I think we can go ahead and get started. Good morning, everyone. Francis Dolan here. I'm one of Tyler Van Buren's supporting associates. Thank you so much for joining TD Cowen's 46th Annual Healthcare Conference. For our next session, we have a hybrid presentation and Q&A with Zentalis. It's my pleasure to introduce Julie Eastland, President and CEO of Zentalis. Julie, it's a privilege to have you here. Thank you very much for joining me.
Well, thank you. Thank you for asking us to come and present today and for the invitation. We look forward to the Q&A.
Wonderful. I'll go ahead and hand it over to you to kick off the presentation, when you're ready.
Sounds good. Well, thanks. Thanks again, and thanks to everyone listening today and joining. We appreciate your time and attention. Of course, make a statement here. As we move forward in the presentation, we'll be making forward-looking statements that may involve estimates, and for risk factors associated with those, we recommend you turn to our SEC filings. So 2026 was really a year of momentum for Zentalis. We have spent 2025 building and focusing our strategy for azenosertib in the Platinum-Resistant Ovarian Cancer population patients, especially for patients with high Cyclin E1 protein expression. In 2025, we've begun enrollment in the DENALI trial and have completed enrollment in Part 2A or the dose comparison portion of that seamless design, which we'll talk about a little bit later in the presentation.
we've also aligned with the agency around our registrational strategy for our phase III confirmatory design. This will be a randomized trial against standard care, and we'll cover that again a little bit later in the talk. we've maintained and have very intentionally allocated capital so that we can execute on this strategy, get to a key readout in the DENALI trial at the end of 2026, and have a runway until late 2027 to support our activities both in DENALI and in the phase III trial. That really set us up in 2025 to execute in 2026, and to reach some pivotal milestones, including the readout from Part 2A of the DENALI dose comparison portion of that trial.
We also plan to start the enrollment in our confirmatory Phase III trial called ASPENOVA in the first half of the year. Lastly, we reiterated our milestone that we expect the top-line readout of the DENALI trial by the end of 2026. Along the way, we're gonna talk a little bit more about why we feel that Cyclin E1 PROC patients is the area of focus, and this really is supported by extensive data that we have with this agent in this setting. Azenosertib is the potential best in class. This is an orally available non-chemo option for patients who have high Cyclin E1 protein expression as defined by our proprietary cutoff in our IHC assay.
You can see here this is important because patients who have high levels of Cyclin E1 protein typically have a poorer prognosis and don't do as well as the total population. In a standard of care chemo therapy setting in the PROC population, response rates are low, 4%-13%, and could potentially be even lower for patients with Cyclin E1 overexpression. There are significant data here to support the development in PROC, including a very manageable safety and tolerability profile of this agent as seen across hundreds of patients to date. For that reason, we're focused in not just in PROC, but taking a moment here to talk a little bit about Cyclin E1 protein expression.
Here, I think it's important to understand our development of a companion diagnostic in this setting, where we believe that about 50% of the total PROC population, has protein expression levels that may correlate and benefit, from the use of azenosertib. Cyclin E1 protein expression is broader than just gene amplification, which many people may be familiar with. Overexpression can be the result not only of gene amplification, but also of other gene transcription factors. In addition, it's likely that the protein in some cases doesn't degrade, and therefore high levels of protein remain. On the right-hand side of this chart, there's 2 graphs showing how patients in our trials retrospectively analyzed, looking at patients with high levels of protein expression benefit to azenosertib, whether they are CCNE1 amplified patients or not.
Over 85% of amplified patients have high levels of Cyclin E1 protein expression. Importantly, 40% of patients without gene amplification still have high levels of Cyclin E1. The takeaway message here, and what's important, is that all patients should be screened for their Cyclin E1 protein expression levels as they may benefit from azenosertib in therapy. What does that translate to in terms of opportunity? Well, of course, importantly, in this setting, these patients have no approved or directed therapies in the Cyclin E1 setting. PROC alone is a large indication with a number of patients that potentially could be eligible for azenosertib, reaching about 50% of the total population.
That is about 21,000, twenty-one and a half thousand patients in the U.S., EU four, and the U.K., so a substantial population. We note here that there is a demand for biomarker selected agents. If we take a look at Ela here as an example, who just reported out their 2025 earnings of significant revenue here of $607 million, really mostly underscoring that there is a demand and a need for agents for these biomarker selected populations. I'm gonna turn now to the patient population in and of itself because I really want to drive home that as patients go through the ovarian cancer treatment paradigm, through first-line and second-line and other maintenance earlier, they eventually become platinum-resistant.
These platinum-resistant patients, as you can see on the right-hand side of the slide, have no real great new therapies that have come into the space. There remains a very high unmet need, and in particular, as I mentioned, for Cyclin E1 patients that potentially don't do as well, there's an even higher unmet need. Obviously, these patients coming into the setting have seen chemotherapy and infusion as their IV therapy, as their therapy as they progress throughout their treatment. They've seen a lot of neuropathy, they've seen a lot of hair loss, and coming into the PROC setting, so far today in the standard of care, they still only have available to them IV infused therapies that are chemotherapy based, either single agent or a combination with chemotherapy.
That will be true as we think of new agents coming into this space, including ADCs, that are also payload chemotherapy driven. Azeno really offers a very unique position for these patients who have Cyclin E1 progression, where they can have an opportunity to have a chemo break and have an agent that's more convenient, which is an oral option, as opposed to spending time traveling to and sitting in the infusion centers. A very high unmet need and a real important opportunity for patients to experience a different path. I want to next turn to just 2 slides that just reiterate some data that we've presented earlier, including the safety and tolerability at doses of 3 and 400 milligrams. These are single daily doses that are given on a schedule of 5 days on and 2 days off.
In this chart here, these are all patients, regardless of their Cyclin E1 status. Looking broadly across these two different dose cohorts, you can see that the tolerability is manageable and also fairly comparable between these two dose levels. An opportunity to study 300 and 400, two active doses that have a manageable tolerability profile, as we've seen across multiple different prior studies. Low grades of events here, of course, toxicities of interest include hematological toxicities as well as GI toxicities. You can see here, high grades of these are very low incidence, and what you might expect from other similar cytotoxic agents in a chemotherapy or in a late-stage cancer setting. The next slide here, we're illustrating some of the activity, again, across our earlier studies.
In this chart, all of these patients have made the cutoff for having high Cyclin E1 protein expression. You can see here there was meaningful activity both at 3 and 400, where patients had both responses and deep responses. The number of patients at 400 milligrams is greater than the number of patients here at 300. This was based on prior studies, and because the DENALI Part 1b trial enrolled over 100 patients at 400 milligrams alone. Importantly, though, we see meaningful response rates at 400 milligrams over 30% and over a median duration of response of 5 months, which are important rates to show for patients in this setting. We see that consistently across multiple different trials. That led us to believe that the path forward for Azenosertib in the PROC setting is in that setting.
Of course, because the number of patients that were previously studied at 300 milligrams were in other trials, more heavily pretreated patients, Project Optimus is required here to compare both of these doses in the same patient population. An important design was set up for the second part of the DENALI trial. This is part two of the DENALI, which is intended to stand for registration for accelerated approval. This design is a seamless design, and what that means is that in the first part of this trial, we'll look at dose comparison. These are patients who come into the setting who are PROC, have one to three prior lines of therapy. If they have folate receptor alpha high expression and have availability to mirvetuximab, then they can have one to four prior lines of therapy.
We also are using our proprietary assay to prospectively screen patients into this trial. We announced at the beginning of 2026 that we had completed enrollment in the first part of this trial, where we've enrolled 30 patients in each of the dose arms. What's unique about this study design is that we can continue to enroll patients at 300 and 400 as we allow the data to mature from the first part so that we can make dose selection.
This will create a slight inefficiency in a dose that won't go forward, but it allows us to continue to have rapid enrollment and get to an answer by the end of 2026 for all of DENALI Part 2, which we expect to be about 100 patients. The primary endpoint here is ORR with supportive data from median duration of response, and PFS, and of course, safety and tolerability. This is a design that's been discussed with the agency and certainly as we think about continuing to support the accelerated approval pathway, we've also had discussions with the agency about the confirmatory phase III randomized trial in the same setting that will support the approval of Azenosertib for accelerated approval in the US.
I want to just briefly touch on that trial design because it's one we have aligned with the agency around at the end of the year, and we do expect to begin enrollment in this phase III trial in the first half of this year. Same key eligibility criteria that you see in DENALI is the same criteria you see here for ASPENOVA, which is the name that we've assigned to the phase III trial. Again, same population of patients. Here, this is going to be a randomized trial against standard of care or investigator's choice, which can include single-agent chemotherapy, such as PLD, gemcitabine, topotecan, and of course, paclitaxel.
In this trial, because we felt it was important to start as soon as possible with unique design where we have some optionality to start this trial at both the 400 dose should we be ready to enroll this trial before the DENALI reads out. The DENALI data from part 2A will be the basis for our dose selection and will inform us of the dose going forward in ASPENOVA as well. We'll simply drop th arm that does not go forward, and this will be a standard 2-arm, 1-to-1 randomization of the selected dose going forward against standard care. This allows us to begin enrollment early, and that's important.
It's important because it builds a body of data in a control arm where we can see in a randomized way how Cyclin E1 patients do in a standard care chemo setting. And it also allows us to move the enrollment and hopefully the full approval date for the trial up as early as possible. Primary endpoint in this trial will be PFS with secondary endpoints of OS and ORR. We're excited about getting this trial going. Obviously we want a place for patients to be able to experience Azenosertib as we complete enrollment in DENALI and the ASPENOVA trial will be sort of a seamless transition for those sites that intend to do both. I think overall, I just want to bring this to a close.
We're laser-focused on bringing Azenosertib first from a strategy perspective across the line in the PROC setting, focused with the DENALI Part 2 study. This Part 2 will serve potentially as registration for accelerated approval, which of course will be supported by the ASPENOVA trial, not only for the PDUFA for accelerated approval, but also as a trial that stands for full approval for Azenosertib in this population. We're well on track with two registrational trials we plan to enroll in 2026. In addition to that, we also think about the opportunity for this WEE1 inhibitor in other settings. First and foremost, we've been looking at earlier lines of ovarian and have been studying the combination of Azeno with bevacizumab in the MIREE trial.
We just presented a poster, a trial in progress poster at ASCO last week, where we discussed a further expansion of this combination in earlier lines of ovarian, where we intend to seek signal finding and proof of concept for Azeno in earlier lines of ovarian. Of course, we have great interest in expanding Azeno into other tumor types, where we can see a strong rationale for WEE1 inhibition, in those settings. With that, I'll pause and just again, thank you all so much for attending today, and for your time and attention.
All right. Thank you very much for the detailed presentation. Before I get started on Q&A, for those in the audience, feel free to chime in or raise your hand if you have a question. We can get started.
Sounds good. Joining us up here today is Ingmar Bruns, our Chief Medical Officer.
Thank you so much. All right.
Thanks.
You know, broadly across the MAMMOTH and DENALI trials, Azeno led to a consistent, you know, 31%-35% ORR and a 4.2-6.3-month DOR in CCNE plus PROC patients. How would you say that this compares, you know, to the. Obviously, you mentioned there's a 4%-13% ORR for chemo monotherapy. How does it compare to any other ADCs or other modalities that are coming down the pipeline in PROC?
Yep. It's a great question. Ingmar, I think from a landscape perspective, do you wanna talk about what we've seen in PROC from response rates?
Absolutely. I mean, I'd like to start always with, you know, what's still standard of care for most of the patients who are not folate receptor alpha positive, and that's single agent chemotherapy, where we're actually looking at 4%-13%. That is in an all comer population, is not the population that is Cyclin E1 positive, right? Where we, you know, really expect a poorer outcome. As Julie just said, you know, that's something that, you know, certainly the ASPENOVA trial will shed some light on, right? We've also seen novel ADCs beyond mirvetuximab. While these are mostly early data set has been disclosed, right? Some of the response rates, you know, have shown to be a little higher than what we historically observed with azenosertib.
For the duration of response, that remains to be seen. I don't think I have seen any really mature data sets, I think we're, you know, definitely well-positioned there. The main difference for us really, I just came back from Copenhagen and the ASCO meeting. The main difference for us and for investigators, you know, who really more focus on this, is the oral route of administration. We're, you know, bringing this drug to patients where they actually are, That's usually far away from a cancer center. They're elderly, they enjoy the time, you know, they still have because let's face it, as sad as it is, none of these patients will be cured in the PROC position. I think time toxicity, as they call it, really is a very important parameter here.
That's where we see this. I think it's really an option going forward for many and, you know, probably a much larger population that we can actually face because I think, you know, an initially higher response rate is probably not offsetting the time you spend in a hospital setting, and then potentially also shorter duration of response.
I think I just wanna add that I think we really welcome an opportunity for patients to have meaningful choices. Right now they have very few. This is not Azeno or other therapies. This is really Azeno, and this agent has a place for, again, Cyclin E1 patients in the PROC setting. This is really about sequencing. It's not about whether or not physicians should think about ADCs or Azeno. We really see the opportunity here, as Ingmar pointed out, for patients who've seen nothing but chemo coming into the setting to have a chemo break for a biomarker-selected population that we've seen correlate to response, and for an oral agent that allows to give patients more time. Just sort of summing up, I think ADCs are great. We're happy for that.
There's lots of ADCs being developed, but not all of those are gonna be used.
Absolutely. Moving on to the DENALI Part 2 trial, I think you mentioned that enrollment in Part IIa is complete or near in completion?
Completed. Mm-hmm.
Completed. Both dose cohorts are still open. How are you thinking about Part IIb enrollment over the next couple quarters? What needs to go right operationally throughout, you know, 2026 to keep the year-end guidance for top-line data? I think while also still allowing follow-up, adequate follow-up for late responders.
Sure. I think so we've given guidance that Part IIa is enrolled, as I mentioned and you mentioned. We continue to enroll in both dose cohorts while the data matures from the IIa population. We are, you know, really at a point here where all of our sites are up and running. We have robust enrollment. We have not provided enrollment guidelines in terms of Part IIb. Obviously, as we continue to enroll, we'll need fewer and fewer patients at the selected dose in Part IIb to complete enrollment, which we do expect to be about 100 patients at the selected dose. We reiterated our guidance that we believe that the top-line readout of the DENALI trial will happen at the end of 2026. Obviously all of that is dependent upon enrollment of patients.
We still feel confident in that timing for that guidance.
Wonderful. In DENALI Part II, you plan to enroll healthier patients with 1 to 3 lines of therapy, excluding mirvetuximab-experienced patients, where it's 4, opposed to 4+ over 4, which was in the earlier trials.
Mm-hmm.
What are you seeing at this point in terms of baseline patient mix, and how does that influence any expectations for, you know, response depth and durability relative to what was previously reported?
We haven't looked or reported on the demographics for those patients. I think the difference, as you just, you know, pointed out, is one to three prior lines, four if they're folate receptor alpha positive, and then in geographies where mirvetuximab is approved and reimbursed, and previously was one to five prior lines. There is a difference in terms of the inclusion. We'll have to see, right, how the prior lines of treatment come out in terms of the median lines of prior treatment. We know Some limitations, right? Earlier lines of treatment certainly have an advantage on both efficacy and potentially also the tolerability effect.
Mm-hmm.
What we see so far, there's other measures in place that are probably even more effective in, you know, keeping tolerability and safety or ensuring tolerability for patients and safety, and that's really the trial oversight and management. It's supportive care.
Mm-hmm.
All of this has significantly been improved and stepped up since Part Ib. At the information, again, we haven't seen aggregate data, and we're not supposed to look at that. The feedback that we get and the spot checks that we, of course, do for the medical monitoring, they very clearly show that these measures are effective and we expect, you know, to continue to develop this, you know, very tolerable and manageable drug that way.
Got it. What's the specific response rate that you're underwriting, and what durability requirements would go with it for you to feel comfortable moving forward with accelerated approval?
Yeah. You wanna go?
Yeah. I think the good news is that's really what we demonstrated multiple times across trials and, you know, I'm, you know, still impressed by how consistent across the different trials, really starting with the dose escalation, which was a fairly large trial, and then the MAMMOTH trial, and then DENALI Part 1. We've really seen consistent response rates.
Mm-hmm.
also the duration of response that we reported last year at SGO, it's right there, right? Even above probably. I think this is showing the bar-
Mm-hmm.
Could probably be that's not our intention and goal, but you could probably be a little bit below that, even right at 30% ORR, 5.5-6 months duration of response is also, you know, based on conversations we had, perfectly acceptable still for the accelerated approval. We had multiple conversations with the agency also over time that, you know, confirmed this. That's also the perceptions that we get from investigators and key opinion leaders. That's pretty much where it is right now.
Wonderful. Let's talk about Azeno's safety profile. There's been, I believe, over 800 patients treated with Azeno since 2019. What safety insights have emerged thus far? you know, what opportunities do you see to help physicians and patients better understand and manage Azeno's tolerability?
Yeah, I'll just a high level, and then Ingmar, you can fill in because I think you have again, you know, insight into how physicians think about the use of this oral agent. It's a very broad data set from a safety. When you look at the safety as we looked at in the prepared remarks just a few minutes ago, you really have an agent that looks very similar to other cytotoxic agents in the chemotherapy setting. Very manageable tolerability around the toxicity of interest here in this case, where we follow hematological and GI toxicities. There are ways to manage and support patients in this.
This was some of the learnings from the earlier trials that Ingmar mentioned, that we've put in new supportive and new education measures, including MedAffairs, including a large clinical scientific staff who can help support physicians and patients in understanding the use of these supportive care agents and how to help patients manage the study drug for longer periods of time. We, you know, had an unfortunate situation back in 2024, as we're all aware of, which drove a clinical hold, where there were some grade 5 events that were had many sort of confounding factors. Outside of those events, when you look at the totality of the tolerability profile, this really looks very similar, as I mentioned, to other agents.
I think Ingmar, it'd be helpful for the audience to hear just a bit about how physicians think about the agent in the context of studies today.
Yeah. I think that's really also changed, right? I think now we've, when we speak to some investigators who, you know, have enrolled individually as many as 10 patients, right? Really kind of relevant experience here. They now have, you know, of course, the experience with multiple patients, but also the experience over time.
Mm-hmm.
They now conclude that it is really a very, a well manageable and tolerable drug. You know, it's quite common initially, of course, if you bring new sites and new investigators on that there's a learning process, which as Julie just explained, I need to go back to that. You know, this it's an education and also a little bit of control, right? You look at the data consistently and, you know, call out any potential deviations from the management. That's education, right? Their perception really now is in the landscape, even for the experimental drugs, is really a not only a convenient but also an actually efficacious and tolerable option.
Wonderful. Moving on, in the last couple of minutes for your phase III confirmatory ASPENOVA trial, is there any level of enrollment in ASPENOVA that would be required to support accelerated approval?
Sure. It's a great question. From a regulatory landscape, of course, the agency's been clear about wanting sponsors to substantially complete enrollment in a randomized phase III trial in order to support the approval in the accelerated pathway. So a specific number is not something.
Mm-hmm.
That, we've had discussions with the agency about. Really the objective here is to enroll sufficient numbers to support that accelerated approval pathway. We do intend, as we've started ASPENOVA as early as possible, to have the majority of that trial, to the extent possible, enrolled-
Mm-hmm.
At the time of a PDUFA for, Azenosertib in the PROC space. We don't believe that we'll necessarily need all patients enrolled, but we certainly need substantial amounts. Of course, it is always dependent upon the strength of the data that drives that level of enrollment. We think very conservatively here, and our objective is to enroll as much of that trial as possible before the PDUFA.
Great. One final question, just quickly.
Mm-hmm.
As you think about the market, you know, what would you say is the total addressable market looks like for Azeno in CCNE1 plus PROC?
Yeah. For patients in the PROC setting who have Cyclin E1 protein expression levels, based on our cutoff, it represents about 21,500 patients just in the U.S., EU4, and in the U.K. Worldwide, that number is obviously bigger, but 50%, 21,500 is the 50% of the PROC. A substantial number of patients in the setting.
Right. With that, I think that we're all set. Thank you so much for your time, and thank you to the audience for attending the conference.
Yeah.
Have a great rest of your morning, everyone.
Thanks so much. It's gonna be an exciting year.