Good. Good afternoon, everyone. I'm Andrew Berens, senior biotech analyst at Leerink Partners. Thank you for joining us for day one of our healthcare conference. We're here at the W Hotel in a very nice environment. Very happy to have with us Julie Eastland, the CEO of Zentalis, Ingmar Bruns, the CMO. Thank you for joining us. Thanks for inviting us. We're pleased to be here. It's a great venue. It is good. It is nice to be out of the Northeast and the Arctic tundra that has been upon us for like two months now. For those that are not familiar with Zentalis, maybe you could just start with an overview of the company, Julie. I am happy to do that. We are proudly developing azenosertib, which is a Wee1 inhibitor with a focus in platinum-resistant ovarian cancer patients who have high expression of cyclin E1. Our focus over the last 1.5 years has been really around the development of azenosertib in this space as an initial foray into the market to get the drug to patients. We are currently enrolling in the DENALI Part 2 trial, which is a registration-intended trial for accelerated approval. We announced at the beginning of the year that we had completed enrollment in the first portion of that trial, which was looking at the 300 mg versus 400 mg dose. In addition to that, we announced at the beginning of the year that we will initiate the phase 3 confirmatory study, which is a randomized controlled trial in the same population, to support the accelerated approval pathway. We've named that ASPENOVA. Lastly, we've restated our milestone for year end 2026, when we expect to have the readout of the DENALI trial, to determine whether that trial has read out positive or negative. Great. It's a big year for you guys. Big year. Congratulations. Thank you. Maybe we start with just an overview of PROC. What's the current standard of care for PROC, what do you see, as the bogey for success here? Yeah, no, the great question's important. You know, patients in the PROC setting have obviously come into the setting having experienced mostly chemotherapy agents. When they become platinum resistant, they have additional single agent chemo as current standard care. That ranges with response rates of 4%-13% and minimal PFS benefits. Very high unmet need overall in the population and certainly for patients who have cyclin E1 high expression, that is typically seen as patients with poor outcomes. Even a greater unmet need for patients in this setting. We've seen other agents, of course, notably mirvetuximab, have response rates around 30%, duration of response between 5 and 6 months, and we think those are clinically meaningful responses for the total population and probably even more important, again, for this biomarker selected population, which potentially typically doesn't do as well as the overall population. Maybe you could summarize. You've had data in PROC already. What have we seen with the zeno to date? Yeah, I'm happy to answer that, but I'll have Ingmar here. Go ahead, Ingmar. Yeah. You're asking for the bar, right? Where we see, The data today. zeno today. Yeah. I mean, the data today is, you know, very much in line with, you know, what we've presented, you know, for 1b. You know that we have, you know, communicated the full enrollment of 2A on the 2 dose levels. Based on, again, FDA conversations, but also our own observations and KOL feedback, we really think that, you know, the bar where it is still, you know, where the data we have reported have landed in the past, right? It is certainly a ORR level of about and above 30%, right? With the duration of response that we have observed in the past between 5 and 6 months. That remains, as Julie already alluded to, in the light of, you know, what's still currently standard of care, and then also the nature of the specific selected population, which is Cyclin E positive, you know, an attractive and realistic bar here. Maybe just adding that, you know, of course, cross-historical studies, which we presented back in January of 2025, we really saw very consistent overall response rates in the PROC population. These were studies that included our 001 dose escalation trial, which was in obviously more heavily pretreated patients, as well as the MAMMOTH trial, which was a study that looked both at combinations of PARP and also monotherapy and post-PARP setting. Of course, the DENALI part 1b study, which was in PROC patients with 1 to 5 prior lines of therapy with a median of 3. Across all of those studies, we saw a consistent level of response and a very manageable tolerability profile, especially at the 400 milligrams, which is a single dose daily, 5 days on, 2 days off. I think we feel very confident that was really the strength of the data that allowed us to really make the call about our strategy and to focus in on the PROC cyclin E1 patients. A lot of historical supportive data. The prior data sets, which ones were enriched for CCNE1? All of those prior studies were all comers, but we retrospectively looked at archival tissue block from patients to determine where the cutoff of cyclin E1 expression correlated as best response for patients. That's what really derived our cutoff in that IHC assay to prospectively enroll patients in DENALI part 2 and what will be the phase 3 ASPENOVA trial. Using the cutoff that you've chosen, what was the response rate historically? I know it wasn't prospectively defined, but retrospectively, have you disclosed? Yes, we did. We looked at both on an integrated analysis at the 400 dose as well as individually. Certainly, we can walk through a little bit of that here, and it's also slides on our website, which we'll absolutely go through the details. Again, it's consistent, we saw response rates in the cyclin E1 population at 400. Those response rates were over 30% or greater. In the case of DENALI Part 1b, which probably is the single largest data set of over 102 patients at 400 milligrams, we saw overall low 30s% response rate there. For the intent-to-treat population, it was closer to 35%-36%, mid-30s. You know, robust response for these patients. Okay. Can you just talk to us about the different doses, the 300, 400? What's the reason you have two doses, and what happens when you choose one dose? Do the other patients are not, they're not eligible for the analysis? Yeah. I'll talk about why we have two doses, but then, Ingmar, maybe you could talk a little bit about the, in effect, the dose selection process. Mm-hmm. The reason for 2 doses is, of course, both of those are active doses. Typically, the agency requires a look at 2 active doses in the same patient population to understand the best dose to move forward. The company had certainly studied both 300 milligrams and 400 milligrams on an intermittent dose schedule. That's the 5 days on, 2 days off, in a number of different studies, but really hadn't looked at that population in the current PROC population that we're going forward with, meaning patients who were 1-3 prior lines of therapy, because in the other studies, again, these were more heavily pretreated patients. There's a very good reason for 2 active doses. It kind of leads into what are we doing in DENALI 2a, the first part of our current trial, in terms of understanding how we might think about that dose selection. Okay. When you choose a dose, the other patients won't be part of the submission? That's right. Do you wanna talk about the-? Yeah. Yep. Yeah. I think the, as Julie already alluded to, the tolerability and safety profile is very comparable between the two doses, right, 300 and 400. The difference that we've seen before in the integrated analysis was about 10%, right, on the response rate. You know, that naturally will, you know, we expect to be that the main driver of the decision. We also have a PK/PD model in place, right, which, you know, is number one an FDA requirement to have that in place, but it could also support the decision, right? We expect, you know, the response rate, of course, to be the main driver also based on past experience. You know, to your design question of that continues to enroll. The design is seamless. As we already announced and I mentioned earlier, we had, you know, the 2 times 30 patients in the 2 dose levels enrolled, we don't stop at this point, right? We continue to enroll both doses and continue to enroll the dose arm that eventually will be selected at 50% efficiency, if you will. Therefore, of course, the number of patients to be added for 2B once the dose decision has been made shrinks, right? We're driving as a reminder and as you know, to the 100 patients, which we think is an appropriate registrational data set, and that's basically something that the FDA has also confirmed, you know, at the last meeting we had with them, end of last year. The patients who won't continue then, meaning the dose that will not be selected, those patients will obviously continue on their dose cohort, especially if they're benefiting from that efficacious dose. Of course, the safety database or tolerability database will be all patients. Patients that will continue on at the selected dose will be the patients that will be evaluated for the primary outcome of ORR. There's no crossover, you know, in the trial. Patients will continue on their selected dose, even if that dose isn't one in which we'll move forward. Okay. I think you touched on this a little bit, Julie, though. What's the background differences between what you've shown previously and the 2a data? The demographics of the patients in terms of, what are the key differences, I guess? Yeah. I think maybe, I'll focus in well, I'll mention briefly the 001 trial, again, dose escalation, single site, heavily pretreated, multiple different tumors, 1 to 19 prior lines of therapy, so a very different, you know, pretreated population. In the MAMMOTH trial, that was 1 to 9 prior lines of therapy, and again, you know, postpar patients. In DENALI Part 1b, which is maybe more applicable in that it was very much selected obviously for the PROC patients in a population that we thought was, you know, interesting to study going forward. That was 1 to 5 prior lines of therapy with the median being 3. DENALI Part 2, we further limited to the lines of therapy to 1 to 3 prior lines unless patients are folate receptor alpha high, where they are indicated and can have access to mirvetuximab, then that potentially is 1 to 4 prior lines for those patients. The differences really are just kind of tightening around that prior lines of treatment, eligibility for our current trial. It's prospectively screening patients for cyclin E status based on the cutoff, and again, kind of narrowing in on the patient population. In PROC, are the patients that have been able to survive and get longer, more therapies, do they tend to have less aggressive disease or more aggressive? Some tumors are unique in that regard that it may be better to enroll patients with more prior lines of therapy. I'm just wondering if this is one that somebody. I think you said 19. I'll let the medical person answer that. Okay. Yeah. Very good question. I think you said 19 prior lines. 19 prior lines is a lot, right? Yeah. Yeah. Is that a very lucky person or? Right. Right. It's a good question. No, it is. I think, you know, I don't think the, it necessarily... I mean, the aggressiveness and prior response and duration of response to prior lines, of course, you know, to a certain degree matters, right? We don't have a systematic analysis for this, we know that prior lines of treatment is a factor, right? If we do post hoc, right, which we, you know, have in our corporate deck, then you see that, you know, if you have fewer prior lines of treatment, then, you know, the response rate goes up, right? With all the caveats of post hoc analysis, of course. Generally, I think we also see in patients that, you know, certainly have been pre-treated within the eligibility, you know, and had sometimes relatively short responses to prior lines of treatment, you know, can really have long-term benefit of the Zeno. I don't think it's a, you know, completely linear or a complete correlation here. We really overall impressed by the duration of the responses that we've seen and the response responders that we observe. Yes, I mean, again, predictor, prior number of prior lines of treatment, and there's an aspect of aggressiveness, of course, if someone, you know, only had a 6-month response to even the PSOC setting and front line, then that probably translates. overall surprised or positively surprised by some long responses, also after, you know, relatively short responses in prior lines. Okay. There's reason to believe that the pivotal trial, is gonna have less-- or patients that are more sensitive to Wee1 inhibition. Yes. of course, cyclin E1 protein drives that... Right ... alliance right on Wee1. Enriching for that perspective. inhibiting. Yep. That may be more of an indicator than even the number of prior lines of therapy. Okay. You mentioned the bar. I just wanna clarify. Do you think the bar for regulatory approval is around 30% or so and 6 months duration of response? That... what examples are there of drugs that have been approved with that? That. You wanna go ahead? Right. You go ahead. Well, I mean, there are, for sure examples, right? For, you know, I mean, I like to use the CDK4/6 inhibitors, where, of course, only abemaciclib has a single agent, or monotherapy, approval, which is lower, right? We, of course, look at mirvetuximab and SORAYA study as well... Yeah ... in the exact same space, where, you know, this landed, around the same OR, you know, comparable duration of response. I think that bar still exists. The, you know, statistical readout and positivity is of course lower because you exclude, of course, the upper bound of single agent chemotherapy. I think there's again, the same bar, but both regulatory as probably also commercial, let Julie comment on this, but bar for, you know, especially an oral drug right now is still at the 30% level with the duration that we described between 5 and 6. That's sort of an all-comers population. You know, again, we think that would be very robust for cyclin E1, overexpressers. Yeah. I mean, there is nothing approved for CCNE1 positive- Right. Right Right ... P-ROC right now. Yep. I would think that the FT, the regulatory bar should be more flexible. Maybe, you know, best to focus on standard of care in the landscape. Yeah. Yep. The alternate therapies. Yeah. What about the confirmatory trial? Let's talk a little bit about that. Can you give us some background on it? Yeah. It's a great study. It's ASPENOVA. Ingmar can talk about the design. I think importantly, that was a, it's a randomized controlled trial in the same population, the discussion with the agency around the design of that study did allow us to have, you know, even a second conversation with the agency around DENALI serving in its design for accelerated approval. We're excited to start ASPENOVA much earlier than we may have intended. That was because the agency was very open to what I think is a very clever design that Ingmar and his team came up with. I'll let you, Ingmar, talk about Phase 3 design. Yeah. Thank you. Yeah, we used an adaptive design in the first part of ASPENOVA, which essentially is repeating the dose confirmation, which enabled us to, you know, have the conversations and get the buy-in of the FDA early before, you know, having either completed DENALI completely or having the dose confirmed on DENALI, right? It's also written in a way that, you know, once the evidence is provided through DENALI, at the time we start ASPENOVA, which, you know, guided to is happening this first half of the year, we can completely drop them, right? That becomes a conventional, randomized controlled phase 3 trial in the same patient population as Julie already said. We can also add a start to trial, we wouldn't wait for the evidence to be complete from DENALI, we can start ASPENOVA. If we had a handful of patients enrolled, then still the majority of the evidence would come from DENALI, and we wouldn't continue the arm, right? If, you know, unlikely, You know, this trial starts before there's any confirmation through DENALI. We could just fully enroll the trial. Therefore the, you know, number of patients varies a little bit. Yeah ... depending on if we have an additional dose level to enroll. You may ask, like, why did we do that, right? What's the benefit? Of course, starting a phase 3 confirmatory style for full approval, it's obvious the sooner you can start that, obviously the faster you can hopefully get to full approval, really pull valuation up and get the drug to a broader set of patients. ASPENOVA also is going to be one of the first trials where there's gonna be a controlled randomization into a control arm that will specifically be looking at cyclin E1 patients in the setting of current standard care, which is single-agent chemo. Really important to gather that information, which can be very supportive throughout the process of agency interactions for accelerated approval, you know, and has the benefit, obviously, of having a place for physicians to put patients once DENALI is fully enrolled. Really important that we got ASPENOVA started, as soon as possible, and this was the way to do that prior to the full readout of the dose comparison for DENALI. What are the remaining gating factors to that trial? That trial is operationalized. Sites are opening. We expect to have the first patient enrolled in the first half of this year. There are no obstacles at this point, which was the reason for this sort of adaptive design in the beginning. Okay. If we end up with the dose on DENALI prior to enrolling any patients in ASPENOVA, we'll simply enroll at the go-forward dose. It lets us start earlier if we're ready. Yeah. The FDA had, you know, a couple years ago suggested that you have to have your confirmatory trial largely- Mm-hmm ... enrolled before an accelerated approval. Is that... I mean, obviously a lot's changed at the FDA, but, is that still their belief that they wanna see that largely enrolled- Yeah ... do you think you'll be there by the time they would approve? Yeah, that's our intent. Okay. Mm-hmm. like, over 50% or? Sure. Yeah. Okay. You know, depending. They've been, I won't say clear in terms of public guidance per se, but they have been clear about having confirmatory randomized trials fully enrolled or the majority of it enrolled at the time of an accelerated approval PDUFA date. The extent to which you need enrollment will probably matter on the strength of the data at that time and also on the unmet need of the population. While the agency doesn't give you an exact number, I think you're always safe to plan to have the vast majority of that study enrolled and certainly another reason to start now versus waiting to the end of the year until you have, you know, full DENALI readout. What's the sample size for ASPENOVA? Yeah. It's 420-450 patients, depending if we enroll the adaptive part that I just described or not. Okay. How many sites are you guys planning to have? We haven't disclosed that. There'll be more sites than we have, of course, in DENALI and more countries added. I think you can look at other comparable trials that have been run in this setting to sort of understand the breadth and size of design that probably makes sense. Okay. We feel good about the sites we have, obviously, in DENALI. Not all of those may convert, but certainly those sites that have patients and need to have an ongoing place and wanna support the drug, we think will roll into ASPENOVA. Okay. I know we're down towards the end here, but I would like to talk a little bit about moving earlier in ovarian cancer. I know the company had different strategies along the way, but how do you see getting earlier in lines of therapy and what's... You know, obviously that's a combination approach, but you have a trial called MIRROR planned. Maybe we could talk a little bit about that. I think last year we were, you know, planning or thinking or hoping we could move into earlier lines and, you know, it's been a year, and we have some progress there. I'll turn that again over to Ingmar, but the MIRROR study is an open trial that looks at combinations with the Zeno and therefore a perfect place for us to think about testing in combination with bevacizumab in earlier lines. Do you wanna describe where we're heading? We're chosen a second-line maintenance setting in a population that has progressed while on PARP inhibitors in the front line and otherwise the eligibility is very broad because that's really a defining characteristic for the prognosis of these patients. That gives us a relatively early proof of concept opportunity because once you subtract the induction therapy for those patients, they have like 3 to 4 months PFS essentially, and you know, any changes on top of that, right, through the addition of ZNO-02 plus bevacizumab, which is the combination we're attending here in MIRROR, is, you know, first early and hopefully clearly visible, right? Doesn't necessarily mean this is the final population for next steps, right, you know, registrational trials. It would enable certainly given the similarity of these populations, a front-line setting or indeed a broader second-line setting, right? We just wanted to be pragmatic and efficient also with our resources, and we feel that is, you know, very efficient and designed with a potentially clear readout. You mentioned the entry criteria, are gonna be patients that have prior PARP inhibitors. Would you expect to get mostly HRD positive patients and BRCA patients? Or do you think you're gonna get a mixture? At the moment, it's still a mixture, right? Because, I think while, just for lack of alternatives, right? I mean both in the large, you know, geographies, in the US as well as in the, in the EU, territory, it's still a common practice, also to enroll into the HRD negative population, right? It'll be a mix, and interestingly, if you look at the literature, then, the, the outcome is very comparable between the two, right? That's why I said if you progress while on PARP inhibitors, that seems to be, really a, defining biological event for this patient population. We expect to enroll in both. Of course, there are some sites who will be hesitant, to, you know, give PARP inhibitors in proficient patients, right, HRD proficient patients, and there's probably a slightly smaller, proportion of those being added. Yeah, the expectation is clearly to have a mix of those. What about CCNE1 status in this setting? Yeah. We haven't disclosed these details, but, you know, that's certainly something that we don't think in combination is necessary to select, right? It's something that we're still, of course capturing and, you know, it can in a retrospective approach. Right ... apply them. Is CCNE1 status, mutually exclusive from the HRD status? No. There are patients that. Mm-hmm ... that could have both. Yeah. Okay. It'll be the same process we'll look at obviously retrospectively with the same IHC assay, the same cutoffs just to compare. Okay. All right. Let me see if there's any questions in the audience. Anyone have a question for some panelists?