of both the study on its own, and then recently in discussions with them around the ASPENOVA trial. So I think we feel like we have a solid path forward. And of course, everything's always subject to data, you know, and landscape. But. I may be mistaken, but I think the chart of the phase three study that you have in your slide there, because it also indicates there are actually three arms in this study. Yeah. So just remind us what's behind that design. Go ahead. Go Go ahead. Yeah. No mistake there. So, that was, that was really part of, you know, our acceleration approach here. So we added in order to be able to have these discussions with the agency and, you know, have an immediate start as soon as operationally ready. We added another dose confirmation adaptive part. You know, we wouldn't wait for the final dose confirmation on DENALI to start the phase 3 trial if, you know, in an ideal scenario, it lines up. So, you know, we don't have to enroll the adaptive part. So we would just go forward with the control arm and the selected dose. We also have the ability, and that's been confirmed with the FDA, to just enroll a handful of patients and go ahead. That wouldn't still the majority of the evidence or the total evidence would come from DENALI for the dose selection. So there's really no downside to this. Right. Just, the opportunity for a significant acceleration. Yeah. And the acceleration is important, because it allows us to build a randomized control arm, which will be the first sort of clinical data set of patients in the PROC setting who have cyclin high expression in that control, and we'll see how they do against standard care. It's also important that it just is going to move up a full approval date. So from an NPV perspective, it's of value. And lastly, of course, for accelerated approval, you need the majority of your phase 3 trial enrolled by your PDUFA date. And so this really allows us to operate and execute in that accelerated fashion. Of course, you know, it's, as Ingmar mentioned, there may be one or two or a handful of patients in that adaptive design for ASPENOVA, or we may not need to enroll a single patient, but DENALI will inform us of dose. The agency was very aligned on, you know, sort of, supporting that design. I think in getting this drug to patients in the fastest way possible. Makes sense. Accelerating things. Do you expect patients who have a different prognosis or different natural history if they have high cyclin E expression? Mm-hmm. I'm happy to. Ingmar, go ahead. Yeah. So, yeah, we do believe that. And it's not just that we believe that. There's, you know, some evidence for that, that cyclin E high expressors have a poor prognosis. And there's information across, you know, multiple trials, mostly from control arms. But, you know, there has never been a head-to-head comparison, really. Right. With this. And that's the data set that Julie alluded to, which will, of course, help, you know, with our even the accelerated approval effort, because these are not, you know, independent efforts. Right. The two trials are clearly connected, you know, for the, for the, you know, as accelerated approval as well as full approval. And you will, you know, be able what we expect to be an, you know, a real lower response and durability of responses or PFS in this patient population. So far, there is evidence, but it's all cross trial and, you know, not in a randomized controlled structured fashion. Yeah. How likely is it that, as you know, demonstrates overall survival as well in the ASPENOVA study as opposed to just PFS, in your opinion? Yeah. We're, I mean, we're somewhat guessing that, of course. Right. And we haven't disclosed any overall survival data previously. And, I don't want to do this now, but, you know, we're confident that this is something that we will be able to demonstrate. Okay. And then, yeah, I mean, in platinum-resistant ovarian cancer, there is, I mean, how widely do you expect, or how frequently do you expect prior bevacizumab use? There's PARP inhibitor use as well. And then obviously Elahere. And how does that affect perhaps the activity of azenosertib in these studies, in your opinion? Yeah. I think we, we generally believe that, you know, it's mostly the number of prior lines that are predictive. You know, as you know, in the mirvetuximab trials, they probably saw a difference between SORAYA and MIRASOL, you know, based on the percentage of patients that had prior Bev. In our case, we really have a very high percentage in all the trials with prior Bev use. So, not worried about that. I think, you know, given that the MOA is so differentiated from everything else. Right. The ADC is out there and, you know, chemotherapy, that there's nothing specific. Right. No cross resistance to be expected. So, you know, this truly is an advantage of this MOA. Right. Other than you, you know, have even different toxophores on ADCs. Right. You know, sequentially given. There's probably still some cross, you know, resistance that you could expect. We don't see this here. Yeah. And in your opinion, what is the efficacy bar to support accelerated approval in DENALI Part 2? Yeah. I think it's where Part1 B was. Right. So I think there's, of course, a statistical bar that, you know, is much lower. That depends on the confidence intervals. Right. So where you want to exclude, you know, the upper bound of single agent chemotherapy that, you know, is probably relatively easily achieved. We're not concerned about that. The regulatory bar or, you know, what makes the agency excited about accelerated approval, that's still the 30% ORR, right? About maybe a little bit below, maybe a little bit above, and something between 5 and 6 months of duration. You know, as a reminder, we've seen already 6.3 months median duration of response, which, you know, certainly above what's needed and, you know, up to 35% ORR. So that certainly is above the threshold right now. That threshold hasn't changed in our view. And then how do you think about the longer term opportunity, perhaps in combinations either with some of the ADCs or with other therapies that are used in ovarian cancer? Yeah. We're really excited about thinking about azenosertib in combination with others. Obviously, the company has pursued combinations with other chemo agents. That data's been published a while ago, and updates to that could be forthcoming. But we certainly think cytotoxic agents in combination with azenosertib; there is a path there for combination and management of those two agents. And then we've had preclinical data showing combinations with ADCs, again, another form, obviously, of chemo, but yet one in which we think could be, you know, pretty exciting, not just only in ovarian cancer earlier in the setting, but obviously in tumor types outside of ovarian where we think azenosertib can play a role adding its effect to cytotoxic agents like platinum-based, you know, paclitaxel and others. Right. Okay. And then I know you've also had a study ongoing in USC, the TETON study. Just reminders of where you are with your plans and activities in USC. Sure, sure. So, in last fall in our Q3 earnings, we noted that that trial was fully enrolled, and that we plan to provide that data this year. USC obviously is a smaller indication and one where the landscape has shifted significantly. So from a commercial opportunity, it's not at the top of our list. But certainly if we were to pursue something there, it would be either with a partner or with another way to fund that study. Just to iterate our priorities, you know, priority number one to PROC and getting azenosertib sort of to patients, priority number two into earlier lines of ovarian. And if there is a priority number three, it will be to explore in other tumor types, probably in combination, but potentially as monotherapy. Dollar number three is really a question about how fast we can move in ovarian in order to free up money just to pursue other combinations or other tumor types. Okay. but USC likely won't be where we would spend that. Right. But just to get a sense in terms of how many patients are in this cohort and what dose was used there? Ingmar, can you? Yeah. So it's a, you know, similar to DENALI 1B, you know, about 40 patient data set. You know, clearly, you know, an active agent in that indication. But, you know, as Julie said, nothing that, you know, would rise to the top of priorities here. Right. And then maybe just lastly, longer term, you know, several years ahead, do you expect Zentalis to be exclusively focused on azeno and the opportunity there, or, or do you envision perhaps bringing another asset at some point in the future? Yeah. I think once we, you know, have azeno, you know, over the line, certainly 2025 is around aligning the portfolio, executing to get DENALI going. 2026 is about completing that, but also thinking about the broader strategy, not just for azenosertib, but for Zentalis. And certainly it would have to be a program if it's outside of azenosertib that really fit within the skill sets of the company, and of course, of interest to investors, because obviously additional capital would have to be formed. So nothing on the horizon there. But I think we always want to keep our eyes open for what Zentalis can be once we get through proof of concept with azeno. Great. All right. With that, we have to wrap up. Thank you, Julie and Ingmar. I really appreciate it.