Great. I'd like to welcome everybody back to our morning session. I'd like to welcome everybody again to the H.C. Wainwright BioConnect Investor Conference at NASDAQ. Presenting with us next is Zentalis Pharmaceuticals, and we have Chief Executive Officer and President Julie Eastland, and we have Zentalis' CMO, Ingmar Bruns. Welcome, and it's my pleasure to host you today.
Wow, thanks for having us, as always. We really appreciate it.
Of course. Let's begin with a high-level overview for those less familiar with the company. How would you describe the company's current mission? What makes the lead asset azenosertib a potentially transformative therapy for ovarian cancer?
Thank you. Again, thanks for everybody who's also listening and attending today. Zentalis does offer a really unique opportunity, I think, for patients with platinum-resistant ovarian cancer. This is with our lead asset, azenosertib. We are on a mission to bring azenosertib to patients, in particular to patients in this setting that represent a large population of cyclin E1 positive or overexpressing of the cyclin E1 protein in this population. These patients have very few options, all single-agent chemotherapy, and they have typically poor prognosis for the future. We see a real opportunity with our agent, which has been studied in multiple different clinical trials, both in dose-escalating and in combination with other agents.
We presented data earlier this year, quite a large body of data in January, that looked at single-agent azenosertib across a number of different studies in this population and showed consistent responses and a very manageable tolerability profile that has led us to starting the registration trials or registration-intended trials in the PROC setting. These trials are starting in what's called Denali. The Denali trial is a multi-part study. We're currently enrolling, and we announced just in April that we have started to enroll the first part of that trial. That's what we call Part 2A. This is a dose comparison portion of the trial that will allow us to confirm our preferred dose.
Once we've done that and enrolled that trial, we'll continue to enroll at that dose to reach about 100 patients in the full Denali Part two as a way to move forward in an accelerated approval pathway. We've had discussions with the agency around that seamless design, and certainly we'll have continued dialogue with the FDA after we have confirmed the dose in order to complete enrollment and looking forward to top-line data in that accelerated approval-intended study at the end of 2026. Our mission is clear: get azenosertib to patients. Again, this is an orally available, very active agent in this setting, provides a unique opportunity for physicians to treat this biomarker-selected population.
We have certainly generated a very broad data set for these cyclin E1 patients that allows us to really understand, from a proprietary perspective, what the cutoff is of overexpression that then will relate to a companion diagnostic that will be developed alongside azenosertib for also commercial use in selecting patients.
Great.
That was a lot.
No, thank you for the very helpful overview. Ovarian cancer is seeing a renaissance as of late, from PARP inhibitors to the approvals of ADCs targeting folate receptor alpha. Zentalis is currently leveraging a biomarker, cyclin E1. Put into context, what makes this biomarker for azenosertib such a compelling opportunity, both clinically and commercially?
Yeah, I mean, we have seen with our cyclin E1 proprietary IHC assay a very clear cutoff and correlation of overexpression to response. We presented some of that data earlier this year, for example, based on our cutoff. Patients with high cyclin E1 protein expression see about a 35% response rate across our studies. Those who do not or have a negative result from that IHC assay have single-digit response rates. Very clear data to say a correlation between high cyclin E1 protein expression and benefit for this patient population. That is not too different than folate receptor alpha, obviously, where they also looked at high rates of expression and correlated that to response. There is a small overlap between folate receptor alpha patients and cyclin E1 patients. It represents about 20% of the PROC population.
We think there is an opportunity there for those patients to see both a mirvetuximab and azenosertib in terms of treatment. Certainly, the cyclin E1 patients do not have any other options other than single-agent chemo. We think that there is not only a rationale here in terms of the science, but in terms of the potential market opportunity with our cyclin E1 cutoff. It represents about a total of 50% of the population of PROC that could be eligible or could be sort of subject to the levels of expression that they could benefit from azenosertib. Just as a reminder, I think the folate receptor alpha is about 35% of that population. Certainly, two distinct opportunities in PROC and quite a significant opportunity from both a patient and a commercial perspective.
Great. Diving a little deeper into the clinical profile of azenosertib, you've consistently shown greater than 30% overall response rates and a median duration of response around six months for these cyclin E1-positive, platinum-resistant ovarian cancer patients across monotherapy studies. From a clinical development standpoint, what elements and benchmarks are most important to support the possibility of potential accelerated approval there?
Yeah, and I'll have Ingmar take that.
Yeah, I think Julie already alluded to the interaction with the FDA last fall we had, and the company had. It is indeed overall response rate and the duration of response is the primary benchmark. We're currently with the data that the studies have consistently shown, and Julie already mentioned, above 30%, around 30%, up to 35%, or the range of five and a half months up to 6.3 at the latest update. That certainly is about that benchmark, right? Again, response rate and duration of response are the endpoints here.
Very helpful. Can you expand on the dose selection process between both arms, the 300 mg arm and the 400 mg arm? Talk about some of the trade-offs you're weighing in for the Denali study and how this might impact your final registrational strategy.
Yeah, certainly. So both doses are active, right? That's an important statement to make. We've seen at 400 mgs, five on, two off, intermittent schedule, that there was a higher rate of responders. Having said that, it's a bit of an asymmetrical data set, right? Because Denali Part 1B included exclusively 400 mg patients at the five on, two off schedule. We then gathered the 300 mg data from studies in the same population, sometimes a little bit more pretreated across the Zentalis portfolio to compare that in the cyclin E1 positive patients. It's not an intra-trial comparison. It's an inter-trial comparison, right? As I mentioned, the 300 mg population was slightly more lines of prior treatment. Therefore, it's not really an apples-to-apples comparison. Confidence intervals are overlapping on the overall response side.
We felt, well, believe in 400 mgs as our primary dose of interest, that it's worthwhile to compare the two. Independent of that, of course, it's a requirement as per Project Optimus that the FDA still requires us to fulfill. The design is pretty much the gold standard of Project Optimus with the prospective randomization and the number of patients we include into those arms.
Very helpful. You have shared compelling subgroup data showing better responses, of course, with patients with fewer lines of therapy. Could this data reshape the eligibility window for a broader registrational trial or perhaps influence your companion diagnostic deployment?
Yeah, so that's true. We have a small subgroup analysis, which pretty clearly demonstrated that fewer lines of prior treatment lead to improved response rates. That's certainly something that we have employed into the part two of Denali already with just one to three prior lines of treatment. The trial also includes a prospective selection of cyclin E1 positive patients above the proprietary threshold here. Julie already mentioned that earlier. It's going to be other than part 1B, where this was retrospective in inclusion criterion.
Very helpful. And digging a little deeper into how confident are you that cyclin E1 expression is capturing the full breadth of patients likely to benefit from azenosertib, especially given the overlap and divergence with CCNE1 amplification?
Yeah, I think this was really an important point. Cyclin E1 overexpression certainly is driven by CCNE1 amplification, but it's not the only reason for cyclin E1 overexpression. There are other factors that can affect the overexpression of this protein. Our focus here in well over 200 patients, taking a look at their cyclin E1 status and overexpression, have led us to really be able to have a very solid set of data for this cutoff for understanding these patients who respond. While CCNE1 amplification certainly is part of the story and represents about 20% of the PROC population, it's only a portion of all patients who have cyclin E1 protein overexpression that would be potentially eligible with our companion diagnostic for azenosertib treatment.
It certainly is our plan to complete this companion diagnostic, which is well underway with a lot of data and discussions already have been had more broadly with the FDA. We now, as Ingmar noted, will be prospectively enrolling patients in the registration trials with this, and we'll be confirming and validating the CDX and launching that alongside azenosertib. An important part, the CCNE1 amplification, just because there's a lot of literature really showing how poorly those patients respond and how quickly they progress. That amplification along with the cyclin E1 overexpression means that patients really have a bigger unmet need typically than potentially patients who do not have that overexpression.
Very helpful. Thank you. Across the 350 patients thus far treated with azenosertib and the favorable safety profile that the company has been able to generate, how do you view the tolerability profile influencing treatment decisions in the real world, obviously particularly compared to single-agent chemo? Can you give us some context there?
Yeah, maybe I'll do a quick response and, of course, Ingmar can chime in. This is the population that we're looking at as these patients who have the choice of single-agent chemo. Obviously, that profile is different than this orally available azenosertib molecule, the WEE1 inhibitor. In the single-agent chemotherapy, you have tolerability around neuropathy, hair loss, as well as GI and other issues. That is a different profile than azenosertib, which has a very manageable profile when it comes to both GI, hem-onc toxicity, and just does not have these characteristics that you see with single-agent chemo. Importantly, too, also not seeing things that some of the ADCs are seeing when it comes to issues around vision impairment, et cetera. I think it has its own tolerability profile that is quite manageable.
It is not uncommon to other small molecule orally available agents that have been developed in the past. This was really an opportunity for us to help to ensure that physicians understand how to use this molecule, how to keep patients on drugs through the use of standard supportive care measures, and that this will allow patients to not only have durability on azenosertib, but hopefully that will lead to more scans, more responses, and longer duration of therapy.
Given the breadth of patients that have been treated thus far with azenosertib, curious on your thoughts on historically, there have been some hematologic AEs that were unforeseen. Can you talk about some of the safeguards or mitigation strategies moving forward you're putting in place either in Denali or looking beyond Denali Part two to optimize patient safety there?
Yeah, I'm happy to. That's been a big part of our job in the last six months and actually something that I think we identified from the beginning when we first, with a first look at the data. I think we can certainly be confident this is a drug here right there, which has declared its efficacy already and that you could put measures in place to also manage the safety profile, which was not always optimal in the past. We think really high-touch monitoring, you already mentioned it, the consequent use of supportive care, frequent assessments really do make a difference here. You could now say, if a drug needs such a tight oversight, then how is it going to perform in the real world?
I think I would argue every drug pretty much in oncology with a certain toxicity profile requires a learning phase, which starts during the trials. Then while investigators get more familiar, in the future, prescribers get more familiar, everybody learns about it. We already see that effect during the trial. We've seen it in the past, right, in the second half of the trial already where this became certainly saw an improvement overall. We do think trial oversight, high-touch management of the trial, constant analysis of the data that comes in, and also follow-ups on the use of supportive care is key here.
Great. Very helpful. Starting with the potential of an accelerated approval as the next topic, can you share more on your ongoing discussions with the FDA and even more importantly, feedback you've received regarding the clinical bar or study design, given that you have beat chemo so handedly? What are some of the internal kind of benchmarks of success that the team has?
Yeah, I think Ingmar mentioned those sort of early on, certainly in seeing the efficacy across the lines, also looking at other agents in the PROC setting, which also had a north of 30% ORR and durations that were nearing or exceeding six months. These are not conversations we've had with the FDA specifically. Obviously, we've talked with the FDA about the design of the Denali Part two study, the seamless design with the dose confirmation, and then the completion of that enrollment at dose for the intent of an accelerated approval study. We'll obviously need to go back and talk to the agency about the bar for success once the dose has been selected. That will be coming up in the first part of next year once we've enrolled Part 2A. Once we've had the data, we'll obviously go have a conversation with the agency.
At that point, we'll talk about what the bar is. The design of the study and the endpoints of part two as a potential accelerated approval trial has been discussed with the agency. We'll continue to have, and the agency I'm referring to is the FDA. Just to be clear, that's with US FDA. We'll continue to have dialogue with them, not just on Denali next year, but a little bit later this year in the second half, we'll talk to them about the phase III confirmatory study, which obviously needs to go along with the accelerated approval for eventual full approval. We'll have an initial conversation in the second half of 2025 on the phase III confirmatory design.
Of course, once we have dose next year, we'll complete our discussions with them on both the Denali part two for accelerated approval and for the phase III confirmatory endpoints.
Great. As one of our final questions, as top line Denali part two data is expected in late 2026, can you talk about how you're thinking about resource allocation across your core PROC franchise and the potential for other indications for azenosertib?
Yeah, that was really very clear. One of the things we really wanted to do when we came into the company last November is make it really clear what our strategy is. Dollar number one is going to get azenosertib across the line in platinum-resistant ovarian cancer. So that's dollar number one. And we're allocating our capital to do that. We had a transformation at the beginning of the year where we reallocated our resources and capital to that part of the pipeline. But we do have other studies ongoing. In our 002 trial, which is an ongoing combination trial, we're looking at bevacizumab plus azenosertib in platinum-sensitive ovarian cancer patients. So still ovarian cancer, but earlier in the lines of therapy. In addition to that, and these are sort of signal-seeking finding studies, we also have the ongoing 004 trial in USC. And that trial is enrolling.
We have promised that data in the first half of 2026. We will be looking at that as another potential tumor indication. Lastly, we have a number of investigator-initiated studies. These are in tumor types in combination with standard care for triple-negative breast, as well as in HER2-positive solid tumors. Again, if we see signals there, we will look at how we may either reallocate capital to those if we have excess capital or look to partner or find a way to fund additional development so that we can expand on the xeno franchise and other tumor types.
Great. I think that's all the time we have. On behalf of myself and the entire H.C. Wainwright family, I'd like to thank Zentalis Pharmaceuticals, specifically Julie and Ingmar for being here with us today. We look forward to future updates.
Thank you so much, Andres. It's always a pleasure.