All right. Welcome to this fireside chat with Zentalis Pharmaceuticals. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim. It's my great pleasure to welcome Julie Eastland, President and CEO, as well as Ingmar Bruns, Chief Medical Officer. Welcome. Thanks for joining us. Just jumping right into questions, Julie. You joined Zentalis. I looked it up exactly one year ago this week, I believe. Remind us of the key strategic priorities and goals that you and the team implemented since joining and how that's been going. Yeah, thanks. Thank you for having us. We certainly appreciate Guggenheim and your hosting us here today. Of course, I just have to make a mention that we'll be making forward-looking statements today. There are risks and uncertainties associated with those, so we direct you to our SEC filings for the most recent updates of those risks and uncertainty. I'm well schooled by my legal counsel. You are right. I think, actually, Ingmar reminded me, I think it's this Thursday, is one year since we joined Zentalis. We had a very clear vision and a priority coming into the company back then. That was really to clarify and set a strategy that would allow us to bring azenosertib forward in patients with platinum-resistant ovarian cancer who had high cycling E1 protein expression. We have done a lot of work on that, including restructuring the company at the beginning of the year in order to allocate our runway to get to data and to have runway beyond that. Today, we are focused on developing azenosertib both in the PROC setting from an accelerated approval pathway opportunity in our DENALI Part 2 study, as well as preparing for the phase III confirmatory trial to focus on the full approval for azenosertib. Great. Maybe stepping back for one minute, let's talk about the platinum-resistant ovarian cancer space, which seems to be getting more competitive, especially given that there have been numerous new ADCs that have been announced and are advancing in various trials. If we step back, how do you think about the opportunity for azenosertib in the space as an oral small molecule inhibitor? Yeah, I think this is really important because these patients really have very limited to no therapies, especially the cycling E1 high-positive patients. There's no targeted or approved therapy for that patient population. In addition to that, these patients have single-agent chemo as their standard of care, which offers actually quite low response rates. We, of course, welcome any new agents in the space for these patients because that's what we're really focused on. How is azenosertib different? It is different in a number of important ways. As you mentioned, it is an oral molecule. It is also a non-chemo option for patients who've seen nothing but chemo coming into the space. Lastly, it will be for this biomarker-directed population specifically. We think that there's great reason as to why this agent is differentiated. ADCs, while there are many, all look similar in terms of their payload for the most part, and in terms of really sort of their efficacy as we see. We think they'll be important agents, but we think that these patients who typically do worse would benefit from an agent that we know has correlated response to azenosertib. These patients should see that agent. Then they can go back to getting chemo, even if it's directed chemo. I invite Ingmar if he has any competition or any comments about competition. No, I think you said it all. I mean, I just reiterate the fact that we are obviously happy for the additional options that patients seem to get, right? I also see ADCs, especially the TOP1 inhibitors, essentially as one class of drug, right? Or one drug, one class of drug they are, right? One drug. I am thinking that the impact on azenosertib is somewhat limited there. Yeah, we were just at ASML, and some of the discussions there were clearly saying that they would prefer a biomarker-selected drug in a setting that would give some direction to how to use some of the options, which should, I think, benefit you. Maybe stepping back then again, remind us how the clinical profile of azeno so far stacks up in the category. Sure. We had a large data announcement earlier this year in January and a follow-up on the DENALI trial in March at the SGO conference. What we're seeing across a lot of our historical studies is a very consistent profile in terms of responses, greater than 35%, up to 35%, in the DENALI I-B study. In addition to that, I think durable responses with median duration of responses over six months. This is really an important watermark when, as you remember, standard of care right now for these patients, again, is single-agent chemo. Response rates, they average 4%-13% for the total population. These particular patients who are cycling E1 positive tend to do worse and likely may not even benefit that much by current standard of care. The other thing that folks have been focusing on historically with the azeno was the tolerability profile in general for the class of WEE1 inhibitors. There has been a lot of data generated with the AstraZeneca molecule historically. I know you have spent some time dialing in a dosing schedule that is tolerable. Just remind us again of the tolerability profile and what your comfort level is around that. Sure. I'll let Ingmar go ahead and. Yeah. Especially in comparison maybe with competitor drugs. As you mentioned, adavo, which is the AstraZeneca WEE1 inhibitor, other molecules are a little bit earlier or very early actually in their development or even preclinical stage. Azeno was developed as a more selective WEE1 inhibitor. I think we're seeing this, right? If you look at the off-target kinase profile, it certainly is a much cleaner drug than compared to adavo. This translates into the fact that we're really seeing in the core adverse event groups, GI as well as cytopenias, that there's significantly fewer high-grade cytopenias. Having said that, we're still looking at low double digits here, right? If we compare this with other drugs like the TOP1 inhibitor ADCs, that's probably a fourth of that. Overall, we actually think that's not a very limiting profile here. The other group is GI toxicities, including diarrhea, nausea. There is also a clear differentiation there with adavo. Having said that, of course, these are cross-trial comparisons with all the caveats that come with them. We think it is a differentiated drug for sure. Maybe one additional comment. That is this has been studied in hundreds of patients. Azenosertib has been in monotherapy and in combination over 700 patients. I think that the tolerability profile is fairly well characterized. There are always exceptions to that. In the overall scheme of things, it's really been quite manageable with the right sort of supportive care mechanisms and the right attention to patients being an oral drug, right? Maybe just one more on the landscape. There are also CDK2 inhibitors that are being advanced for cycling E1 amplified or cycling E1 overexpressing cancers. Some of them are, I think most of them are still in earlier stages. In general, just given the overlap in target market, how do you think about that class of drugs relative to WEE1? Do you want to talk about the difference of? Yes. I mean, we've seen some clinical data with the probably most advanced one. And it looked okay for sure. But I think the WEE1 inhibitor and specifically azenosertib has the advantage that with WEE1 inhibition, you target G1S as well as G2M phase, right? While CDK2 really targets G1S. And we know that most tumor types are more reliant on G2M as a checkpoint because the tumors kind of override the G1S anyway. I think a drug with the purposes to drive towards mitotic catastrophe during inhibiting DNA repair, we clearly have an advantage of addressing two checkpoints here. Okay. Okay. Super helpful. I know you just announced that you now completed enrolling of the phase II portion of the DENALI study. Is that correct? That was actually of the TETON trial. Oh, TETON. Sorry, I missed it. Yeah, that's okay. Maybe how are you doing with enrolling DENALI, I guess, at this point? I think that's a great question. We've guided that we plan to provide top-line data at the end of 2026 in the DENALI trial. That's parts 2A and B combined. We are on track for that enrollment to achieve that objective. Of course, as we get closer to dose selection, we'll provide updates to the market on the advancement of our clinical progress as we march towards the end of 2026. Okay. I think the study does have this dose selection lead-in phase where you're comparing two doses. Yeah, any updates on how that has been going and how close are you to selecting one of the two doses? Yeah, we haven't provided specific guidance on that. I can tell you that there's a lot of enthusiasm, again, for a differentiated molecule. We have had a rapid site enrollment from the perspective of bringing sites on. That then, of course, drives enrollment. We're certainly on track for Part 2A. Once we have dose and alignment with the agency, we'll provide more of an update then on dose selection in the 2A. Okay. Did you guide to timing around that? When When do you think you might reach that point? We haven't. One of the reasons is the part 2A is up to 30 patients in each of the doses. As we enroll, we may have an answer sooner, or we may have an answer at the end of those 30 patients. We soon will be able to provide an update where we are on that enrollment. We just haven't guided to that for this year. Understood. We're enthusiastic. I think I want to make sure I leave that the enrollment is going really well. We have no concerns there. We'll certainly provide an update, as I said, as we get to that data point. Understood. And then just to confirm, so this will be a seamless transition to the Part 2B portion. Is that correct? Yeah. I think Ingmar can talk about the trial design. Yeah. It was designed as a seamless trial. Julie just explained the 30 patients per dose arm. While we're kind of analyzing the data, we'll continue enrollment into both arms, right? That causes some slight inefficiency, of course, because you continue to enroll also in the arm which you're not going to take forward. It also brings your enrollment forward on the selected dose arm, right? For that matter, saves time for sure, right? We don't need to add the full 70 patients that we talked about to get to a data set of about 100 then. Right. This may be a very obvious question, but I guess what are the criteria with which you select one dose over the second dose? What the criteria would be, yeah. Number one, it's, of course, efficacy as measured by the response rate. The other one is overall the tolerability profile, right? That's a little bit more nuanced, of course, than the ORR. It's supportive, right? If the first two are not as clear-cut, then we also have a PK/PD model that will allow us to look at exposure in more detail here. Gotcha. I think I know the answer to this, but will you be able to share any findings from that Part 2A study prior to completing the phase II-B portion? Yeah, that is likely not possible because the data set from 2A, along with the data from 2B, will form the basis of the data for filing. If there's a way we can think about doing that, we would. I do think that providing a dose and continuing on the path to accelerated approval data at the end of 2026 certainly means that we think we're on track to achieve the goals. Makes sense. What are your thoughts or plans around the confirmatory phase III study? Yeah. We have noted in our corporate presentation that we do expect to have the same patient population that will enroll in the phase III randomized trial. That's, again, prospectively identifying cycling E1 positive patients who have one to three prior lines of therapy and four if they have seen mirvetuximab. That would be against current standard of care or single-agent chemo. It will be two-arm randomized against standard of care. That study will have more information on that as well as we conclude conversations with regulators around that. We think about initiating that trial design and the launching of the study next year. Okay. Super helpful. In terms of the biomarker selection or the biomarker assay, I suppose, or test, how far along are you in how finalized is that test, I suppose? Is there anything else you need to do prior to starting the phase III, for example? Right. I'm happy, Ingmar, if you want to speak to any of the logistics around the biomarker. We are in good shape historically. We've looked at hundreds of patients retrospectively, not only to identify the cutoff, but to test the IHC assay itself. At this point, we are validating the prospective use of that assay in the DENALI trial and in the phase III trial. Of course, we'll need to do that to build the body of evidence from a regulatory perspective. Anything you want to add? Yeah. I think we're on track with all the milestones we need to hit with this, right? I mean, there's, of course, the FDA process in the U.S. for an accelerated approval. There's also the IVDR process in Europe, which will be like a separate path, essentially, for European approval next to the actual trial filing and approval. I think that really is on track as well. Right. Maybe just another question going back to DENALI Part 2. I think we all know that the response rates for chemotherapy is very low. I think it's in the low teens at best. Is there a minimum effect size that you need to demonstrate in DENALI in terms of superiority over that that would be recognized by the agency as being differentiated or approvable, I suppose? I think I would just hearken back to the data that's been presented that's quite meaningful at a 35% response rate. That's almost 3x standard of care, especially for this patient population that probably doesn't do as well even as the low double digits or low teens of response rates. That's being generous. As we think about going forward, certainly from a medical perspective, that bar certainly is a bar that's reasonable and acceptable as a differentiation from current standard of care. Of course, we'll discuss with the regulators once we have dose and data, the regulatory bar. Okay. Super helpful. Another landscape question and perhaps thinking about future steps. We did see recently at ESMO presented data on pembrolizumab for the first time of a positive phase III study in PROC, the KEYNOTE-B96 study. It was, I think, not the effect size was moderate, I think. I think there was some enthusiasm among prescribers around using a PD-1 in this phase as well. Does that affect, how does that affect the landscape in your opinion? Perhaps does it offer opportunity for future combination studies? Yeah. Ingmar was there. Yeah. I mean, first and foremost, great to see that there is finally a success for IO in the disease area, right, in the indication. Overall, I think it's a relatively small patient population that's eventually eligible for that because a lot of patients have all pretty much, right, have received paclitaxel in the every three-week schedule in early lines. They know that there's specific side effects that are not very popular, such as alopecia, in particular neuropathy, relatively deep cytopenias as well, which also is the reason why single-agent paclitaxel, which is the actual combination partner in the KEYNOTE-B96, B96 trial, is weekly. The actual use of weekly paclitaxel is relatively small, even in the single-agent chemotherapy setting. I don't think that will increase significantly. I think it's a great opportunity about we heard from some investigators at KOLs, and that's kind of in line with our estimates, 10%-15% of patients. That's where we see this. We do think that azeno is a good option, especially for the biomarker-selected population. Poor prognosis, as Julie already mentioned earlier, is an earlier opportunity here even, right? Great as a treatment option, adds to the armamentarium overall. Don't think it's a threat for especially an oral single-agent opportunity here in this space. Okay. Yeah. Super helpful context. Maybe shifting over to TETON. That is the study, phase II study that I guess the analysis is fully enrolled now. That is in USC. Just remind us again, I think originally there was a registration opportunity for azeno in USC. Is that still the way you think about it? What are you looking for in the study? Yeah, sure. I appreciate the question. The TETON trial, as we announced, is fully enrolled. We have guided to providing an update on that data in the first half of 2026. That has been our sort of consistent guidance. A couple of important things to note. The landscape there has changed since that trial started. It represents about 10% of the endometrial sort of cancer. If we think about what the value proposition there will be, I think it will be an interesting sort of proposition for additional either partnering or capital that could be allocated. However, we want to make it really clear. Our prioritization that we have been clear about since the beginning of the year is dollar number one goes to PROC. The second dollar goes to earlier lines of ovarian. We have not allocated future dollars to the USC indication into TETON. We do provide drug availability to an investigator-sponsored study in that setting. We will certainly be interested in seeing the readout of that data as well. We want to make it clear to the investors that our primary focus is going to be on PROC. Okay. Super helpful. Maybe final question. How do you think about the longer-term outlook for Zentalis? Are there other product candidates under consideration that you could potentially bring into the company and diversify a bit from azenosertib down the road? Yeah. We are really excited about 2026. We are also really excited about azenosertib. I mean, obviously, this is an agent that could have a lot of opportunity, sort of a product in a pipeline, of course. I think if we had our wish list and unlimited funds, we certainly could think about bringing in new assets, of course. I think we want to do our homework and get azenosertib over the line in PROC. We are also super excited about earlier lines. We have a combination with bevacizumab in earlier lines of ovarian. That is our 002 trial. We also are very interested in thinking about combining with other agents, in particular, potentially with ADCs. Certainly, there makes a lot of sense there to have a combination with an ADC agent. That could be in many different types of tumor indications. There is an investigator-sponsored study currently ongoing looking at the combination of in HER2 and azenosertib in HER2 positive solid tumor. We are not in charge of those trials, but we are certainly going to be interested in seeing those advance. We think azeno has a real opportunity in and of itself to be broader. Of course, as we bring that forward and have success against our milestones, there is always the opportunity and the eye for what is next. Okay. Sounds good. With that, I think it's a good time to wrap up here. Thank you, Julie and Ingmar, we appreciate the time. Thank you. You too. Appreciate it.