All right. Good afternoon, everyone. I am Stephen Willey, one of the senior biotech analysts here at Stifel. Glad to have with us for the next and final session, Julie Eastland, who is the CEO of Zentalis. Julie, thanks for joining us. Really appreciate it. Any opening statements or kind of brief overview you want to provide before we jump into Q&A?
Yeah, sure. Thank you, for starters, for having us here today. We always appreciate the invite, and hopefully worth the wait. Being last in line here, it'll be the best. Maybe just to begin with, I can give you a bit of an overview. Before I start, I just want to ensure, as is customary, a reminder that today's fireside chat will be making some forward-looking statements. The statements are based on our current estimates and beliefs, and actual results may vary. Please refer to our most recent filings with the SEC for any descriptions of our risks.
As for the company, though, we are intensely focused on our strategy, which is registration intended development of azenosertib, which is our investigational potential first-in-class Wee1 agent, for the study of platinum-resistant ovarian cancer patients who are known to be cyclin E1 positive or overexpressers of the cyclin E1 protein. Today, we're conducting and enrolling two registration trials associated with this. The first is our DENALI trial. This is part two of a multi-part study called DENALI. This is looking at patients in the PROC setting who've had one to three prior lines of therapy and have an opportunity here to experience azenosertib, which is importantly a small molecule oral agent that is not a chemotherapeutic agent, so really an opportunity for patients to have a differentiated asset here that can support them in their journey through PROC.
This study is slated to be a trial that is designed for accelerated approval in this setting. We are expecting a data readout on this trial at the year-end this year of 2026. In addition to that, we announced earlier this month that we have initiated the phase III randomized confirmatory trial in the same setting. This is called ASPEN-OVA. That trial will be supportive of a single-arm registration trial for accelerated approval.
I guess lastly, we'll talk a little bit more about this. We're including additional work here to extend azenosertib, which really has the promise to have a franchise potential here, not only in ovarian, but also in other tumor types as a combination agent or as a single agent. We can talk a little bit more about that, and feel well-capitalized here to get to an answer and beyond with cash running towards the end of 2027. That's sort of the company in a nutshell and where our focus is.
All right, great. Very good intro. Maybe we can start with last month's big announcement, which was the nomination of the 400 mg QD dose that you're now going to be taking forward into this DENALI part two and in the phase III ASPEN-OVA trial.
Yeah.
Maybe you can just remind us of the interim analysis that you conducted in part two-A of DENALI, and then what you qualitatively communicated to investors on the safety and efficacy fronts, and how you now think about this de-risking the program going forward.
Thanks so much. I think that last point is important. The study here for DENALI has a few parts within it. Part two A is the dose comparison. This is looking at 400 and 300. That was enrolled in January. That was 30 patients in each arm. In April, we announced that the data from that showed that the 400 milligram once a day on a schedule of 5 days on, two days off, was comparatively different and significantly better on an efficacy or activity perspective from the 300 milligram dose. Both doses were quite comparable in terms of the safety or the tolerability profile. It made it quite, I think, a clear decision that 400 milligrams would be our go-forward dose for the rest of DENALI part two, as well as for the ASPEN-OVA trial. That is our monotherapy dose in the PROC setting.
That interim analysis, of course, was conducted to select the dose. We are not sharing the detailed data here because all the patients at the selected dose will be part of our NDA or registration with the agency. We did try to help the audience understand a few things. one we can certainly enroll the trial. That's been going really well. Secondly, we have now dosed. That is certainly a clinical de-risking event for this particular agent, so nice to have that box checked. Lastly, we talked about a few improvements that we're seeing with regard to tolerability as compared to the DENALI part one -B trial.
That is that we see really across both dose cohorts, again, very comparable safety, but in particular, we don't see any grade five or treatment-related deaths, and we don't see the level of discontinuations that we saw in part one-B. In fact, we see approximately half of that level. Really coming into a nice profile that one would expect here for part two, and we'll see as we enroll the balance of the trial what the totality of the data will obviously look like at the end of the year.
I thought the comment that you made in the press release about seeing about a 50% lower discontinuation rate versus phase one-B in DENALI was important. I know that you guys have done a lot of messaging on the site and investigator specific level with respect to trying to improve the management of adverse events. Do you think that this reflects the implementation of better supportive care measures? Do you think this reflects more aggressive dose modifications, or do you think this is probably some combination of the two of those things?
Well, there certainly is a constellation of those things that would go into how patients are able to stay on study or how they discontinue. I do think that as you increase the number of sites and the new investigators coming into this setting with a new agent, with an oral agent, that's different, obviously, than patients going to infusion center, that you have a learning as well, and an experience level that PIs have with the agent. We did make some specific steps where we could be supportive of the sites, supportive of the patients, and that was to bring on a Medical Affairs group and a Clinical Science group that really can help to ensure that physicians are supported in how the patients are progressing from a lab value perspective.
We also added some strong recommendations for the investigators, which frankly, they know these measures to support patients because it's certainly not a known how GI and neutropenic and other hematological toxicities can be managed in oncology. This was a way to really help clarify how to use some of these agents on this schedule. For example, patients who are on a five-day on, two-day off, if they experience a Grade two neutropenia, the recommendation here is to provide fast-acting G-CSF on the off days to help support that. Just these kinds, I think, of recommendations are helpful. It provides some guidelines not only for investigators who have experience, but obviously for a large number of new investigators who are coming into DENALI, and then, of course, subsequently, even a larger set of investigators that will be working in the ASPEN-OVA trial and the phase III trial.
I think those things have all helped.
Yep. You're guiding to a top-line disclosure from DENALI Part two before the end of this year.
Can you talk about the rationale for having a separate Part two C in this trial? I understand these patients are perhaps a bit more heavily pretreated. They're allowed to have seen prior taxane. I'm guessing all this data will inform a potential NDA submission. How does Part two C kind of fit into the whole labeling and utilization part of the story?
Yeah. No, thank you. It's a great question. Of course, importantly, in the landscape of accelerated approval, you want to make sure that your study population is representative of patients who've had an opportunity to be exposed to approved agents. Currently now, as we know, in the first part of this year, there were a couple of new taxane combination agents that were approved. We had been planning on adding this cohort two C in order to allow a sort of a deepening of the number of patients that we have in the trial that are taxane exposed. Part two C was really as a way to sort of deepen the number of patients that we have in the trial where we can show, obviously, clearly, as we've seen in the past, the ability to get a response from patients who've had prior taxane exposure.
In the past, of course, that's been mostly single-agent taxanes. Of course, mirvetuximab being an ADC as well, and that's representative, obviously, of populations that have seen a folate receptor alpha-targeted agent. Just important to have a nice representation of population going into your final data set. Here we have seen patients, obviously, in Part A and B who have had prior taxane exposure, but two C allows us to just strengthen the numbers in the trial. I don't think consistently it really changes the label. As you may remember, Part A and B are patients who've had one to three prior lines of therapy, and if they're eligible and indicated for mirvetuximab, that would make that four lines of prior therapy.
For the taxane patients, we've allowed one-four prior lines in order to give them an opportunity to potentially experience some of the new agents that have recently been approved.
Okay.
That's really what two C is about, is just assuring that we've got a representative population.
Okay. When you disclose this data before the end of this year, I'm guessing obviously a response rate, safety data. Would you expect to be able to communicate a median duration of response statistic at that time, just kind of given where you are now and the kinetics of enrollment?
Yeah, I think that we have been guiding that at the end of the year, the DENALI trial Part two is primary endpoint is ORR.
That's really going to be a determination of whether the study's met its primary endpoint or not. We are comfortable today in saying based on where we are in enrollment, that we would expect to be able to read out whether or not that top-line endpoint has been met. Whether or not duration of response will be fully mature at the end of the year is unknown. To your point, we'll have to see how two C enrolls. I think two A and B are going to be completed, two C will follow from that. I think in terms of the primary bar for success here, it'll be ORR, we expect to have that data by the end of the year.
Okay. Should we also assume that you are using the DENALI trial to prospectively validate the companion diagnostic that you're using to define cyclin E1 positivity in the commercial setting? Just maybe you can make some comments as well around your level of confidence that this doesn't become a rate-limiting factor in the regulatory review.
Very important, not only for the U.S. accelerated approval, but continued validation, of course, the assay for full approval in ASPEN-OVA. The entry criteria here for both DENALI Part two and for ASPEN-OVA is first, whether patients are cyclin E1 positive based on our cutoff with, obviously, standard IHC assay. That is part of the entry criteria that is prospective screening in both DENALI and in ASPEN-OVA. That will allow us to validate that assay, provide the right bridging analysis here over the research data that's been generated to date.
Of course, with our companion partner here for the CDx commercialization, be ready from a regulatory and a commercial perspective here to ensure that there's wide adoption and availability of the assay, so that patients who have recent tumor resection hopefully will all eventually just be screened like everything else at that time to determine whether they're cyclin E1 positive. When they come into the PROC setting, then they'd be eligible for azenosertib at that time. We're on track for that distribution and the commercialization. We're sort of not treading new water here. This has been done obviously with mirvetuximab very successfully. We feel that we're in good position here to be on track for a simultaneous regulatory process for both the IHC assay as well as for azenosertib in and of itself.
Okay. What's your level of confidence the ASPEN-OVA trial will achieve the threshold level of "sufficient enrollment" that the FDA requires at time of any accelerated approval?
Yeah. The FDA doesn't provide specific guidance there other than to say that you need to be substantially complete in your phase III confirmatory study to support the PDUFA of accelerated approval. We certainly feel, and that's one of the reasons why we wanted to lock in that trial design at the end of 2025 and be ready to start enrolling the ASPEN-OVA trial early this year. Couple of reasons. One, we want as much enrollment there as possible before we get to both the filing and potential approval in the U.S. So we feel that we're on track to do that. As that trial broadens, which is a global phase III trial, we'll have a better understanding of our enrollment rate and our status with that.
We do expect to have this enrolled sufficiently, to the level that the agency would be supportive of DENALI as accelerated approval. We'll provide more guidance on enrollment timing and readout of ASPEN-OVA as the trial sites begin to broaden, and we start to see enrollment rates that we feel confident to project. At this time, we haven't provided a guidance on that yet. We think we're going to be in good shape from an FDA regulatory perspective.
Okay. At AACR, you presented some pretty interesting real-world data that highlights that cyclin E1 overexpression in ovarian cancer yields a poor clinical prognosis to standard of care therapy, including agents like mirvetuximab. I think that prognosis worsened even further in the context of cyclin E1 amplification. I know you haven't talked about the IHC threshold or cutoff that you're using in the registrational effort, but can you just qualitatively speak on how this data and the determination of cyclin E1 positivity in this retrospective study might be directionally similar and/or relevant to either DENALI or ASPEN-OVA?
The data that we presented at AACR was both real-world data as well as data from our studies. The analysis here was patients who were both enrolled in our historical trials, who were classified as cyclin E1 positive based on our IHC assay and our cutoff, as well as analysis on patients from really the Tempus Lens database, which classifies the cyclin E1 positivity based on more of the CCNE1 RNA expression levels. This was sort of a combination look both at real world and real data. We think because of this, certainly what we've seen historically over several hundred patients that have been treated with monotherapy azenosertib, where we see consistent sort of correlation of responses to our cutoff. Of course, we need to prove that out prospectively.
We believe that that data certainly is both, I think, representative of what we expect to see, and certainly does show that these patients, in both the real world and in our study, definitely don't do as well from a prognosis perspective. Therefore, azenosertib really is a novel agent and an opportunity for these patients in PROC to see an agent that they know really correlates potentially to response. I say knows, but we see it, and we certainly have to prove that out.
Okay. Is anything known about the correlation between folate receptor alpha and cyclin E1 expression? Is there any overlap there?
In terms of correlation of expression, I think based on our analysis of commercially available samples, we haven't found any correlation between folate receptor alpha and cyclin E1 expressions. Certainly, there's an overlap of patients who express both folate receptor alpha high and cyclin E1 high. That represents about 20% of all of PROC patients have both of those expression levels. An opportunity here for these patients to have two agents that might benefit them more disproportionately than an all-comer agent.
Okay. I'm sure you're well aware that there's a number of antibody drug conjugates that are in development for PROC. Probably the least surprising statement I've made all day. There's still a number of questions here, right, with respect to can you actually sequence these agents, right? They all kind of share the same topoisomerase derivative payload. A lot of these agents are kind of giving you response rates north of 50%, durations that are kind of north of eight months. Do you think that we're going to see at some point some of these ADC sponsors presenting efficacy data as a function of cyclin E1 expression status? Would you expect there to be some pace of counter-detailing that starts to increase as you get closer to approval?
Well, I think if they were going to do that, they'd have to, depending on their own assay and on their own cutoff, what they might look at as to cyclin E1 protein expression. Of course, some of these agents may have looked at patients who have different gene amplification status. As we've seen and shown in our data, gene amplification status does not tell the story of cyclin E1 protein expression. Protein expression definitely drives here activity of tumors and of the use of Wee1. I think that would be interesting because my guess is if it's true that in all other cases of chemotherapy, which effectively ADCs are, because of their Topo1 payloads, we don't believe that patients would do quite as well.
If they were detailing and were to show how their cyclin E1 positive protein expressing patients did in their trial, you may see actually not quite as good of an ORR and a DOR for those patients. I think for us, whatever that detailing might be, I think it's really important to bring back a reminder here. Patients need new therapies. We're happy to see a bunch of new therapies for these patients. They have very little. What they have today is chemotherapy options. They've had a bunch of chemo in their first line, second line. They've had neuropathy. They've had hair loss. They've had other fatigue. They come into the setting, right now they have as an opportunity more chemo. ADCs may bring higher ORRs, they still bring chemo side effects.
What we are offering from a market perspective is a drug that we know is correlated to response for cyclin E1 patients, a drug that is an oral agent, it's convenient, it's not infusion time, and a drug that is not chemotherapy, avoids these incremental adds of chemotherapeutic side effects like neuropathy and other items. We think that regardless of which ADC may win here, or multiple ADCs, they won't be sequenced likely one topo after another. We think that that's great, that patients will have another chemotherapeutic opportunity that might even be better for them in terms of responses. We think that those should come after the cyclin E1 specific patients have an opportunity to benefit from this non-chemo oral option.
That's sort of where we see the positioning of this, and I don't know if ADCs would see an improvement in ORR over their all-comer population for cyclin E1 patients if it really is true that these patients have poor prognosis and typically don't do as well on these agents.
Okay. I know there's a few other companies that are pursuing the development of CDK2 inhibitors in the same cyclin E1 positive patient population. What do you think of that data that you've seen to date, and is there any biological rationale as to why targeting Wee1 might be a better solution therapeutically than CDK2?
Yeah, I think the answer is yes and yes. We've seen other agents here. Obviously, Incyte has a CDK2 inhibitor. It seems to be the most advanced in the setting. So far their data looks okay, around 30% response rates at a recommended dose in about 3.6 months of DOR, which is a bit short. That could be possibly driven by the fact that CDK2 is impacting really only one checkpoint in the cell cycle process. Here the biology is different in that Wee1 is a master regulator of a cell cycle, so it has the opportunity to be impactful at both checkpoints in the cell cycle process.
Really driving cytotoxicity versus really sort of a cytostatic disease that a CDK2 might get an initial response but may not be able to sustain that as tumors break through and utilize the escape mechanisms of the second checkpoint that's not being inhibited. We do think there's an opportunity here to see something different with a biological rationale behind that.
Okay. I guess that rationale would perhaps lend some suggestion that you could possibly use these agents in sequence without any real trade-off on efficacy. The way you just described it would seem to me like you could sequence a Wee1 behind a CDK2, but perhaps not vice versa.
I think you would want to do it the other way. The reason why is you want to get as much durability of cytotoxicity, and that's what a Wee1's going to give you because it's going to hit both checkpoints and cause greater opportunity for tumor stasis. A check two or a CDK2, excuse me, inhibitor is really hitting only one checkpoint in the process. While you may have some response, you may not have durability. I think if you really want to give, again, patients who may be progressing quickly the best chance to have response and durability, if you're looking at those two agents, you would want a Wee1 inhibitor in order to see that durability. I think it's all going to depend on the data. I think you're right. You could sequence those. I don't see those in combination.
I don't see any value there. As a Wee1 agent, I think you have a better opportunity for both response and durability over a CDK2 inhibitor.
Okay. I know you're also looking at the MIRROR trial in an effort to potentially expand the utility footprint of azenosertib across the spectrum of care. I think you're going to be presenting some of this data at the upcoming ASCO meeting. Yeah maybe talk about what you're going to be showing and what you think investors should be focused on?
Yeah. We're really excited at the opportunity that this MIRROR trial, which was started some time ago, which is really a combination with the ZENO trial. There were two parts to that. The first part was in combination with chemotherapeutic agents. This included paclitaxel, gemcitabine, carboplatin, et cetera. Those combinations, I think, are interesting because it's going to show us that azenosertib can be combined with cytotoxic agents. That will be helpful not just within, say, the PROC or in the earlier ovarian setting, but also could be very valuable as a translation into other tumor types where we could look at combining a ZENO with PAC in other places.
We focused the ASCO presentation on the combination of ZENO plus PAC because it's most relevant to us in terms of where we would go in, say, the second-line induction setting in ovarian, but also could be very interesting in looking at combinations with PAC in other tumor types. We're going to focus in on that. There were several dose cohorts there, and we'll examine where we think we have the best opportunity to move forward. In addition to those chemotherapeutic combinations in part one of the MIRROR trial, we've also done a combination in part two with the bevacizumab compound. This is in patients who've progressed while on a PARP inhibitor. In the maintenance setting in particular, this is the second-line maintenance setting in the PSOC setting.
Here we're doing a dose expansion for those patients that did progress while on PARP in first line. Here we hope to see not only a signal from a PFS perspective in the second-line maintenance setting, but also again, more data on the combinability of a ZENO with bevacizumab. This will be a great signal finding trial of about 40 patients that we'll look at in this setting that will really provide a launch for azenosertib in a label expansion mode for first and second-line maintenance down the line. Important proof of concepts on combination, both from safety and for activity. We're excited to present that certain combination with paclitaxel at ASCO coming up.
Maybe last question because I know we're up against the hour now.
Sure.
How big of a commercial footprint will you need to support an initial launch effort in PROC, and when do you start building out that infrastructure?
Well, I think we are bullish on our opportunity here for accelerated approval, that's going to be U.S. market launch. The footprint that we need is a pretty typical oncology indication here for the U.S. Importantly, that commercialization process always begins well ahead of NDA filing and approval. We've begun that process of ensuring that we're spending the right time and money on a gated basis on building our pre-commercial launch plans. We'll look to complete that build-out in terms of sales force size, et cetera, as we move into 2027 post the data at year-end. I think we're in good position there to start preparing for commercial launch. Outside of the U.S., different story. We definitely think that we'll want to have partner support there, that will come fairly quickly, I think, really after a U.S. launch.
Things we're thinking about altogether here today.
All right. Very good. Julie, really appreciate it. Congrats on all the progress, and perhaps our paths will cross at ASCO. Appreciate the time.
Yeah, hope so. Thank you. Appreciate the platform.
All right. Thanks everyone.
Thanks, Steve.