All right. Good morning, everyone. Tyler Van Buren here. Thank you very much for joining TD Cowen's 45th 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, and joining us for Q&A. We'll also have Dr. Ingmar Bruns, the Chief Medical Officer of Zentalis. Julie, thank you very much for being here. It's a privilege.
Oh, thank you, Tyler, as always. Good almost afternoon to everybody here. I think I might be standing between you and lunch, so we'll try to be efficient. Thank you for joining us. Of course, before I begin, I'd like to remind you that we'll be making forward-looking statements. The risks and uncertainties associated with these statements, I suggest you read our 10-Ks and 10-Qs filed with the SEC. I'm pleased today to have an opportunity to share with you our strategy and our vision for Zentalis, in particular in how we plan to move azenosertib forward into patients in the PROC setting. I want to make just a couple of overview points here today. First, there is a clear unmet need for this patient population. PROC patients typically have a standard of care monotherapy chemo.
We typically see low responses to these agents, as well as shorter duration of response. In particular, Cyclin E1 patients are known to have poor prognosis and poor response to these therapies. Second, the PROC population, in particular the Cyclin E1 positive patients, represent a large portion of this market. This is a large ovarian cancer meaningful market in terms of size, and the ovarian cancer market is expected to almost triple over the next few years. The successful recent launch of mirvetuximab in the folate receptor alpha high expressing patients shows a clear need for targeted therapies for these particularly biomarker-selected patients. The overlap between those patients and Cyclin E1 patients is less than 20%. This gives an opportunity for azenosertib in Cyclin E1 positive patients, an opportunity for a large share of the market. Secondly, we've accumulated a large portion of data.
This clinical data demonstrates that patients with Cyclin E1 positive in the PROC setting overwhelmingly respond to azenosertib with objective response rates of over 30%. This has been seen consistently across our monotherapy arms in multiple clinical studies. Next, the path forward is very clear. We have FDA alignment on a seamless trial design where dose confirmation cohort will lead directly into a second part of the Denali Part 2 study, which will allow us to move forward in a trial that is designed to be registrational and, in particular, accelerated approval from a registrational pathway. Finally, we announced in early January that we had made some changes to execute on our strategy. These changes involved a reduction in staff and an elongation of our cash runway into late 2027. This enables us to have cash to last through our read-through of the Denali Part 2 study.
I just want to spend a minute on Cyclin E1 patients. First off, these patients, which we believe represent at least 50% of the PROC setting, are patients that have overexpression of Cyclin E1 protein based on analysis with IHC assays and with a proprietary cutoff that we have developed. Importantly, these patients have protein levels that are regulated both at the DNA, RNA, and at the protein level. This includes patients that have DNA amplification that leads to protein overexpression. The benefit of the IHC assay is that it enables us to capture all of these disparate mechanisms of Cyclin E1 in one assay that can be used to prospectively identify patients for our registration trials.
The second important point here is that there have been multiple published manuscripts looking at retrospective analysis, which suggests that Cyclin E1 patients that have overexpression is a valid biomarker for poor prognosis and low benefits for chemotherapy. Patients with this activation tend to have a poorer outcome and typically have a shorter duration of response. Before I get into the data, I wanted to address the current treatment landscape. Except for patients who have folate receptor alpha high markers, single-agent non-platinum chemotherapy is the standard of care for these platinum-resistant ovarian cancer patients. This typically includes agents like paclitaxel, topotecan, PLD , and gemcitabine. The response rates for these agents are from 4% to 13%, typically with a median PFS of only three to 3.5 months.
The literature showing that these patients have a poor prognosis likely means that Cyclin E1 positive patients have even less of a response than the published data in monotherapy chemo. Obviously, new treatment options are needed. Let me turn now to a brief overview of the data that we've generated to date. We provided a very detailed and comprehensive review of this data on January 29, earlier this year. The data comes from three studies. The first study is the 001 study, which was our first in-human dose escalation study in solid tumors. Additionally, in our Mammoth trial, which studied previously PARP-exposed patients in both monotherapy and in combination with niraparib. Lastly, in the Denali Part 1B study, which was in all PROC patients at a dose of 400 milligrams.
As you can see, we have significant characterization of the safety profile in over 350 patients, which included PROC patients at both the 400 and 300 mg doses. Next, we're going to review the safety profile. Here we show side by side the 300 and 400 mg intermittent doses. As you can see, these are broadly comparable when shown next to each other. While febrile neutropenia and sepsis were observed at the 400 mg dose, it was at a low frequency. There are far fewer patients in the 300 dose cohort, which we'll address in a minute as we talk about our registration pathway. In addition, we see very manageable profiles when it comes to the hematological and gastrointestinal toxicities. We see that this profile actually compares favorably to other WEE1 inhibitors that have clinical data published, particularly the Ignite study with Adavo.
Moving on to responses here, as you can see, we've treated over 70 patients who've had Cyclin E1 PROC in the PROC setting at doses of 400 mg and 20 patients at the 300 mg. In the 400 mg dose, you see a very meaningful response rate, whether it's response evaluable or intent to treat population with ORRs of over 30%. I do want to point out here as well the median duration of response, which is at a very consistent 5.5 months. We will provide an update on this as it is increasing. We announced today that we'll be at the SGO conference in the middle of this month and provide an update on the Denali Part 1 study data, in particular the duration of response. Okay, let me turn now to our future plans. This is the trial design called Denali. Denali was a multiple-part trial.
We described already the Part 1B patients and their outcomes in the Denali study. We now intend to use the Denali trial with the Part 2 as we go forward, not only in dose confirmation, but in the final enrollment for accelerated approval. As you can see here on this slide, we plan to align with the FDA, which we've done in Part A, to do the dose comparison of 400 and 300 for patients who've had one to three prior lines of therapy and who meet our IHC cutoff for Cyclin E overexpression. Those patients will be enrolled and randomized between the 300 and the 400 mg cohorts. Once we've established that dose, we'll have further conversation with the agency regarding the bar for success and accelerated approval. However, we won't have to stop our enrollment.
All the patients that have been enrolled in the dose that continues will be counted towards the final analysis. That is the seamless design that the agency has agreed to. Additionally, we'll have conversations with the agency on our phase III dose confirmation study. This is a randomized trial. It'll be looking at a control arm of standard of care and chemo agents. As I mentioned, the Denali Part 2 study will be enrolling patients who have one to three prior lines of therapy. In Part 1B of Denali, those patients had anywhere from one to five lines prior therapy. The question is, do fewer lines of therapy matter when it comes to outcomes and responses? This is a question that has been asked multiple times. We're pleased today to provide you with a short subgroup analysis regarding the prior lines of therapy.
In this particular analysis, you can see that for patients, whether it's in response evaluable or intent to treat populations, one to three prior lines of therapy had better overall response rates than for patients who had greater than four lines of therapy. We do believe that in these Cyclin E1 PROC patients at 400 mg, which is the body of data here, that having fewer lines of therapy matters in these patient populations. Of course, all the caveats that these are small numbers with overlapping confidence intervals should be taken into account. This does provide us with confidence as we move forward into our registration setting. Okay, lastly, just to wrap up, we are intensely focused on the development of azeno in the PROC Cyclin E1 population setting.
As we continue throughout 2025 and into 2026, we'll continue to update the market on our progress, both from a regulatory and a clinical perspective. As we mentioned earlier, we will initiate Part 2A in the Denali study, which is the dose comparison or dose confirmation part of that trial. That will begin very shortly. In addition, we'll continue to develop the rest of our pipeline as we have funding and availability. Of course, we'll provide data updates when appropriate to the market on these other trials. Thanks again for joining us here today. We're very excited about the data that we have, and we're excited about our path forward with a very clear and focused strategy on azenosertib in the PROC population for Cyclin E1 positive patients. Thank you, Tyler. Back to you.
Wonderful. Julie, thank you very much for that presentation.
Perhaps you and Ingmar could come join me for Q&A. Julie, you experienced much success at Harpoon before you joined Zentalis. I would love to just start by asking you why you decided to join Zentalis and what attracted you to the story since you joined recently.
Yeah, sure. That's easy. Great data. I think, you know, fortunately, Ingmar and I and Haibo, who's here with us today, our Chief Business Officer, all had an opportunity to take a look at the integrated analysis that was presented to the FDA post the clinical hold. I think what we saw really excited us for a population of patients who have nothing directed to them specifically. One, obviously, patient need was primary of importance always in evaluating programs.
We saw a real opportunity here to bring this to market based on the resources that were available in the company. It was a no-brainer. Ingmar can speak for himself because we joined together.
Ingmar, anything you could say about this integrated analysis as well?
Yeah. About the integrated analysis, yeah. I mean, what are you looking for specifically?
I mean, just curious, was it just like a very robust presentation of the data or was it?
Yeah, it was the FDA briefing book that was provided upon the clinical hold that enabled the agency to lift the partial clinical hold very quickly without dose modification and without schedule change. It was the data that we were able to see while we were under CDA that unfortunately the market was not able to see until we presented that in January.
I think that's what got us excited to join in November. Of course, you know, as good diligence is, Ingmar spent his time making sure that the data was really robust and the database was clean. Then we presented that data in January. What you saw at the end of January was really along the lines of what was presented to the FDA. Of course, the FDA data was a little bit earlier data cut than what we presented.
In addition, we really saw the opportunity to improve by trial management and study oversight, something that, you know, in all honesty, was probably a little bit suboptimal in the past. You know, in that context, clearly the data is even more remarkable. That's something that became apparent pretty quickly, right? That's a relatively easy leverage.
Obviously it requires a lot of work to do that, you know, to turn a study around and, you know, get to even better data.
How do you expect to improve trial management and oversight moving forward?
Yeah, I mean, one thing, of course, is having a more hands-on approach, right? Get really close to the sites, focus on continuous data review and monitoring. There are also aspects that you can already incorporate into protocol, right? Have more visits, have more time points, things that we've done for laboratory assessments. Also, you know, more extensive use of supportive care, which, you know, was happening at pretty random time points and infrequently in the past.
You know, there specifically, if it comes to GI and hematological toxicities, there is a lot of upside that, you know, can be generated without compromising the convenience of the oral formulation of the drug.
Got it. Okay. You know, modifying the protocol and making sure the patients are getting a standard of care is one thing. Visiting sites more makes me think that you guys might need to add more individuals. Yet you guys are cutting costs. I presume you already have the people in place to do that.
We have a master plan. Yes. There were 165 folks at Zentalis earlier this year. We had a 40+% reduction. You know, we have thought about not only just what is the right number of people, but what are the areas that those resources are needed in.
We've already aligned on how we're allocating those resources to the clinical effort manufacturing. We also need to obviously support the physician in the market through medical affairs. It was a wholesome look, not just a top-line 40% reduction. It was done with a structured review.
Okay. You reviewed the data that's been presented so far. The table with the subgroup analysis was exciting to see, but makes sense based upon what we've seen with historical data in the space. The Denali Part 2 registrational trial initiating in the first half of this year. Part 2A, what do you need to show in Part 2A to get FDA alignment and be able to move to 2B?
We're looking at three areas, right? Number one is, of course, the response rate. And this will be confirmed responses.
Number two is, of course, safety and tolerability profile between the two arms. Lastly, of course, there's also PK to see that, you know, there's a clear difference between these dose levels. There will be some overlap naturally because these are relatively close and it's an oral drug, but those are the main parameters.
Based upon the data, the 400 mg seems to be better, right?
Yeah. This is, we think it's certainly our dose of interest with 400 mg. But, you know, as you're familiar with FDA's Project Optimus, you have to, you know, look at a second dose that's still clinically active. In our case, this is 300 mg fulfills that criteria and compare it in terms of, again, efficacy and safety in particular.
You know, we agree we're trying to confirm 400 mg here, which based on the data that Julie just presented and seen at our more comprehensive disclosure is, you know, well tolerated and really efficacious in that patient population. You usually pick the lower dose to really kind of distinguish between those two. That is the effort here that we're going through.
Got it. Do not have the slide up, but how many patients again in 2A do you need to enroll?
2A is two arms, two interim analyses after 20 patients per arm and then 30 patients per arm. If the difference becomes visible or clear after 20 patients, then, you know, this is an opportunity for acceleration for an FDA interaction. We are planning on 30 per arm, so 60 overall.
We will continue enrolling both arms and not lose time when meeting with the agency such that as we meet with the agency and get their alignment around the data for the dose, the recommended dose will then drop the second dose and complete the 100 patients, about approximately 100 patients, that will be needed in that single dose to go forward. That is the part of the seamless design that allows you to continue to enroll while you seek agency alignment on the data around the dose.
Got it. Okay. Yeah. I mean, when the clinical trial hold happened, I saw that enrollment curve. It was parabolic. I do not think you guys are going to have any issues enrolling this trial. Obviously, you are going to have maybe more controls over it with the sites and make sure that you have got enough oversight.
I would expect, I guess, part 2A to be enrolled pretty quickly. Then it's just a matter of getting follow-up to present the data in 2026, right?
That's right. High-quality speed is important here.
Amen. Okay. Just for part 2B, if what you see in the patients who had one to three lines of prior therapy, if what you've seen with the existing data, if you replicate that, you believe that'll be sufficient for approval. Has the FDA given you any guidance or?
Yeah. The design, and I think that's really the most important part, as seamless as it is, because we're adding in part 2B while we continue enrolling, right? You know, waiting for the decision which dose to take forward. We'll just add enough patients in 2B to get to 100, which is considered still an appropriate data set for accelerated approval.
The FDA has seen and agreed with that design, right? Naturally, you need data to discuss the actual bar for accelerated approval, like the eligibility lower bound and supportive data, right? The usual list you receive from the FDA that, you know, given that we haven't had data in that setting right now, it's of course still pending and the FDA interaction is already planned. You know, you've seen the data, so it's very unlikely that this is going to be below the threshold for success, right? Because it's in the FDA guidance and in the public domain. Your competitor, if you will, is single-agent chemotherapy. You shouldn't cross the upper end of the confidence interval there, but calculate where this is.
What's the upper end of the confidence interval?
It's 4-13%, right? It's the ORR.
You know, I'm not saying the number now, but I think it's lower than the 30% or 35% we've shown here for Zeno.
You know, we will see as we develop the phase III confirmatory that it will be against a comparator arm of single-agent chemo in Cyclin E1 positive patients, which data set doesn't exist. If it's true that these patients do worse, then that 4-13% on average from a chemotherapy may actually be a lower bar. Nonetheless, you know, even a doubling or tripling of the current highest level of chemotherapy would be a very good outcome for patients.
Got it. You mentioned the 5.5 months median PFS SGO conference coming up. It's going to be greater than five and a half months. It's tough to tell how much greater, obviously.
Is there any insight you could give us into the amount of follow-up that these patients are going to have prior to what we previously had as we think about that data set?
It's probably the data cut-off difference, yeah.
Yeah. It's the difference in the data cut-off, right? We had a December data cut-off.
December 2.
Now this is further matured to February. So it's about two months.
I think it was January.
One and a half, yes.
January. January 8.
It's about six weeks.
Okay.
January 13, I think, was the cut-off.
All right.
Five to six weeks, yeah.
Got it. It's not going to 10, but it could go percent.
No, it's not. I think, you know, from what we hear from our investigators, certainly five months is very meaningful compared to chemo at three.
Would it be better if it was closer to six? Absolutely. Let the data mature and see where that comes in.
That's great. Okay. Safety, 356 patients in active doses. You know, historically, Adavo's grade three AEs heme tox has been significantly higher, yet the KOL enthusiasm was quite high. You know, and then Adavo program got canceled, which was disappointing to a lot of the lead investigators. I guess how are you taking advantage of that? What's the KOL feedback that you're getting on safety, especially as you look to continue to control it better moving forward?
Maybe you can talk about your recent interactions with KOLs regarding the data set.
'Yeah.
We just had the pleasure to have some interactions with European KOLs around the ESGO meeting enrollment, also talked to DMC that will be in place for part two of Denali. Those were investigators, very experienced investigators, but who do not necessarily follow, you know, data disclosure events or any news outlet that is more geared towards investors, right? They really saw the data for the first time. They were really impressed, right? They really thought that was both from an ORR as well as a DOR perspective. They considered the safety profile and tolerability profile really as manageable because the comparator is single-agent salvage chemotherapy still, right? Apart from those, and it is not, you know, broadly available yet in Europe, those in the folate receptor alpha high population can get mirvetuximab.
The comparator, as Julie said, is still single-agent chemotherapy with, you know, weekly paclitaxel, probably the most active regimen. That has about, you know, a low double-digit overall response rate. The heme tox as well as GI tox is higher than what we see. Yet the convenience is lower because you need to get in every week, right? For an infusion, there's neuropathy as a side effect. There's a chance of hair loss in these female patients, which so patients really don't like it. That was clearly the perception of these European investigators who had pretty much the first contact with the data.
Okay. That's helpful. Related to the confirmatory study, sometimes these confirmatory studies take years to conduct. Obviously, if standard of care chemos are control arm, it's not going to take years, unfortunately, for the patients.
You're starting it next year. What else needs to be done to get it initiated? I'm presuming you need to have discussions with the FDA. What all is going on to get that started?
Yeah. The times where you can take years to run the confirmatory trial are over for better or worse, right? We definitely, we think we need to get to at least an 80% enrollment status. You know, the moment the dose has been confirmed in Part 2A, we will also start the confirmatory randomized control trial at the same time. You can also look at those somewhat combined at the data set in a blinded way, maybe part of the submission then.
I think, Tyler, just for preparations, we have an advantage now over the course of this year to talk to the agency to prepare that study from a logistics perspective so that when we get the dose, we're able to just rapidly start enrolling in the confirmatory trial and it'll enroll alongside Part 2B of Denali. Okay. That's helpful. You enroll Part A, get that data dose, and then you enroll Part 2B in the confirmatory study at the same time. Yeah. If the confirmatory study is set up and agreed upon ahead of time, then you're just ready to slot patients in.
Got it. Any idea how large that study needs to be?
We don't have an end on that yet, but it'll be several hundred patients, I'm sure. When I say that, I don't mean 200.
I mean some several hundred patients we'll have to discuss with the agency on the statistical plan around that.
Okay. As we think about the market opportunity, you showed the number of patients on the slide in terms of the total addressable market. Can you just talk a little bit more about CCNE1 testing? Is amplification overexpression the same thing? Where's testing at and how are you going to continue to improve that as you approach the market?
Yeah, it's not the same thing. Let me start with this. We do think that, and Julie showed the slide, there is overlap. Meaning that the amplified population is included to the absolute majority in the overexpressed population. With our proprietary cutoff on the IHC assay, this is about 50%, at least 50% of the overall PROC population.
I think it was a really important point because CCNE1 amplification and Cyclin E1 overexpression do have an intersection. Cyclin E1 overexpression can be caused by other things other than gene amplification. That is why you see CCNE1 being 20% of PROC, but Cyclin E1 overexpression being 50% of PROC. That is because expression comes from other places. While the vast majority of CCNE1 amplification is Cyclin E1 overexpression, it does get contributed in other ways to generate a larger population that has overexpression of Cyclin E1.
Do you see significant differences in efficacy between those two populations?
No. Again, just to add to Julie's point, I think the ones that are amplified but do not overexpress Cyclin E1, that is a single-digit percentage. That is a really, really small group. In our data set, we have not seen any difference between the gene amplification and the overexpression.
Okay. It's lunchtime. Maybe to wrap up the conversation, I'll ask you what you believe is the most underappreciated aspect of the Zentalis story by investors right now.
I think that maybe investors, I don't know if it's underappreciated, but I think they're learning. I think the opportunity to have conversations like this in one-on-ones to help people really look at the data, understand it, and appreciate the support of that data for a registrational pathway is important. Secondly, I think investors will come to understand that the finances are available not only to achieve that initial top-line data set in a registration trial, but have runway beyond that. We're financed, we're focused, and right now we're an execution story. We're going to bring this drug to patients.
Wonderful. Julie, Ingmar, thank you very much.
Thank you.
Thank you.
Thanks, everyone.