All right, we're going to go ahead and get started. I'm Stephen Willie, one of the senior biotech analysts here at Stifel, and glad to have you with us to kick things off today. We have Zentalis and Julie Eastland, who is the CEO. Julie's going to give us an overview of the company. There should be some time for Q&A, so I'm going to hand it over to you, Julie, and thanks again for coming.
Yeah, thanks for having us, and thanks to Stifel for having us today. For those who take the time to be here with us today or listen to the presentation, we appreciate your time and attention. Before we get started, the slides are not advancing. Thanks so much. Before we get started today, I would like to remind folks that we'll be making forward-looking statements. These carry risks and uncertainties, where actual results may differ from those forward-looking statements, and we advise you to review our recent SEC filings for those risks and uncertainties that are described therein. Zentalis today is very excited about the current ongoing late-stage development of its lead candidate, azenosertib. Azenosertib is a potentially best-in-class, orally available non-chemotherapy for patients with our first indication and focus in those patients who have Cyclin E1-positive platinum-resistant ovarian cancer.
We've presented a large body of data. We'll go over some of that today, but we see very encouraging, consistent response rates that are meaningful at over 30%, as well as duration of response that exceeds six months in these patient populations at our 400 mg, five days on, two days off dose and schedule. Cyclin E1 protein expression is a marker of potentially poor prognosis for patients in this setting. They typically have less benefit for current standard of care, which is single-agent chemotherapy in this setting. That runs about 4%-13% from a response rate, and it's likely that these patients don't even do that well. We've treated over 350 patients or more at these active doses of 300 mg and above, and over 200 of those patients are in this PROC setting. Again, those are Cyclin E1 patients.
We have a manageable safety profile, and we'll talk a little bit more about that in a few slides. It's been a busy year. We've kicked off the year prioritizing the pipeline and really thinking about appropriate capital allocation and where we could bring to bear azenosertib in the broadest and quickest way to patients. This resource allocation was to prioritize azenosertib first in the platinum-resistant ovarian cancer space for patients who have Cyclin E1-positive protein expression. This year, so far, we've demonstrated and provided an update on a lot of clinical data across a number of different studies. We'll look at the integrated analysis of that in a few slides.
In addition, we certainly have established, based on retrospective analysis of many patient samples as well as real-world data, what the proprietary cutoff is based on the IHC assay that could be a predictive biomarker for azenosertib in the PROC population. We have also initiated Denali Part Two. This is a phase two study that's a multi-part study, and Part Two is designed to be registration intended and an accelerated approval pathway. Upcoming milestones for next year, it's going to be an exciting year. We're really energized by the progress that we're making and the opportunity in 2026 for these patients, which includes not only enrolling and getting to the dose selection for Denali, but to also initiate the phase three confirmatory trial. We'll talk about that in a few minutes.
I first want to kind of take a step back and really make sure that this understanding of Cyclin E1 protein overexpression has some context. Protein expression here is really driven by multiple things. I think the best-known thing, of course, is gene amplification of the CCNE1 gene. In addition to that, there is also potential additional protein overexpression based on additional gene transcription factors, as well as a protein that does not degrade. What you see on the right-hand side of this slide is really a look at how that breaks down between patients who have amplified gene and non-amplified gene. As you can see, for patients who have gene amplification, and again, this is our data based on our cutoff in our assay, we see over 85% of patients who have gene amplification also have Cyclin E1 overexpression based on the cutoff.
Importantly, and we would be missing a lot of patients if we did not understand this, over 40% of the patients who do not have gene amplification also were positive for response based, again, on the cutoff. The takeaway here is that all patients in the PROC setting, regardless of their gene status, should be screened for overexpression of Cyclin E1 protein. We would not want to miss the opportunity here for patients who could potentially benefit from this therapy. The size of this particular population is actually quite large. There are no approved therapies for patients in the PROC setting who have Cyclin E1 overexpression. In the PROC population, we believe that to be about 50% of that market, which represents about 21,500 patients in the PROC setting.
The companion diagnostic that we've developed is ready to use, and we are using it to prospectively identify and enroll patients in the DENALI trial, and it will also be used to enroll patients in the phase three. I think if we're thinking about what's important here in terms of patients, it's not only a large market of patients to address, but certainly it's financially a positive market to be developing a drug in. We always think about investing our dollars to support patients, but also in a way in which we think about our shareholders. Of course, probably the closest analog here is Elahere, mirvetuximab, which was approved for biomarker-selected patients in the folate receptor alpha population. That was a potential of about 35% of the PROC population, whereas Cyclin E1 is about 50%.
Importantly, we can see really the demand for biomarker-selected agents in this setting by looking at the launch of Elahere, which is about two years in. In the first half of this year alone, they've seen sales over $330 million for half a year. We think this really underscores both the market opportunity as well as just the patient need and demand. What are patients' needs? We've talked a little bit about a high unmet need, and I think as you think about the development and the treatment pathway for agents in this setting, in the PROC setting on the far right-hand side of the slide, here we really see patients who have high unmet need, where only single-agent chemotherapy or monotherapy chemo is available for patients in this setting, other than, of course, Elahere for patients who are folate receptor alpha high.
There are no approved therapies, and response rates of single-agent chemo are actually quite low, between 4% and 13%. Because patients with high Cyclin E1 are known to be poor performers or poor prognosticators of disease, they likely do not benefit even as much as 4%-13%. I think this just underscores the high unmet need in this space, particularly for this biomarker-selected patient population. Earlier this year, we presented some information on an integrated analysis across the studies that had enrolled in the PROC setting. I'm going to show you two slides, one on safety and the other one on efficacy or activity. In this particular slide, we're comparing the active doses of 300 and 400 milligrams, again, at the same schedule, five days on and two days off. We see that the tolerability profile here is broadly comparable between these two doses.
This includes patients who were on our 001 dose escalation study, patients who were on the single-agent azenosertib arm in the Mammoth trial, which was PARP-experienced patients. In the first part of the DENALI trial, Part 1B, those patients were all dosed at 400 milligrams. What you can see here is a roughly similar tolerability profile. While they're numerically different, they're really broadly similar in terms of frequency. In addition to that, earlier this year, we also presented, again, in the same set of studies, the integrated analysis around the 400 milligram and the 300 milligram doses in those trials. You can see here there were meaningful responses across these studies at greater than 30% ORR, with the duration of response at the time of this data cutoff, which was December of 2024, of having over five months of duration of response.
You can see the number of patients at 400 milligrams is greater than those patients at 300. That's primarily due to the 102 patients that were enrolled specifically at 400 milligrams in the Denali Part 1B trial. In that study at 400 milligrams, we saw a response of evaluable patients at almost 34% in that trial. Clearly, there were fewer patients at 300 because those patients came from the Mammoth trial and from the 001 trial. While that response rate was not as high, it was not studied in the same patient population. As a result, this is very encouraging data and certainly encouraged us to initiate the Part Two of the Denali trial, which was to look at these two doses initially head-to-head and then to complete enrollment in Part Two. We'll go over that study design here next.
In the prior DENALI trial, part 1B, we had enrolled patients with one to five prior lines of therapy. In this part, which is part two, we will limit the lines of therapy to one to three prior lines. If patients have seen ELAHERE or are indicated for mirvetuximab, then that would be one to four prior lines. Importantly here, we are using our IHC assay to look at patients who would be eligible for the trial based on our cutoff of their Cyclin E1 protein expression. First off, we understand if they're eligible for Cyclin E1, then they're enrolled in the trial, and they're enrolled at one to one in terms of randomization between 400 milligrams and 300 milligrams. This is called part 2A of the DENALI trial, which is a potential accelerated approval pathway for azenosertib in this population.
That has been discussed with the FDA last year, and this is a seamless design. As we reach the enrollment in the two doses in Part 2A, and we are looking at the data, we will continue to enroll while we align with the FDA such that in Part 2B, we will complete enrollment in the selected dose such that we have about 100 patients or so that would serve as supportive data should the data be positive for accelerated approval. We've agreed on the endpoints, and certainly when we talk to the agency about the dose selection, we'll also talk with the agency about the bar for success in this clinical study. However, noting that we've already shared data historically and very meaningful response rates for these patients against current standard of care. We are very encouraged by hopefully seeing a repeat of that in this trial.
Of course, every accelerated approval trial has also a requirement to run a phase three confirmatory study. This is a randomized trial against standard of care. It will be the same eligibility criteria in the phase three trial, and we plan to conduct that concurrently as we complete the enrollment in the Denali Part 2B design. We're well on our way in that design and discussions, and we'll have more to say about that as we complete our alignment and provide trial initiation on the phase three, which we expect to do in 2026. I mentioned on the earlier side, excuse me, that we are enrolling patients in the Denali Part 2 trial that have one to three prior lines of therapy. One of the questions, of course, is, does that make a difference?
Quickly on this slide, we've just taken a look with all the caveats of a post-hoc integrated analysis, but looking at a subgroup here of prior lines of therapy for these patients at the 400 milligram five days on, two days off dose. This is across those three studies that we presented earlier in the safety and the activity slide. You can see that patients who have fewer lines of therapy do benefit from response rates all the way down to progression or to median PFS if there are fewer lines of therapy. We'll see if that holds true, but we do think it's important to be thinking about the differences between Denali Part 1B and Part 2, and this is one area where we expect to see some improvements. I just want to kind of conclude and hone in on our focus.
Azenosertib, of course, is an agent that could be studied in a number of tumor types. We have made a very intentional and specific focus to get azenosertib over the line in PROC patients with Cyclin E1 protein expression that meets the criteria and the cutoff of our IHC assay, and that is where we will be focusing. We also have been clear that our top-line data in this trial will be around the year-end of 2026, with some updates along the way in 2026, of course, around dose selection, etc. We will also initiate that randomized phase three trial in 2026 and complete the enrollment in the other studies, including the ongoing dose escalation enrollment in combination with bevacizumab in earlier lines of ovarian cancer. The key takeaways today is we've been intentional about our focus.
We're excited about the opportunity for a very large patient population that has a very high unmet need. We believe this will be the both first and potentially best-in-class WEE1 inhibitor based on the large body of data that we have shared with you today. We continue to execute well, and we're on track on the phase two part two of the DENALI trial, again, with the consistent milestone of reading out top-line data towards the end of 2026. The companion diagnostic is ready to go and is being used to prospectively identify patients in these trials. As we said, we think this is a significant opportunity to serve a broad number of patients in this setting.
Our cash runway, which we have rationalized at the beginning of the year, continues to support the development of this through late 2027 and certainly well beyond the top-line readout in 2026. Very good. Thanks. Thank you, Julie. Maybe you can start off a little bit just talking about what you've done in Denali to try to improve safety tolerability, specifically as it pertains to just investigator education, supportive care measures. Are you doing anything in Denali 2 that is, I guess, unique or different relative to the prior trial experience? Yeah, I think you always learn a lot, and it's important to take those learnings and really move them forward.
We have, and our CMO, Mark Bruns, is here today, and I really give him credit for the development of a really great program in which we're partnering with our investigators around how to use supportive care for GI, how to use supportive care for any hematologic toxicities, including neutropenia. Here, what the real learning is, is how to use these agents, how often, and when to use them. What's important, of course, is to be really close to patients and their progress. This is oral, which is great. It's non-chemo. That's great. That's the differentiated aspect of azenosertib. That means that patients are taking this agent at home, and it's just an important reminder to physicians to be in touch with patients and to educate patients about what they should expect and how they should reach back out to the physician.
We have a large group of folks internally who are doing medical monitoring as we support both enrollment and patients on trial. We also have a large clinical scientific group who is there to support sites in terms of data and data monitoring. We think that this will be not only helpful for the physicians and the patients, but we think that will translate, hopefully, into longer duration and potentially an opportunity for more patients to have scans and maybe have responses.
Okay. In Part 2A, can you just talk about where you think you might be from a timing perspective in terms of your ability to declare dose? Kind of what are the next steps once that dose has been declared? Is there a regulatory interaction that needs to occur? Is there some kind of temporary pause on enrollment as you kind of figure that out? How does that work logistically?
Sure, sure. Yeah. We haven't guided specifically to 2A because we're enrolling up to 30 patients. Anywhere along the way, if we see a clear dose, then we can go have a conversation with the agency, drop a dose, and move forward. There will be an interaction with the agency, and we'll provide a little bit more guidance on that next year about how we think about that timing. We have, and we are consistent with our thinking around the full enrollment and top-line readout for Denali, both parts, by the end of the year.
To answer your question on any pause in enrollment, that's what we would like to avoid and what we actually have already agreed to with the agency around the seamless design. We likely will have some small inefficiency of over-enrolling, potentially in a dose that we won't take forward, but it does allow us to get to the data, have a conversation with the agency, continue the enrollment so that when we do drop the dose, we won't lose time on the dose that's moving forward for Part 2B.
Okay. Just given the timelines that you've laid out for Denali and this conversation that you may have with the agency with respect to an accelerated approval pathway, how do you think about just harmonizing that with the potential initiation of the confirmatory phase three, which would need to be sufficiently enrolled in order to get an accelerated approval across?
Yeah. The conversations around the phase three are ongoing, and we've had really positive and encouraging interactions with the regulators. We have plans to initiate that phase three enrollment next year. We think that there's plenty of sites in which we can complete Part 2B as well as enroll or start the enrollment in the phase three. We do expect to be at least at 80%, if not full enrollment for the phase three as we get towards the accelerated approval timeline.
That is part of agency guidance that they'd like to see the trial fully enrolled. That is not guidance to us. That is just general guidance to the population that for accelerated approval pathways, they like to see significant enrollment in the phase three confirmatory trial. Certainly 80% is probably a reasonable bar, but that will be a discussion that we'll have with the agency as we complete the design of the phase three. Okay. We are funded to get to that enrollment. Okay. Yeah.
How are you just generally thinking about drug development in platinum-resistant ovarian cancer right now? I know it is a little bit of a crowded space. There are a lot of different ADCs there. As it pertains to Cyclin E1, we have some of the CDK2 inhibitors that are also in development. How is the competition just for patients in this setting? Has it been challenging to enroll? Do you see that getting harder? Do you think this cutoff that you've been able to institute to screen patients gives you an advantage on that front? Just any commentary around what you're seeing?
I think it's been coming off of FMO. It's been great to see a bunch of data in the ADC front. I think one of the things we're seeing is pretty consistent responses with those ADCs and that they're all sort of the same topo-1 payload, right? We think of a number of ADCs. We think of them all fairly similar, and we know that investigators and physicians won't be treating patients with multiple ADCs with the same payload one after the other. I think there'll be a winner there in that.
We think that's great and an important component of adding therapies in this space where there really aren't any therapies. Importantly, Cyclin E1 high protein expression patients, as I mentioned, just do not do well. We have a non-chemo option because ADCs are great, but they are basically directed chemo. Patients have seen nothing but chemo coming into this setting. To provide them, and especially this particular subgroup of patients, this biomarker-selected group, with an agent that is not chemo that has a correlation to response, we think it is important that those patients see that agent, and then they can always go back to chemo, whether that is an ADC or some other form of weekly paclitaxel, etc. We think that there is plenty of room in the space.
I kind of harken back to some work we did in another company with multiple myeloma, and we think about the amazing opportunity for patients there as that field developed and there were more agents. We are fine to have more agents in. We just think this biomarker-selected population really deserves a chance to have an agent that can potentially benefit them that is not chemo. That is sort of our thinking on the field. Certainly, we did share at ASCO and at 2024 ESMO some preclinical data on combining with ADCs. That is an area of interest for us because it certainly makes a lot of sense scientifically to be thinking about the combination of those two agents.
We're looking forward, if we have the cash and the availability to do that, to think about how we could also think about combination plays, not just in ovarian, but actually more broadly because azenosertib certainly could apply in a number of different indications and tumor types.
This notion of Cyclin E1 high being a poor prognostic, has that been, I guess, retrospectively broken out of any of the other competitor data sets? Did Elahere, for instance, right, within their publication, did they show a subgroup analysis for the Cyclin E1 high patients?
Not that I'm aware of. I think we look at literature where there have been studies to look at these patients in real-world data to see how they've progressed. In March of this year, earlier this year, Fiona Simpkins presented some data on that at the SGO conference, which showed that patients typically have a poor prognostication of benefit from chemotherapy agents. This is all based on literature. Our phase three trial will certainly have a control arm in this population, and we'll hopefully be able to see if that makes a difference.
Would you suspect at this point that that control arm is just investigators' choice chemotherapy?
Yeah, monotherapy chemo.
Okay. How many sites are in Denali 2? I guess, where are you in that activation process? I guess, of the investigators and sites that you're bringing online, what proportion of those have prior experience with the drug?
Yeah. In Denali Part 1B, a significant number of the sites for Part 2 have had prior experience. We do plan, I think it's probably out on clinicaltrials.gov, up to about 80 sites. We have had really great response with site initiation. We're hitting our targets there, which, of course, lead to the enrollment rates that we're looking for. We have initiated sites across the U.S. and European countries, in Australia and in South Korea. We are well on our way to not only meeting the goals for site initiation for DENALI part 2, but that will also then leverage those sites and new sites for the phase three.
Okay. Dar, you have a question?
Maybe talk a little bit about how patients get tested for biomarker currently, and if there's any leverageable biomarker education done by Elahere that azenosertib can benefit from.
Yeah, it's a great question. Today, patients are screened, and the NCC guidelines look at gene amplification, but they don't necessarily include, obviously, a biomarker screening automatically for Cyclin E1 because that's what we're bringing to bear. We do hope and expect that as this is utilized, that that would eventually be included in standard testing. This biomarker is an IHC assay that pathologists and institutions would already have experience with. It's not a new platform. It is similar to what Elahere would be using. This is going to be something that will be familiar to pathologists. It'll be a different cutoff, obviously, and a different read for the purposes of Cyclin E1. We think that we'll be able to educate and to enroll and validate this assay in line with the completion of the clinical trial so that both will be available, obviously, for market launch.
I think a minute ago, you alluded to topo after topo efficacy and the future landscape of PROC, right? I see that you allow prior Elahere use in your trial. How important is generic data in those patients? How would you set expectations for people looking at that component of your trial development to assess Asena's post-ADC efficacy?
We would expect Asena to be used before an ADC because, again, these patients are not doing as well. As we talked about, if you have further lines of therapy, patients do not do as well. By waiting, you have actually given a patient less opportunity to respond to a therapy that they know correlates to response. In what I meant by ADCs with topo-1 payloads, it is likely that physicians will use one of those ADCs, but they will not use them in succession.
If a patient progresses on a Topo-1 payload ADC, they likely will not treat that patient again with that same payload. We do think that Asena should come first to give patients the best opportunity to have a response. Again, they have had nothing but chemo. If they have progressed on Asena, then there is always an opportunity for either ADC or for monotherapy single-agent chemo that they could certainly go back to. I think we would be doing a disservice to patients asking them to wait beyond an ADC for an agent, again, that we know correlates to their biomarker status.
All right. There are no further questions, Julie. Really appreciate your time. Thank you. Thanks.
Thanks for everybody for coming. Appreciate it.