All right. Great. Good morning, everyone. We'll give it just a few seconds here to make sure everyone's able to join. All right. Thanks again for joining. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thanks for attending TD Cowen's Sixth Annual Oncology Innovation Summit. For our next session, we're very pleased to have Q&A and virtual fireside chat with Zentalis. It's my pleasure to introduce Julie Eastland, the President and Chief Executive Officer of Zentalis. Julie, it's a privilege to have you here. Thanks for joining me.
Thanks, Tyler. Thanks for having us. This is always such a great forum. Thanks to all the listeners here who are joining today and their interest in Zentalis.
Of course. We'll get straight into the questions now. For those of you logging in, if you have questions that you'd like us to try to get to for the end of our discussion, you can email them to me at tyler.vanburen@tdsecurities.com or cowen.com. Again, that's first, not last. With that, maybe we'll go ahead and get into the main topic of discussion for Zentalis, which is CCNE1-positive platinum-resistant ovarian cancer. Julie, maybe you could start with just a high-level overview of the company for those who are less familiar and what makes [lead candidate] azenosertib potentially transformative therapy for PROC.
Oh, great. Happy to do that. You know, we agree as azenosertib represents a potentially transformative therapy for ovarian cancer patients. This is a convenient oral non-chemo treatment option for patients who have ovarian cancer and potentially in other tumor types as well. You know, we have shared a large body of data on azenosertib over the last four months, most recently an oral presentation at SGO. This was on a recent data cut from our DENALI Part 1b clinical study in platinum-resistant ovarian cancer or PROC patients. That particular study was at the 400 mg 5/2 dose schedule. We believe that this data, as well as a very large amount of data of monotherapy for azenosertib, really demonstrates a meaningful benefit for Cyclin E1-positive patients.
That is our initial focus for azenosertib is in the Cyclin E1-positive PROC patients, where standard of care here is really non-platinum chemo regimens that have very low- single or low- double digit response rates and short duration of benefit. We think that azenosertib offers not only a different non-chemo regimen, but offers an opportunity for patients to see a much better therapeutic outcome.
Great. Maybe just focusing in on the Cyclin E1-positive platinum-resistant ovarian cancer, maybe you could kind of double tap on why azenosertib is well suited for these patients and mechanistically why it makes sense to focus on Cyclin E1.
Sure. I think, you know, quite simply, we have developed a proprietary IHC assay and looking at really a large body of our patients across multiple studies have determined that the cutoff for these patients who have Cyclin E1 overexpression accounts for almost 50% of the PROC patient population. This is really a substantial subgroup of patients that provides both an attractive commercial opportunity as well as just addressing, obviously, a huge unmet need for these patients who typically have poor prognosis if they are Cyclin E1 high. We see a real clear difference for these patients with a zenosertib above and below our Cyclin E1 IHC cutoff. For example, in the DENALI Part 1b study, we saw a 35% response rate for patients above the cutoff, while the response rate for patients below the cutoff correlated to more mid-single digit overall response rate.
A clear rationale for this patient population, both in terms of need and in terms of a zenosertib's benefit that's been demonstrated in the population.
Is there anything more you could say about that cutoff as you look to define CCNE1 overexpression based on IHC?
What the.
Pardon?
Or what that cutoff is, sorry.
Yeah, we haven't disclosed the cutoff. It is proprietary. I think there's not much more I can say other than it's a standard assay. This will not be difficult to overcome. To the commercial setting, we're obviously developing a companion diagnostic here that would get launched with the drug and really allow the industry to test patients so that they could achieve, excuse me, so that they could be eligible and have a zenosertib available to them. Again, you know, for patients with poor prognosis, you know, we want to treat them with an agent that we know actually is correlated to good outcomes.
I think it'll be fairly straightforward in terms of the technology of the assay, and the cutoff itself is proprietary, but does address certainly in our studies, which has been in more than 200 PROC patient samples across multiple studies, we see a really strong correlation, as I mentioned, with our cutoff in terms of response.
Okay. That's helpful. Just final question as we think about the opportunity and potential competition, what's the overlap between folate receptor alpha patients and CCNE1 patients in PROC again?
Yeah, it's a great question. You know, we see an overlap of around 20%, you know, plus or minus. And you know, we think that this is really a wonderful opportunity for these patients in that they really only have the folate receptor alpha and chemo as options. But here, azenosertib would offer another treatment option. Again, you know, treating patients potentially first with a zenosertib so that we can address them quickly. And then, of course, their folate receptor alpha high status could be addressed with mirvetuximab or potentially in combination. We did show data at SGO where we can combine in a preclinical setting and see synergistic effect between a microtubular inhibitor and a zenosertib . So we think there's a nice opportunity to see a better response. That's a clinical study that obviously has to be run.
This is good news for these patients who have this overlapping expression profile.
Okay. Very interesting. Now getting into the clinical data that has been presented that you alluded to earlier across the MAMMOTH and DENALI trials, azenosertib led to a consistent 31%-35% response rate and five and a half month median duration of response in CCNE1- positive PROC patients. Maybe you could compare that to what you would see with standard of care in these types of patients.
Yeah, certainly. As you noted, at the 400 mg 5/2 dose, which is really our preferred dose where we saw a very consistent response rate of over 30% across multiple studies and durable responses. At our last presentation at SGO, we showed that an updated median duration of response was over six months at 6.3 at that point. Of course, there are patients that were ongoing in the trial as of the data cutoff. That was still an interim look. The standard of care for patients, as you mentioned, and we talked about single agent chemo, really has very poor prognosis, generally speaking, for the population. This is single to low- double digit response rates, low progression-free survival rates.
With Cyclin E1 overexpression indicating patients have even worse outcomes than this on chemo, something that our KOLs and our clinicians who study these patients do describe and described in our January presentation, that potentially even half of that value is all that these patients typically see. Critically, a real need for Cyclin E1 high expressive patients.
Okay. Patient dosing has recently been initiated for the DENALI Part 2 trial in CCNE1 PROC to support accelerated approval. You've got this dose selection process between both arms in Part 2a at 300 mg versus 400 mg. What do you think is the likely dose that you'll select and why do you have to do this? What are some of the trade-offs that you're weighing between the two that will help inform your decision?
Yeah. Thanks for the question. You know, across our previous studies, which we presented in January, we had treated about 70 patients who were Cyclin E1 positive based on our cutoff in the PROC setting at the 400 mg dose. That was five days on, two days off, but only about 20 patients across these multiple studies at the 300 mg. Of course, you know, the point here for Part 2a is to confirm our preferred dose of 400 mg. In alignment with FDA's Project Optimus, really the goal here is to look at a patient population that is randomized one-to-one between 300 mg and 400 mg, where we can actually show the difference between the safety and the efficacy of these two doses in Part 2a.
This is really about, you know, aligning with Project Optimus, having a clear patient population who've had the same inclusion criteria for enrollment and can be compared. That is the reason why we are doing this dose comparison. It's not because we don't understand the efficacy or the therapeutic profile of these two doses, but it's really that we need to see these two doses compared in the same patient population in order to comply with that. That is the reason for it. Of course, the dose coming out of this will inform not only the balance of Part 2 or Part 2b enrollment, which will be at that dose, but will also inform the confirmatory phase III trial dose that would be intended for full approval, excuse me, full approval, you know, at that dose.
It's an important part of the study and one that just is more of a confirmation than it is necessarily trying to understand the differences between the two.
Okay. Since you mentioned enrollment, how is enrollment progressing thus far? When do you expect to be fully enrolled for Part 2a and Part 2b? I guess in between the parts, is there a brief pause where you have to decide on the dose and discuss it with the FDA before you can start enrolling Part 2b, or can you just continue forward?
Right. Really, really important question. So, you know, as we mentioned, we announced in April that we have dosed our first patient in the Part 2a. So we're off and running. We haven't provided guidance specifically on the completion of 2a enrollment, but we have disclosed that we expect top line data in all of Part 2a, that's 2a and 2b, by the end of 2026. After that, we'll share the completed data set. We can't provide an interim update, not unless we run the risk of introducing bias in the Part 2 study. You need to think of it a little bit like this. This is what we call a seamless design, which we discussed with the agency last fall, where we would post the dose confirmation between 300 mg and 400 mg.
We would continue to enroll at the selected dose without interruption, and that the complete data set of Part 2 would be used potentially as registrational data in an accelerated approval fashion. We likely will not share interim update, but we will have at appropriate time discussion about dose selection and confirmation and any outcome of FDA discussions. Those are milestones along the way that check the box of the study progress.
Okay. Yeah. I mean, historically, this trial has had no issues enrolling patients, right? You guys have enrolled hundreds of patients. I guess the focus here is not necessarily speed of enrollment, it's quality of enrollment and enrolling the right patients and making sure that you've got the right protocols in place. On that topic with DENALI Part 2, I believe you plan to enroll healthier patients with one to three prior lines of therapy as opposed to four or many with five plus. How would you expect this to change the benefit that you might see in these patients relative to the data we already discussed?
Yeah, it's a great question. We are restricting the prior lines of therapy in DENALI Part 2 to one to three prior lines of therapy. However, if patients have had prior MRV, then that would be one to four prior lines of therapy. In comparison to Part 1b, patients there had on average one to five prior lines of therapy. We have the expectation that we'll have the same requirement for our phase III confirmatory study as we have for Part 2. Expecting the same inclusion criteria for both of the potentially registration trials. We have conducted, you know, a subgroup analysis to address your question about differences looking at patients who were treated at 400 mg at the 5/2 schedule across the three studies based on prior lines of therapy.
You know, with a very large caveat that this is a smaller sample size, it's a subgroup analysis, you know, confidence intervals here overlap. We do see, however, patients with one to three prior lines of therapy had a better ORR and PFS compared to patients who had four plus lines of therapy. That gives us confidence that we may be able to move, you know, into our registration trials with potentially better outcomes. We did see this obviously in ELAHERE's ORR, which improved from 32% to 42%, and their median progression-free survival improved from 4.3 to 5.6 months between their phase II and phase III studies. We do not know if that will happen, but certainly would be great if that, you know, was the outcome here for DENALI Part 2 and for the phase III confirmatory trial.
Okay. As I alluded to earlier, as you enroll patients and run, you know, DENALI Part 2, you know, protocol and patient management is going to be important, especially with the new management team coming in here and running this trial. Can you just elaborate on that and what opportunities you see for you all and physicians to help kind of manage these patients better to make sure that azenosertib's tolerability and safety is improved versus the historical adavosertib experience?
Yeah. You know, Tyler, you said it earlier, you know, enrolling and managing a study from a quality perspective versus quantity perspective is obviously, you know, really important. And we've studied azenosertib in hundreds of patients across our clinical trials. And we believe that we have a really good understanding of the clinical profile, both safety and tolerability, as well as seeing consistent efficacy. When it comes to the safety profile for the monotherapy of azenosertib, this compares favorably with the published data from standard of care single agent chemo. This is quite known and manageable tolerability profile. For PROC patients who have been treated with rounds of chemo, you know, obviously previously they've suffered from side effects around neuropathy, hair loss, et cetera. A slightly different type of tolerability profile, but nonetheless, you know, well understood.
Patients and physicians here, you know, I think will favor a treatment that forgoes those kinds of side effects since they've already seen them. The same rationale actually may apply when patients and physicians choose between a zenosertib and potentially ADCs, you know, where the tolerability profile here for ADCs can be similar to chemo. Let me just address briefly the question about adavosertib that you bring up. When you go back and look and compare published data from adavosertib, az enosertib, certainly from a preclinical perspective and chemically speaking, is a more selective kinase. Therefore, we think will show a broader therapeutic window than adavosertib.
The clinical data that we've generated, you know, with the caveats, again, these aren't two studies that you can compare between the azenosertib studies and adavosertib directly, but we do show more dose for the azenosertib, the ability to have more dose intensity and better tolerated molecule in terms of selected GI tox, high-grade HemOnc, and other adavosertib published data. We do think a zenosertib compares favorably to the published data that adavosertib has presented so far. You know, we are supporting our investigators with protocol guidance around supportive care, commonly used medications for GI tox, as well as the use of GCSF, which is quite common for neutropenia. These are areas where providing more support and more guidance to our investigators we feel will result in potentially a higher quality outcome.
Okay. That's very helpful. For the phase III confirmatory trial that you referenced earlier, what do you have to do for that? What aspects have been aligned on with the FDA and what still requires discussion?
We will have some conversations with the FDA around the phase III confirmatory design a little bit later this year. We will be starting those discussions in 2025. Our plans are to initiate that phase III study in 2026 once the dose is confirmed in DENALI Part 2a. Of course, that will be a separate discussion with the agency to not only confirm the phase III study at that time, but also to understand the hurdle rates for success around the balance of Part 2 accelerated approval and around the phase III confirmatory design. You know, we're of course very well aware that accelerated approval studies, you know, require confirmatory trials to be largely enrolled by the time of regulatory action, meaning approval for accelerated approval.
We will align with the FDA around those specific phase III enrollment percentages to support that as we have discussions with them. Certainly, we think the guidance that the FDA provided at the end of 2024 helps us to inform where we think we will need to be, which may not be 100% enrollment, but we need to have that conversation with the FDA.
Okay. As we think about the addressable market, how large of an opportunity do you believe it could be for az enosertib and CCNE1- positive PROC?
Right. We certainly see there's an appetite and we think that's appropriate for patients who have certain selected elevations of biomarkers. We certainly saw the demand for that with the folate receptor alpha high performance of mirvetuximab. That was about 35% of the PROC population. We want to emphasize again, you know, we see being able to address at least 50% of the population in this setting. That estimate in terms of number of patients who may be Cyclin E1 positive in the U.S. and the EU and U.K. is about 21,500 patients approximately, of course. We think that there's a really large opportunity here. Of course, we'll continue to monitor, you know, trends in these populations, the identification of these patients, as well as the competitive landscape.
Okay. That's helpful. In the last few minutes here, we'll move to other indications. Several other trials are ongoing for Zeno, including the phase II TETON trial in USC. Maybe you could discuss, understood clearly that the priority is CCNE1- positive PROC, but maybe you could give the latest update on the USC program when we could get the next update as well as any other tumor types with azenosertib.
Sure. Absolutely. You're right. We've strategically and specifically prioritized the Cyclin E1-positive PROC indication as our lead based on the strength of the data. We think the competitive differentiation of the asset and the potential to move forward quickly if in an FDA accelerated approval pathway. The phase II TETON trial that you mentioned of monotherapy of azenosertib in USC is finishing up the enrollment. We are expecting a readout in the first half of 2026 for this study. We're also currently enrolling our combination trial of azenosertib and bevacizumab. This is a dose escalation study of the combo in the platinum-sensitive ovarian cancer population. We'll provide some more guidance around the timing of that data as that trial and enrollment progresses.
You know, these trials, and people may not be as familiar, but we do have some investigator-initiated trials in other tumor types such as triple negative breast and HER2 solid tumors. These all have the potential to provide signals or indicators where we could provide further examination of these tumor types and expand the azenosertib franchise and its opportunity. You know, the resources that we have, which we've allocated very specifically at the beginning of the year to our clinical program in pursuit of the Cyclin E1 positive PROC patients, can be potentially our first approval of az enosertib and establish really the beachhead for az enosertib to launch into other indications. We have great interest here and the data will come, and we will present that, especially in your question around the USC study in 2026.
Okay. I guess just to follow up on combos, is the, I guess the azeno-bev combo is the most obvious one given the lead indication, but are there any other combination regimens that you guys are excited about for azenosertib as you think about it potentially being a backbone? You mentioned HER2 positive tumors and triple negative. Would you potentially look to combine with ADCs ever or chemo?
Yeah, I think we would be really interested in an ADC combination. Obviously, we think while we think about that from a clinical pursuit perspective, that sequencing of az enosertib first to the Cyclin E1- positive patients is really important just given the short duration and the speed at which they progress. We think that this isn't really an or az enosertib or ADC. This is really az enosertib and ADCs or other therapies. These patients have very limited choices, especially the Cyclin E1 high expressors. We think that there's a really interesting opportunity. As I mentioned earlier, you know, we presented some preclinical data that really gives a foundational support for a clinical study of combination with microtubule inhibitors.
You know, I emphasize that one maybe a little bit more just given the overlapping toxicities of topo and az enosertib, but certainly we could think about how we could combine with either of those ADC regimens. We're certainly interested in that. If I have a dollar number three, that's where I'd certainly want to spend it.
Okay. Great. What's the latest or some cash runway before we wrap up here?
Yeah. At the end of Q1, we guided that we have $330 million as of March 31st, and this supports our runway into late 2027, you know, with again, the first dollar going to the azenosertib Cyclin E1 PROC population. Certainly we think there's really interesting other potential combinations or other tumor types, as we mentioned. Certainly if we see signals there, we're going to look for ways in which we can allocate capital, partner, or otherwise fund additional studies in order to expand this franchise further.
Okay. Great. With that, we're up on time. So Julie, thank you for your time and the discussion, and thanks to investors for attending.
Yeah, thanks everyone. Thanks for having us. See you later.
Bye-bye.