Good morning, everyone. Welcome to day one of Leerink Partners' Healthcare Conference. We are very excited to have with us Zentalis. We have the CEO, Julie Eastland, and we have the CMO, Ingmar Bruns, Andy Berens, Senior Biotech Analyst here. Julie is going to give a brief overview of Zentalis for those that don't know the story, and then we'll open it up to Q&A on the floor, and I have some questions of my own. Julie?
No.
The floor is yours.
Thank you, Andy. Appreciate the invite. Good morning, everybody. Before we begin, let me remind you that we'll be making forward-looking statements. For the risks and uncertainties associated with those statements, we encourage you to view our 10Qs and 10Ks on file with the SEC. This morning, I'm again pleased to be able to offer you an overview of our vision and our strategy for Zentalis going forward. We'll include today a conversation regarding the regulatory pathway for this molecule, as well as the clinical data that we've derived so far that's supportive of this regulatory process. Let me first start by making a few points regarding the market opportunity and the patient population in the platinum-resistant ovarian cancer setting, or PROC, as it's typically known. First, ovarian cancer is a large market. It's expected to double over the next three years.
As we've seen a very successful launch of mirvetuximab recently for patients who have folate receptor alpha high expression, this really underscores both the need and the demand for biomarker-selected therapies for patients in this setting. As we will talk about today, our focus will be on the cyclin E1 positive patients who comprise a very large part of this population. We estimate over 50% of the population is cyclin E1 positive, and we'll talk a little bit more about that in another slide. Also, the standard of care for these patients is important because right now, single-agent non-platinum chemotherapy is the standard of care for patients in this setting. In particular, it's been demonstrated in literature that cyclin E1 positive patients tend to do worse than their counterparts and have poorer prognosis.
Even with standard of care response rates and durations on chemotherapy, these cyclin E1 positive patients likely do worse. Of course, we've accumulated a large amount of data on azenosertib, and in particular in the monotherapy setting at a number of doses and schedules. We've seen overwhelmingly an outcome for cyclin E1 positive patients that's quite positive and definitely is corresponding to these particular patient populations. What we've seen is at least an ORR of 30% or higher across all the monotherapy arm studies that we've presented to date. Recently, at the end of January, we've provided an overview of all these studies and the data, and that is available on our website for you to listen to. Lastly, we have identified a path forward here, which we think is clear for cyclin E1 positive patients in the PROC setting.
Here we're going to use our Denali study, which is a current open study where we have already looked at patients at 400 milligrams at a schedule of five days on, two days off. We will continue with Denali in part two, which we believe, given our discussions with the agency and future discussions that we will also have regarding the second part of that trial, that this is potentially a registration pathway for azenosertib. Finally, of course, can we get there? In January, we made some strides in thinking about our organization and alignment of our strategy, and we've been very specific about our focus, which is going to be intensely on the PROC setting and cyclin E1 positive patients.
With that, we also made some changes to our runway to enable us to have sufficient cash to get to these important readouts at the end of 2026 with the runway into late 2027. I think it is important to spend a minute on the cyclin E1 positive population. Through our extensive clinical and translational work, we have established that this has a high sensitivity and can be a very specific predictive biomarker that we can use to identify patients who may benefit more than others in the PROC setting. About 50% of the PROC patients overexpress cyclin E1 protein based on analysis with an IHC assay and our proprietary cutoff that we have developed. Importantly, cyclin E1 protein levels are regulated at the DNA, RNA, and even at the protein level. Proteins can be overexpressed with no DNA amplification, but abnormally slow protein degradation.
The benefit of an IHC assay is that it can capture all of these disparate mechanisms of cyclin E1 and the regulation thereof in one assay to really allow us to be selective in these patient populations in a registration setting. The strong mechanism of cyclin E1 and azenosertib sensitivity, the prognostic significance of cyclin E1 dysregulation in the PROC setting underscores why patient selection with this diagnostic test is really an important part of our go-forward strategy. Before we dive into data, maybe just a minute on the treatment landscape. Except for 35% of the population in the PROC setting that are folate receptor alpha high, single agent, as I mentioned earlier, non-platinum chemotherapy is the standard of care. Here we see things like paclitaxel, topotecan, pegylated liposomal doxorubicin, and gemcitabine.
Response rates are low, anywhere from 4% to 13%, and median progression-free survival of three to four months. As I mentioned, literature also shows that these patients typically don't do as well and likely don't even see these levels of responses. New treatment options obviously are needed, and I think that's underscored in the setting. Today we have provided quite a significant, and I'm going to tell you about an integrated analysis over a number of studies where we've looked at azenosertib in a monotherapy setting. The first trial was the 001 trial, which was a dose escalation study that looked at a number of schedules and doses. The second trial is called the Mammoth trial. In the Mammoth trial, we studied azenosertib in monotherapy and in combination with niraparib in PARP-resistant PROC patients.
Lastly, Denali part one B, we tested our primary dose of interest, which was 400 milligrams at a schedule of five days on and two days off. In total, these three studies, we have treated more than 350 patients across these studies, and within that, over 200 patients specifically in the PROC setting. On slide seven here, we are illustrating the integrated safety analysis and tolerability in, again, a 300 milligram dose compared to the 400 milligram dose. You can see here that this is broadly comparable between these two doses. Overall, we see a very manageable hematological and GI toxicity profile, and this appears to be better than other WEE1 inhibitors that have published clinical data to date, for example, like the IGNITE study.
On this waterfall plot, we're looking at patients at the 400 milligram dose where we see meaningful responses of over 30% and median duration response of over five months. In this particular integrated analysis, you can see that we have more patients at the 400 milligram dose than we had at 300. We will continue to study that, as we'll talk about next in the part two A of the Denali trial. Maybe just a brief mention on this slide of the median duration of response. At the time of publication at this data cutoff, that was at 5.5, a very sort of solid, stable answer or stable readout. We are seeing this trend upwards, and we'll be presenting at the SGO conference this weekend an update on the Denali part one B, and in particular, the duration of response.
Turning to slide nine, we are now going to be talking about our go-forward strategy for Denali, which is the part two of this open trial. We have achieved alignment with the FDA on a seamless design. What that means is that we can support an accelerated pathway through the use of the Denali study. Of course, we have some FDA feedback on the design, and we'll need to go back and talk with the FDA on part two B once we have the dose confirmation data out of part two A. In part two A, we will be enrolling patients who are in the PROC setting here with fewer lines of therapy than we previously studied in part one B. Here we'll be looking at patients with one to three prior lines of therapy versus one to five.
Of course, patients will need to meet the cutoff of the cyclin E1 expression based on our proprietary cutoff in our IHC assay. Once those patients have been selected, they'll be randomized into a 300 or 400 milligram dose arm where we'll, per Project Optimus, complete the look at the difference between those two doses to select the go-forward dose to complete enrollment in this potential accelerated approval design. As we compare those doses, we'll seek again FDA feedback in two areas. One, in terms of the bar for accelerated approval in this trial. In addition to that, we'll speak with the agency regarding the phase three confirmatory study, which will be in the same population setting, and we'll enroll once the dose has been selected.
We had talked briefly about lines of therapy and Denali, and we went ahead and we're getting a lot of questions about does it matter whether patients are one to three lines versus one to five lines exposed. With all the caveats of being a sub-analysis, we went ahead and looked at the prior lines of therapy. Again, these are cyclin E1 positive patients. They're at the 400 milligram dose, and this is an integrated population across all the studies that we looked at, the 001, the Mammoth, and the Denali trial. You can see here that patients who had one to three lines of therapy definitely had an improvement in the ORR compared to those at four plus. That was also true in the progression-free survival.
With all the caveats of a small study, a sub-analysis, confidence intervals that overlap, this certainly still provides us with encouragement and confidence as we move forward into this particular setting in the Denali part two trial. Lastly, let's see, sorry about that. I just went the wrong way. There we go. That makes sense. Just to summarize in terms of where Zentalis is heading, you can see here our pipeline is intensely focused on bringing azenosertib to PROC patients, particularly the cyclin E1 positive patients. We will do that through both the Denali part two as well as starting the confirmatory phase three randomized study. We will have top-line data for the part two of the Denali study towards the end of 2026.
As I mentioned, we'll do a short update on the part one B at the SGO meeting coming up this weekend. The rest of our pipeline is important to us, and we'll continue to move that forward as resources allow. You can see a number of milestones here, including potential data in the Teton trial in the first part of next year. We continue to enroll in the 002 study, in particular looking at BEV patients. We did provide a brief update on the BRAF combination at the end of January. While that data is very encouraging, with the landscape changing there, we'll have to assess what the future might be in that combination. Thanks, Andy, again for the opportunity, and I'll stop there and we can have a conversation.
Great. Thank you, Julie, for the overview. Anyone that has questions in the audience, feel free to ask. I have some that I've prepared. Why don't we start, I guess, with the biomarker strategy since that's an important part of the story and most of the tumors that you're pursuing. I know there's been some speculation about overexpression versus amplification. Maybe you could talk a little bit about that and what you're seeing in the overexpressors that are not amplified versus those that are amplified. I know you showed the Venn diagram that there's overlap there, but I know some companies have said they respond differently, the amplified patients versus the ones that are not amplified. Any thoughts on that?
Do you want to take that?
Yeah, happy to. Yeah, first and foremost, as you've seen, over 50% of the PROC patients show cyclin E1 overexpression. If we look at our data set, that's more than twice what we see for amplification. In our data set, we haven't seen any differences in outcome between the amplified and overexpressed ones and the ones that are just overexpressed and not amplified. There's a small group of those who are amplified and not overexpressed. That's very rare, single-digit percentages overall. For us, the IHC for cyclin E1 overexpression is the much more useful marker and obviously includes the absolute majority of the overexpressed of the amplified population as well, with no obvious differences across different trials in terms of outcome between those.
Okay. I think that as the AstraZeneca trial, IGNITE, also, there was no difference, that both groups responded with WEE1 inhibitors, which is different than some of the other synthetic lethality approaches. Am I remembering that correctly?
Yes, that's correct.
Okay. Maybe V1 is different than some of the other classes of drugs. I guess in terms of the enrichment strategy, it looks like the ORR almost doubles with CCNE1 positive patients, but the median DOR and some of the other durability metrics have not really changed versus standard of care. Any thoughts on why that could be the case?
Yeah, we think these are relatively small numbers, especially in the cyclin E1 negative population. If you look at the data presented for the cyclin E1 positive population, then you see a relatively clear difference here. The other thing I would say is, of course, duration of response is a function of the actual responders other than a PFS. Therefore, I think it's not that surprising that the duration of response in that subfraction that actually has an objective response is not that different. Again, I wouldn't overestimate the data on this small sample size.
Not every, remember this is a retrospective analysis, not prospective. There were some patients where either tumor samples weren't available or maybe there wasn't enough tumor to understand. There could actually be some cyclin E1 positivity in patients that were considered negative because we couldn't identify them through the IHC assay. I don't think we know, but I think we'll see that as we prospectively enroll patients in Denali part two.
Right. The sample, the tissue sample that's used to detect CCNE1, was that from initial diagnosis or when? Does it change as patients are treated in the front line?
It's archival. There's indeed some literature out there and even including our internal analyses where we don't follow patients throughout their journey, but we have samples from different lines of treatment, and that's remarkably stable. That's a question that we asked ourselves as well, but there's little concern in this changes compared to other markers in particular.
Okay. That's interesting. I guess the update that we're expecting in the first half of this year, can you just summarize, I guess, what you're looking for, like how many patients, what kind of durability, what additional insights will we have on the program from that update?
The SGO update coming this weekend is going to be on the part one B patients, the 400 milligram dose. There we will have an update on median duration of response and talk a little bit more about CCNE1 and cyclin E1 overexpression. That is coming up this weekend. We will provide regulatory and clinical progress updates in the first part of the year. Obviously, as the part two A of Denali begins to enroll, we will provide updates on that. There are two interim analyses in part two A, which is the dose selection portion of Denali. Since those patients, whichever arm continues on, will be part of a registration database, we likely will not provide data updates, but we will certainly provide both regulatory and clinical progress updates throughout the course of this year and into next year.
Okay. What do you think that the registrational plan will be in PROC in terms of accelerated versus regular?
Hey, do you want to talk about it?
Yeah. The Denali trial, according to our plan, is going to facilitate an accelerated approval. The Denali study, as Julie briefly showed, is a multi-part study. Part two and part two A is a dose confirmation just to fulfill Project Optimus, a randomized dose optimization confirmation part. The trial will continue to enroll in its seamless nature. We will just add in part two B the patients that are required to get to about 100, so it is an appropriate registrational data set for that. At the same time, once the dose has been confirmed after part two A, which will be another FDA interaction, we will also start the confirmatory trial, which will be about 80% enrolled at that time. It is probably also required.
You could see the connection even at the filing between the confirmatory trial, phase three randomized against standard of care, investigators' choice chemotherapy, and the single-arm Denali trial then.
Okay. Will there be any notable differences in the selection criteria for the patients in the phase two for phase three?
Yeah. The important ones is fewer lines of prior treatment, so one to three versus one to five. Previously in part one B of Denali, as Julie just showed, we believe that makes a difference in terms of response rate for sure. Probably also the overall health status of the patients and frailty of patients and then their tolerability of potential toxicities. We allow for those of folate receptor alpha high prior MIRV treatment, and then it would be one to four prior lines of treatment, but those are the key differences.
Okay. Prospective.
Prospective.
CCNE1. Right.
Yeah, cyclin E1 positivity based on our cutoff.
Okay. All right. What parts? It sounds like you guys have been having pretty frequent dialogue with the FDA and you've reached some alignment on how to get to the dose selection. Is there anything else that the FDA is questioning? Are they questioning the five to two dosing at all or anything else that really remains to be finalized from a regulatory perspective for the program?
I think just to maybe step back to the end of last year when the company came off of clinical hold and the FDA was able to see the totality of the data, there were no requirements to change dose or schedule. That allows us to continue on in part two of Denali with that same dose and schedule, so no modifications. Obviously, the agency will need to see the data between 300 and 400, along with our, of course, recommendation of moving forward with one of those two doses for the rest of part two B and agree upon the bar for success. Of course, the agency will review the design for the phase three confirmatory studies. Those are all future interactions that are planned and expected for this throughout the course of 2025.
Okay. You have Teton listed, uterine serous carcinoma. At some point before you were with the company, that was thought to be maybe the first commercial program that the drug would be approved in. If I recall, CCNE1 was very high expression in that. It was not necessarily, or the company did not think it was necessary to enrich. I think for a time they were actually going to go with the seven-day dosing. Just what is the status of that program that is ongoing? I know you have data first half of 2026, but can you just give us an overview of USC?
Yeah. As you can see, that's still enrolling. We report this in 2026, including subgroup analyses. If we look at the '01 study data on USC, that looked promising. We do think that the therapeutic landscape in endometrial cancer as well with that USC as a subgroup is changing. There is certainly with USC, which was a relatively small indication space to start with, just became a little bit smaller with the HER2 ADCs and HER2 getting indication agnostic approval. Seems to work also in the 1+ HER2 expressors, the low expressors, and then also checkpoint inhibitors coming in, lenvatinib together with pembrolizumab coming in. We think it will push this probably into later lines and making an indication to start with small, potentially even smaller. We will continue to enroll. We will analyze the data and then we will make a decision.
We think the landscape, obviously, in the PROC setting, while it's becoming more interesting with other players in that setting coming behind, there's still a huge unmet need in that population for patients who only have chemotherapy. That became our primary focus for the strategy. Certainly, we'll see what the data brings us on the Teton trial as we get into the first half of 2026, look at the competitive or the landscape at that point and make decisions. Yeah, that's our focus today is PROC.
Are you testing in Teton for CCNE1? Do you think it's necessary for this program to identify those patients?
Yeah. We don't know yet if it is, but that's what I meant with we're looking at subgroups. There's other factors as HER2 positivity or negativity. There's cyclin E1 status, and that's being looked at.
Yeah, collecting all that. We'll look through and see is there a population that does better in a subgroup analysis or is the entire population a population that would benefit? We'll take a look through that.
Okay. I mean, you mentioned the checkpoint inhibitors being used in uterine cancer, potential combination there. I mean, we've seen other synthetic lethality approaches try to demonstrate synergies. I don't think it's been as encouraging as people had thought, but what do you think about the potential for WEE1 in combination there?
Yeah. I mean, generally, of course, interesting with anything that interferes with DNA repair mechanisms probably makes cells more prone to T cell immunology and checkpoint inhibition. We haven't done any work on this, but generally, that's certainly something that could be interesting.
Right. Okay. In ovarian cancer, I know at one point the company was going to go into the HRD negative, but you refocused on PROC for allocation of resources. Do you still see that? I know the combination with the PARP inhibitors has some toxicity issues, but what about in the group that's not PARP sensitive and might be combined with something like Avastin? Do you still think that's a potential for you guys or somebody else to pursue with WEE1s?
Yeah. We have a trial ongoing with a BRAF combination. As you said, the focus right now is on PROC and getting this through registration as fast as possible, but that's certainly something that's of interest. We're generating these data right now.
That's definitely, if we have the money, that's the focus. Dollar one to PROC, but dollar two, of course, to completing our obligations on the rest of the pipeline. That includes some allocation of resources in that setting. We'll see what data we can generate there. We'll certainly be able to come out and describe our strategy in that setting as we have conversations with investigators and think about our path forward.
Okay. There was some, I guess I was confused whether or not can you be HRD negative and also CCNE1 positive? I think the company had said at one point that that's not a viable combination of defects. Is that the patients have both? If you're CCNE1 positive, can you also be HRD negative or?
Yeah. I don't think we've seen that this is mutually exclusive.
You can't have both?
Yeah.
Okay. Great. Any questions from the audience? Fantastic. Thank you for joining us. We look forward to all the progress.
Yeah. Thank you very much for following the story.
Sure.
Thanks, Andrew.