Great. We are on to our next session. My name is Eva Forte. I am one of the biotech analysts at Wells, and we have with us today Julie and Ingmar. Julie is CEO, Ingmar is CMO of Zentalis. Thanks so much for being with us. Well, thanks so much. Thanks for having us. For having us. We appreciate you giving us some time today. Great. So maybe we can start just high level Zentalis, past 12 months, next 12 months. Happy to do that. I won't be remiss in mentioning we're going to be making some forward-looking statements, and we appreciate those listening, taking a look at our SEC filings for the risks and uncertainty around those statements. I have fulfilled my legal obligation. So, on to your question. I have had the pleasure of working with an amazing team the past 12 months, and looking forward to the next 12 months, as we've accomplished a lot on our agenda with our very focused strategy to bring azenosertib to the market for patients in the platinum-resistant ovarian cancer space, in particular for our biomarker-selected population of high expressers of cyclin E1 protein. So in the last 12 months, we have begun and enrolled two parts of our DENALI registration-intended study. This is the DENALI Part two trial, where we've enrolled Parts A and B, and we're currently enrolling cohort 2C in that trial. We also have gotten alignment with the agency, the FDA, around our ASPENOVA phase III. That is our randomized trial that will not only support accelerated approval but will eventually transition the accelerated approval to full approval, and also for global commercialization. So a lot going on. We've even started bringing azenosertib forward in the ovarian space with our MUIR trial Part two in combination with bevacizumab. That is in patients who have progressed while on a PARP inhibitor in the first-line maintenance setting. We are studying those patients in the second-line maintenance setting. So lots has happened. Maybe I forgot, most importantly, we have confirmed and selected our monotherapy dose of 400 mg, a single dose daily, five days on, two days off. Got it. A lot of stuff to talk about. A lot. An exciting time. Maybe we can start with, just remind us, azenosertib was under partial FDA clinical hold. It was tied to treatment-related deaths. Have you fully addressed the safety signals, and have you incorporated any monitoring in the phase III study? Yeah, thanks. Do you want to address, Ingmar? Happy to, yeah. I would like to start by saying that the FDA lifted the hold, right, without any request for changes to the dose and the schedule. That is something that, of course, is important, and I have not seen in my career really that from a hold, without further requests, the hold was just lifted. Nonetheless, that is something that, of course, drove us to rethink management and study oversight, and that is something when we came in, one of the first things that we started to do, and we moved to really real-time study oversight. That means that we have a bunch of clinical scientists and medical monitors that are really focused on really starting their day by looking at the database, see if there is data missing, if there is any signals. Something that is not left to a CRO, but it is really one of the core focuses of the company right now. If there is anything that alerts the team, then we will proactively reach out to the investigator. More importantly, because, of course, you want the investigator to be able to handle the drug, and learn to manage the drug, which certainly given the profile, which we think is very positive, is possible. There is an education piece as well. That is something that we have gone through and where we see this bear fruit by really, the things we preach are really adopted by the investigators and the site personnel, so that really is important. Lastly, we just clarified, mostly not on severe side effects, which are not so many with azenosertib anyway, but those who are, of course, impacting convenience and quality of life. There we just strengthened the antiemetic schedule. Antidiarrheal medication. It just has more clarity and is more straightforward, and also leaves less room for interpretation, and that really resonated. Got it. WEE1 inhibition as a class has historically been limited by heme tox, most famously, I would say. I guess what makes azenosertib's therapeutic window differentiated from competitors that maybe haven't been as successful in the past? Yeah, first and foremost, one of the claims, of course, with azenosertib is that it is more selective as a kinase inhibitor, and that certainly plays a role. But then, even more importantly is that the 1,000-patient experience, which eventually didn't take 1,000 patients, but now it is experience of 1,000 patients that led us to the five on, two off schedule, which is not an uncommon thing, of course. But then again, together with a dose, it takes a long time to establish and be confident in, and I think that's really one of the big accomplishments, to have found a good therapeutic window in this narrow therapeutic index space. That nonetheless is, and that also makes it hard for any followers. Because it does take a lot of patience and time to figure this out, and that's something that we think is really key because it is an ideal scenario with all the schedules tested, where you have enough target engagement, where you have enough exposure over time, but then also give the window for recovery for those patients, which really sounds trivial, but really makes all the difference. I think just to add the context here, that hematological events actually in DENALI Part 1b were pretty modest in terms of incidence when you think about grade three neutropenia rates, which were, I think grade three and above were what, 12%? That's a very low percentage when you think about some of the data you see coming out of some of the ADCs, where grade three treatment-related neutropenia was at 45%. So, this really isn't so much a differentiated profile than other oncology drugs. It's just that it has been overwhelmed with the perception because of the two grade five events in Part 1b, which had a lot of course, factors involved. But importantly, again, as Ingmar noted, when you look at the totality of the patients that have seen azenosertib in monotherapy or in combination, the safety profile is quite good. Got it. How much of this heme tox bothers patients versus the physicians that are actually seeing it? A great question. So say again, how much does it- The heme tox bother patients versus- Yeah. Patients, because it doesn't hurt usually, right? Neutropenia only hurts if you get an infection, and not until then, and the majority of patients, of course, don't have febrile neutropenia and don't have actual infections, fortunately. Because if that happens, then we, of course, and the investigators react. It used to bother physicians in the beginning because that was really the reputation of the drug and the class, and that really changed, right? Just adding to what Julie just said, the neutropenia rate is low double digits. To be precise, 11%, 12%, and half of that at least, is grade three. So any kind of high-grade neutropenia really is a rare event. If you compare this with standard of care chemotherapy or most of the ADCs, then that's really very favorable. Thrombocytopenia even less so, right? There, the grade four is rare. High grade is also a low percentage. That's not something that a patient would ever feel, because usually you don't really see bleeding or anything. We haven't seen that. That's the same. What is certainly something that a patient could be bothered by is anemia, but again, same situation there. The rate is pretty low, and that's what I said initially. So the majority we're dealing with is more GI, is fatigue, which is hard because it's a multifactorial process. A lot of it is driven by the disease, the circumstances, of course, of having this potential terminal illness, and then partially, of course, also by the drug without knowing the exact mechanism here. Got it. Very helpful. Maybe just going back to the 5-2 schedule that you were mentioning. It's been central to tolerability, but is there any risk that it compromises efficacy by incomplete pathway suppression? No, I don't think it's really a matter of complete pathway suppression. As you know, of course, it doesn't require a permanent suppression of the pathway. If you look at the mechanism in particular that really wants to drive these rapidly dividing cells into cell cycle, avoiding DNA repair. They're all damaged, because they're tumor cells, and eventually leading to mitotic catastrophe. That's not something that needs to be absolutely continuous. It should just be most of the time. We think that's why the five on, two off is important. We need the exposure to be above a threshold to hit the target hard enough. We know that, and that's also something that drives a very clear differentiation between 300 and 400 mg. So the schedule matters. We're not worried about two days. Sometimes patients have to do treatment interruptions to manage some of the side effects. We know that for a while, this is not a problem. We just need to ensure that you don't have gaps of multiple weeks or so. Then you see that the tumor markers start to increase, and then likelihood of relapse is increased and higher. So it is important, but it's not a matter of continuous and complete blockage of the pathway. It's just, given the mechanism, not that important. Got it. Maybe just touching on DENALI Part two, the top-line readout. We're expecting it in the first half of 2027. What does a win look like for this readout? Yeah, that's a great question, and I think we've got a number of things to think about there. First off is we're thinking about the DENALI Part two population and where it is looking to make improvements. We know that single-agent chemotherapy is the standard of care globally, and that we see response rates there in 4%-13%. Our primary endpoint in DENALI Part two is overall response rate. We've also seen in all of our historical studies in the P-ROC setting for cyclin E1 patients, and that includes our dose escalation trial, the MAMMOTH trial, which was PARP-experienced patients, as well as DENALI 1b, which was all P-ROC patients. We see in those studies where we have overall response rates at 30%+. That's clinically meaningful when you think back to ELAHERE and its trials against single-agent chemotherapy and their response rates in that range. We certainly see a win here against single-agent chemo of around 30% or greater, and duration of response that's five months and better. That's going to be a win. The bigger the number, the bigger the win. Got it. What does this mean commercially? Again, from a clinical meaningful perspective, it's important that is a significantly better opportunity for patients to have a response and have a duration of response over their options, which is more chemo. As you think about the patient journey coming into P-ROC, it's been a lot of chemotherapy, and their options coming into P-ROC are mostly chemotherapy options. I think all of them are. Most of them I.V. infusion. Really, azenosertib is going to offer a great opportunity for patients to have a chemo break. Those patients who have high cyclin E1 disease have a high correlation to this response, and that's clinically meaningful over what their options are today. Got it. I believe you haven't shared what's the cutoff for cyclin E1 expression. You have mentioned it's about 50% of patients. How reproducible you think this is in a phase III, and also how are you thinking about the companion diagnostic or requirements at this point? I'll talk about the companion diagnostic. You can talk about the cutoff. We haven't disclosed the cutoff yet. We do know that when we look retrospectively across all of these trials that I mentioned before, what we've seen is about 50% of the patients in our historical studies have screened positive for our cutoff for high cyclin E. That's where the 50% of the P-ROC population comes from. Got it. That assay has been very well developed over the past many years and is in a very good place and being used prospectively to screen patients in DENALI and ASPENOVA to validate the assay for regulatory approval, which is on track to align with the therapeutic timeline for approval as well. So those two, we plan to submit together and have both the CDx and the therapeutic approved contemporaneously. Got it. At what point would these patients get tested? Is this something that you could incorporate earlier in the treatment algorithm, or is this something that, as patients continue to progress, maybe they would consider the tests? Do you want to talk about that? Yeah. At the moment, if you look at the studies, it's archival tissue, which is an important advantage, because you can basically use the specimen from the original surgery, and you don't have to undergo a biopsy, which of course, in academic centers, is not a huge hurdle, but for the patient, is an an invasive procedure that clearly is an advantage if you can base your diagnostic on an archival tissue. Then we're allowing for the studies a very wide pre-screening window, so you can basically enroll or pre-screen a patient when still on an active line of treatment. There's no restriction to this. That's something that if you look towards post-launch, then of course, the plan is to establish this in the standard diagnostic panels. You already have this as a physician for your patient in the case of an unfortunately very realistic progression down the road. Yeah. The goal would be at diagnosis, utilizing the tumor tissue that we would hope that patients would be screened for their cyclin E1 status. Should they become P-ROC patients, they would already know they have an opportunity to utilize azenosertib. Got it. How flexible is this cutoff? Is there a chance that once you get the data, you go back to the FDA, and it's like, Hey, maybe let's shift the cutoff? Or is this something that's very well-established, and it's not movable at all? It is very well-established. Got it. Because it is really through a very rigorous process. Initially, it was retrospectively validated, going through MAMMOTH, DENALI Part 1, even the original dose escalation. And then now, for the second part of DENALI and ASPENOVA, the phase III trial, it is prospectively validated. That is really the gold standard of doing this. That is really something that we also perceived as extremely robust, because if you see patients that the few patients that respond, even though they are below the threshold, they are just below. If you look at the ones that have no expression, there is no responders. And there is very few. The specificity of the test is really excellent, and we do not see to, at this point, really the need to adjust this. And it is also a pretty strong competitive advantage over others who, in their registrational trials, still have to validate and determine the schedule. Right. Okay, very helpful. Maybe just talking a little bit about DENALI Part 2c, what drove the inclusion of this patient population and change in landscape? Or was it something that was required by the FDA or something that you decided to do on your own? Yeah. I'll take this one, and then Ingmar can help me out if he needs to. This was actually really straightforward. It was clear that there were going to be PDUFA dates for some additional taxane combinations in the first part of this year. We decided to be ready to initiate a cohort that would enable us to strengthen and add to our population in DENALI Part two overall, Parts A, B, and now C, for patients who have an opportunity to see taxanes in the P-ROC setting. We already have patients in our study who've seen some taxanes in the P-ROC setting. Now patients have an opportunity to experience that in some additional combination therapies. We took the initiative to open up cohort 2c, and we expect to have all three of our cohorts A, B, and C, at the 400 mg, be an integrated data set to support accelerated approval going forward. Got it. You've previously mentioned the Part 2c was kind of the reason why the readout was pushed back a little bit. Yeah. Is there anything about enrollment that wasn't expected or just the fact that you need to operationally? Yeah. As you might remember, or for the audience just to have them remember, the DENALI Part A and B began enrollment in 2025 and finished up this summer for Parts A and B. Part C, cohort 2c, was operationalized earlier this year, so it was already starting its enrollment after we had been enrolling A and B. It is just really the timing of that cohort based on, obviously, the landscape. We want to make sure that we have time for those patients to not only get through their evaluations for their overall response points, but to also have some time to develop maturity for duration of response. It is just unfortunately, the last sort of set of patients in will drive the timing for an integrated look at all parts. Got it. Is there any reason to believe or to expect different efficacy levels for this cohort 2c versus cohort A and B? No. If so, you could argue biologically, this patient subpopulation could be more susceptible to WEE1 inhibition because, given that they had already prior repeated paclitaxel exposure, which of course causes a lot of spindle and chromosomal misalignments that there is more DNA damage, and there is more mitotic catastrophe in the end. But we do expect a similar result there. There is certainly not any cross-resistance to be expected or a large impact of more prior lines of treatment. So, no. Got it. Okay, very helpful. You are running DENALI for accelerated approval. You are running ASPENOVA as a phase III confirmatory trial. How much of ASPENOVA's design is already locked in with the FDA versus what remains open? The end of last year, we met with the agency to align on the design for ASPENOVA. Including the control arm for ASPENOVA, the size, the primary endpoints being PFS, with secondary endpoints of OS and ORR. That design was discussed with the agency. We did that early, prior to the selection of the dose, so that we could begin to operationalize that phase III and begin enrollment in that trial to help support, of course, not only the timeline for full approval, but also to support DENALI's accelerated approval pathway. Because as you know, the agency requires a randomized controlled study to have been started or near enrollment at the time of the review period for accelerated approval. We are enrolling ASPENOVA. It will be a global trial. We will have a much larger footprint than the DENALI study. We are on our way with that effort. Got it. Are there any concerns that the potential accelerated approval for azenosertib is an issue for enrolling ASPENOVA? Yeah. As you know, in the U.S., of course, it will limit enrollment a little bit, globally not. That is why these trials have to have a global footprint. DENALI, Parts A and B are fully enrolled. Part 2c is about 40 patients. It will just be determined when we see the benefit we want to see from 2c, but nonetheless, that will be a small overlap with ASPENOVA. The majority, I think, of sites that are interested in DENALI will then convert over into the ASPENOVA study because we want the patients that have had experience with DENALI to be able to have those physicians move their new patients into ASPENOVA. So I think it will be complementary and not a significant overlap in terms of enrollment competition. For that, yes. But of course, if it's commercially available. Oh, yes. You'll see that. In the U.S., yeah. of course, the desire to participate in a trial is a little bit lower. But that is something that we accounted for, right? Yeah. That is a challenge that every clinical trial, of course, faces if you have the accelerated approval separately. Got it. Okay. Very helpful. Maybe just in terms of, you had recent interactions with the FDA through a Type D meeting. Can you just discuss with us a little bit, how did those interactions look like, and were they more on the positive end, on how do they impact your strategy? Yeah, I will just say we have been very fortunate to have the same team. Certainly, since Ingmar and I joined in 2024, it has been very responsive and very supportive. Do you want to run through the Type D meeting, Ingmar? Yeah, of course. I think I just echo what Julie said. They certainly know that despite some new entrants to the landscape, there is still remaining unmet need that is very significant, right? Because we know that with, not even approved yet, but the additional ADCs eventually will probably move into the front lines and then leave a gap, right? The new taxane regimens are, of course, great for patients, but they also just fit for a relatively small subset of patients because of the paclitaxel or nab-paclitaxel backbone, which, of course, limits the use quite a bit, right? Right now, we are looking at about 10% of paclitaxel single agent use, and that is not for lack of efficacy, right? Because the efficacy of single agent weekly paclitaxel is excellent amongst the chemotherapy options there. But it is still not used that much because of the toxicity, some of the toxicities that are very durable from the front line, when it is used every three weeks. This is something for 10%-15% of patients, and that is a great option with, of course, increased survival data. But that leaves a lot of room. The agency, and especially the group that Julie mentioned, they are very well aware of this, and they want to see additional treatment options here, and especially a completely separate, differentiated mechanism where you do not expect any cross-resistance to the existing and emerging therapies. Got it. Maybe talking within this evolving landscape, one of the things we hear the most is folate receptor alpha ADCs, and how we are going to be getting some of this phase III data for the next gen towards the end of this year, fourth quarter. How do you see that impact your strategy and the commercial viability of azenosertib? Do you want to talk about the clinical or the regulatory aspects? I will talk about the commercial. Yeah, of course. Okay. Yeah, I think clinically, as you know, for the new folate receptor alpha ADCs, you need a full approval to be in the way of azenosertib approval, where we don't see an issue here right now. Again, we don't know for those, if they're really agnostic to folate receptor alpha expression. So that's something that remains to be seen. But certainly, we see that, as I said before, azenosertib is a very viable and differentiated option here, and that at the same time, of course, we're dealing with the existing mirvetuximab, folate receptor alpha targeting- Right drug, where we also need to understand if a patient expresses folate receptor alpha, or is a high expresser, at the same time expresses cyclin E1, what do you do? Of course, we're not unbiased here, but I think given that patients just come off chemotherapy, we certainly think it's more favorable to give them a break rather than have a cytotoxic agent, which essentially the payload of an ADC is, as you know, right after. So that really comes down to clinical judgment. For the newer folate receptor alpha, as I already said, drugs, we'll have to see if they will be expression agnostic or not. I personally have some challenges seeing this from a regulatory perspective, but that's, of course, speculation. I think from a clinical experience, we have mirvetuximab-treated patients or previously exposed patients, both in DENALI Part 1b, but also in our Part two study. So we know folate receptor alpha experienced patients or agents that target folate receptor alpha. These are patients that we can treat and can benefit from azenosertib. I think Ingmar's really hit the nail on the head when it comes commercially. azenosertib's profile is differentiated as being a non-chemo oral option. That's important specifically for our biomarker population, keeping in mind that our target is really part of the disease pathway that cancer hijacks, being a WEE1 inhibitor. These targeted ADCs are targeting the cell surface or protein receptors on cancer cells. It's a different type of targeted therapy, and we think, as Ingmar mentioned, the commercial strategy here really is to bring this drug to these patients, who typically have been known in the earlier lines of ovarian cancer to not do as well, to progress faster, and have seen a lot of chemotherapy cumulative side effects. This is an option with azenosertib to avoid that for some period of time and then have at it with more chemo, whether it's single agent or it's an ADC with a chemo payload, that's still all chemo. It's just new chemo. We really think there's an opportunity here to give patients a break, and that really is more important than anything scientifically. Got it. What's the overlap, the patient overlap with the folate receptor alphas? Is it- It's about 20% of all PROC patients. It's a- Got it. a small fraction of our population. Of course, 50% of our population of the PROC is, we think, is an azenosertib addressable. Then there's a smaller percentage there that might overlap. For those patients that have both of those indications as expressing folate receptor alpha high and cyclin E1 high, then it really just comes down to sequencing which drug they're going to get. They'll have the opportunity, potentially, for both. Got it. Makes sense. Beyond folate receptor alpha, I mean, that's the one that we hear about the most. Yeah Are there other mechanisms that you're tracking? I think in all the sort of ADC classes, it's select your target, but you're delivering Topo1 payload. We know from experience in other settings, physicians tell us they look to breast cancer experience, where similar ADCs with the same payload are utilized in sequence, where there's very little benefit from additional therapy of a Topo1 after Topo1. That certainly is what ovarian cancer patients and physicians are looking at to understand what would be the added benefit of seeing eight of these ADCs in a row. It's likely not going to be something that physicians use. There will be a winner. It'll be great. This is a population that really needs options. There's such a dearth of opportunity for patients in this setting. We welcome all of these agents coming on board. We just believe our agent for these patients in PROC should see this drug first. Got it. You also showed some combination data earlier this year. Maybe can you walk us through your strategy there and what is it going to take for you to continue development down the combination path? Yeah. We have some current open enrollment in our ongoing MIRROR trial, which is a combination of azenosertib plus bevacizumab in the platinum sensitive setting. That is in the second-line maintenance for patients that progressed while on a PARP inhibitor. So that trial is enrolling, and we will look to see both. We already know what our combination dose there is, and we will look to see some signals, hopefully, from that study next year. In addition to that, what you are mentioning is the data that was presented at American Society of Clinical Oncology earlier this year in combination with paclitaxel, which was really a very nice data set that saw a real additive benefit to paclitaxel with azenosertib at a combination dose of 250 mg for azenosertib. So I think it tells us a couple things. You do not need the monotherapy dose always in a setting where you are combining with another cytotoxic agent, which is also driving the process of cell cycle stress. Additionally to that, this population was an all-comer population. So we really see a synergy with other agents where they may not all be cyclin E1 driven as a necessity in combination with these other agents. So we are going to continue to expand in other areas, looking for other combinations and other tumor types to continue on what is really the promise of WEE1 inhibitor, which is to be not only a good monotherapy agent, but a good partner in combination with other cytotoxic agents across many settings. Got it. Very helpful. Maybe just last question. Cash runway and what's included? Yeah. We very much appreciate the investors who've come into the story and who continue to support us and our existing investors. We just raised some money recently, and that will extend our runway into the first half of 2028, well beyond a year or so, beyond our data readout for DENALI. So we're in a good position to support DENALI, to support a registration filing, and to support, of course, the ASPENOVA trial and its enrollment. Got it. Very helpful. Yeah. Exciting times for Zentalis. Yeah. Congratulations, and thanks so much for joining us. Yeah, thanks for having us. We appreciate it.