Great. I'd like to welcome everybody back to H.C. Wainwright's BioConnect conference. We're going to start continuing it with our afternoon session. My name is Andres Maldonado. I'm a biotech analyst here at the firm. It's my pleasure to welcome you. Next up, we have Zentalis Pharmaceuticals, and from Zentalis, we have CEO Julie Eastland. I want to give a warm welcome. Thank you for being here with us today.

Well, thank you, as always, for your great support and the invite. Grateful to be here. Thanks for those of you who are here in person. And for those that will be listening, I just want to take a moment to make a forward-looking statement, make my lawyers happy. Certainly, we're going to be talking about future projections and estimates, and so differences may result in actual reality. So we encourage you to review our filings with the SEC.

Great. So with that, let's kick it off. I guess a great place to start would be just to give a brief overview of the pipeline and walk through the company's current strategy, moving lead assets forward, just a macro view of what you guys have been up to.

Sounds great. So Xentalis is intensely focused on completing a set of registration clinical studies, primarily the first one for accelerated approval. This is called the Denali trial, where we're focused, a Xenosertiv, which is a WI-1 inhibitor, in the platinum-resistant ovarian cancer setting. So in this trial, we're looking to enroll patients who have one to four prior lines of therapy. And the data here, we do continue to expect top-line data at the end of the year in the Denali Part II trial. In addition to that, we have a Phase III confirmatory randomized trial called Aspinova. And we've started to enroll that alongside Denali in the same population. And that will serve as full approval. In addition to that, we are continuing to look to expand this franchise into other tumor types, and in combination, we have started an expansion study of azenosertive plus bevacizumab in the second-line maintenance ovarian cancer setting, and we're encouraged by combination data that will be coming up where we may look at the combination of azeno with other cytotoxic agents and other tumor types, So really helping to build out the franchise value for a Xenocertib.

Great. And for context, there's a rich history of development of Xenocertib and even We1s outside in the field. So it would be great if you give us some context on, you know, what gives you the most confidence that We1 inhibition through the lens of the cyclone E1 positive platinum-resistant ovarian cancer patients is the right strategy there.

Yeah, great. Well, about half of the platinum-resistant ovarian cancer patients have a high expression of the protein called cyclin E1, and that is really used to help cancer cells drive through the cell replication process. They use V1 as a break through that process so that they can repair and go on to replicate. When we block V1, especially in the presence of cyclin E1, we're able to drive these cells into mitotonic catastrophe. And that then creates tumor regression. So that is why this is not only important for ovarian cancer in the presence of cyclin U1, but more generally as a WI-1 inhibitor in other settings as well.

And maybe if you could talk next about, you've recently selected the 400-MIG-QD, five days on, two days off, dosing regimen.

Congrats for that. but give us a little historical context of why you know that's so important and why you know that decision was made and how should we thinking about given that that dose is now locked about the efficacy bars across all lenses and even safety in that matter yeah thanks that's a great question in denali part two we had a lead-in that did a randomized comparison of the 300 milligram daily dose five days on two days off against a 400 milligram dose we have substantial data from prior studies in these doses and it was important to study these together in the same patient population for purposes of project optimus and to really put the final check mark against the dose and what we saw was a significant difference in efficacy or activity between the 400 and 300 meaning 400 had a broader and more potent and meaningful activity level. At the same time on the safety side, we saw comparable safety between the two doses. So that made it quite a clear selection with better efficacy, similar tolerability to select the 400 milligram dose as the go forward. I don't think this was a surprise given the rich history of data with the 400 milligram and 300 in prior studies, But it was an important both regulatory and clinical de-risking to get the dose selected. So going forward, all patients in the Denali trial and the Aspinova trial will be enrolled at the 400 milligram dose going forward. And that will be our monotherapy P-ROC dose for the future.

Great. So maybe digging a little deeper into Denali's part two, Obviously, a lot of us are going to be focused on viewing the top-line efficacy of just ORR. Can you talk a little bit beyond that, particularly around how should we be thinking about either duration of response, PFS, and just consistency across the patient subgroups in the study?

Yeah, thanks. That's a good question. Certainly ORR, primary endpoint for the Denali trial, sort of the meaningful and in prior studies, really the primary endpoint for a single arm accelerated approval trial. Duration of response, PFS or secondary endpoints in that trial. And by subgroups, I think you're sort of meaning patients who've had different prior therapies. We can think about mervituximab. We can think about patients who've received prior taxanes, both as single agents as well as the newly approved combination taxane agents. And what we expect, as we have seen, is that Zenoserto should be able to have a very meaningful response post these different subgroups, as you might call them. They're not technical formal subgroups, but they're certainly different segments of the population. So what's meaningful? Well, at the end, patients really have the benefit of single agent chemo as salvage therapy. And those responses are somewhere in the 4% to 13% overall response rate. And we've seen historically with the Xeno at 400 have consistently above 30% response rates, including mid-30s for response of valuable patients. So that's a very meaningful difference over an all-comer population of 13%. And Cyclone E1 patients typically have worse outcomes, poorer prognosis. So that makes that difference even larger for these patients. When it comes to duration of response, that's always important. What we've seen here is prior studies approved somewhere between five and six months of duration of response. And then when it comes to PFS, that's likely less meaningful in a single agent trial. But I think if we see differences there, then obviously that's supportive.

Great. So digging a little further into the context of that 30% ORR with five to six month duration of response, I guess, you know, looking at the developmental landscape in P-ROC, does that still the bar? And how does that kind of influence, you know, what could make the FDA view Denali as an accelerated pathway?

Well, we've talked to the agency several times about the Denali trial and the Aspanova trial, including the design and the primary endpoints. We'll talk with them again regarding the recent data that we've had with our dose selection. But if you think about, again, the standard by which we're looking at accelerated approval here in a single arm, it's against ORR, against a backdrop of really salvage chemotherapy. So while the current landscape has had some new approvals, these taxane combinations, we're going to include those patients, obviously that's the Part 2C cohort, and show that we can treat these patients like we can with other single-agent taxane or even for those that are folate receptor alpha high from ribetuximab, where we can see these robust responses that are significantly different than salvage chemotherapy. So we think that bar is still the right bar. And, of course, you know, that conversation with the agency is yet to be had, but we'll have that now that we have the dose data.

Great. And just following up again on Denali's Part IIc population, you know, particularly on the inclusion of patients with prior taxane, And I guess help us understand what incremental data that that could give, you know, for the labeling, long-term real-world positions in terms of maybe market size or strategy going forward if it is included on the label.

That's a really good question because I think when you think about the accelerated approval pathway from a regulatory perspective, you certainly want to make sure that your population represents today's population where they can receive these approved therapies. So new approved therapies this year included a couple of taxane combos. Of course, mervituximab's been approved, and chemotherapy's been around. So having a study population that is representative of today's approved agents is important. However, when you think about this from a commercial perspective, you really want to think about the differentiation of this asset. This asset is an oral, non-chemo option for biomarker-selected patients. So as you come in, and if you can imagine the patient journey, who's come in, who's been diagnosed, who's gone through surgery, who's had chemotherapy, then has gone on to have a PARP inhibitor, bevacizumab, and now they're platinum-resistant, and they're coming into this setting. And their options are what? Chemo? Combination chemo? Single-agent taxane? More chemo. And patients really want a break from chemo because they have added effects of neuropathy, hair loss, et cetera. So offering at least those patients, which is about half of the population, who are cyclone E1 high and providing them a treatment option that gives them a chemo break that has a high correlation to response based on historical studies, we think that this is a great option from a commercial perspective to really offer these patients something different. And so we think that this should be positioned in front of other chemo, which they can always go back to afterwards. So I think there's a regulatory perspective of making sure you can treat patients in the landscape, but there's really a commercial positioning here where this agent really is differentiated, not just in today's agents, but I know you're going to ask, but in the coming agents, which are what? ADCs, which are what? Directed chemo. So there's still an opportunity here to give people an option for a drug that really correlates. to their particular biology to give them a benefit of response prior to going back to more chemo, regardless of whatever form that is.

Great. And maybe in the interest of time, a couple of questions on the Aspinov study. So looking back on your interactions with the FDA around the confirmation of the Phase 3 study, how do you balance starting early enough to support accelerated approval while still kind of preserving the ability to optimize enrollment and execution on that study? And if you could maybe remind the audience of what the Aspinova study is.

It's very simple, actually. So Aspinova is a phase three global study. It's a randomized study of a Zen assertive in patients who've had one to four prior lines of therapy in the P-ROC setting. Pardon me, one to three prior lines in the P-ROC setting versus chemotherapy choice for investigators. So those include the current sort of slate of chemotherapy options. The primary endpoint there is PFS, and secondary endpoints are OS. And this study will be about a 420 patient trial. It will be global. And we have, last year, talked to the agency about this design to lock in the design so that we could operationalize it here for the beginning of the year. And we announced, I think in May, that we started the enrollment in Aspenova. And we're doing that for a couple reasons. One, this is a companion trial to a single arm accelerated approval study where the agency wants to know that you've started your randomized trial and you have the majority of it enrolled. So important to get enrollment going. But additionally important for us is that particular control arm in Aspinova. This will be the first randomized trial of cyclin E1 positive patients who are screened prospectively to come into the trial and to show how they really do against today's single-agent standard of care with chemotherapy. And this will be the first really randomized data set here. What this does is really helped, again, to solidify that cyclin E1 patients behave differently. And if that control arm shows that, that will be very informative and helpful from an agency perspective in understanding that this is a different bar for these patients. And so while we shoot for a bar of success for all comers, we may actually be even providing greater benefit to these cyclone E1 patients. And I think the Aspinova trial will certainly help with that, but it's designed for full approval. It'll be a global trial.

And maybe looking at Aspinova, you know, Denali and beyond, you know, one of the kind of big concerns historically with We1 inhibition, you know, has it's come with some tolerability issues. so i guess what have you learned about you know managing the gi the fatigue or any kind of the hemological events you know with the xeno and i guess with the locking in of the dose for denali you know how much of that profile was driven by a schedule driven versus site education versus just proactive monitoring yeah no it takes all of that i mean the reason we do clinical trials is to learn how to use an agent and what we need to do is take those learnings and apply it

in our trials going forward and in denali 1b we learned primarily that we have a new tool for physicians in this setting this is the first oral agent it's first non-chemo agent but importantly it's an oral agent and up to this point physicians really have had to in their armament for ovarian infusions or surgery and so here this is a different touch point with patients so I think the learnings from the prior can be applied to Denali Part 2 into Aspinova and making sure that there is both physician and patient expectations and frankly when you look at the tolerability profile across 400 in the prior studies this looks like any other cytotoxication and oncology it it really doesn't look any worse, and even when you think about the hematological toxicities of neuropathy, or not neuropathy, excuse me, neutropenia, you can see that grade 3 events here are low double digits, whereas you see in some of the ADC trials reported neutropenic rates at 45% in grade 3. So I think if you really take a look at this in its totality, it looks as expected. What's important there is making sure that patients and physicians have the tools they need to manage these tolerabilities just like they do in any other setting. So that is something that we've really applied to Denali Part 2 and Aspinova in ensuring that physicians know how to use GCSF in the context of this oral dosing schedule to really limit neutropenia getting beyond grade 2. And then in addition to that, putting into place measures to ensure that patients have anti-diarrheals or anti-nausea medicines out there ready if they need them, instead of having to wait and get a script and get a fill, that they're ready to go should they experience that, which is not the majority of patients. So I think it's just good planning, good education, and a real opportunity to help physicians as we grow in the number of sites and the experience on how to use this drug. It's sort of similar to the CDK4 experience from the past where physicians and patients just needed to learn how to use a new agent.

Great. So it seems with the dose in hand, good safety profile, and everybody waiting for the Denali 2B study coming up in the fourth quarter here, I guess, could you talk a little bit about just the basic cases of where you see a xenocertib fitting best into the treatment sequencing? sequencing, you know, given that a lot of these patients have seen everything under the sun. And then if you could add a little bit of context of where do you, what, which one of those variables do you think physicians and patients really hone in on the most?

Yeah, maybe just going back to the sort of, I think the important three components here for ovarian cancer, this is an oral non-chemo for biomarker selected in PROC. And so to parse those out in terms of what's important you know oral very important i think this is convenience for patients it presents a different touch point with the patient so again that's a learning about how to to to talk to your patient how to look at your labs for your patient a little bit different than an every three week infusion at the infusion center so i think that's important that's certainly important i think for patients in that they don't have to come into an infusion center once a week and spend their day when they're in in sort of this stage of disease but the non-chemo is i think incredibly important to patients they have experienced chemo throughout their treatment chemo has added effects with neuropathy so to experience more chemo is really asking patients to really continue in that vein and a real suffering so i think both of those are really important and if you're cycling e1 positive and you know that you won't do as well on standard therapy to have an agent that's directed to you so um i it's like asking me which child do i like i think they're all three very important for very different reasons but in combination i think it's really powerful um opportunity they all have good qualities yes so i guess one quick question on the companion diagnostic can you talk to us a little bit about what still needs to happen to you know make that practical at launch you know how are you thinking about you know tissue availability turnaround time and just the brass tacks of uh of physician adoption in the community versus academic setting so it's a really great important question because the companion diagnostic is obviously a companion to the therapeutic so um the company has done a great job retrospectively identifying a cutoff having an assay that is reproducible and that assay then is used to prospectively screen the patient so that's part of the validation process and we are preparing and readying our regulatory process for approval to be co-simultaneous with the therapeutic and we're working with a brand name company that we will use to continue with our pathology development, like much you would do with your PA market development, you're going to do with pathologists, and to really commercialize this assay so that it's available when patients have surgery. Their archival tissue is then sent to a centralized lab to be assessed for their cyclin E1 protein with this standard IHC assay. And that will then start paving the way to ensure that at the beginning of patients' surgical resection, that they know whether or not they're cyclin E1 positive. It's a market build, much like Ella here had to do for imervituximab. So certainly something that is not a new path to TROD. We just need to do it with our assay.

Maybe in the last minute here, I would be remiss if I didn't ask about your strategy, which looks at earlier lines in ovarian cancer of Xenoceratid plus Bevacizumab. I just really quickly, if you could leave us with, you know, what is the right proof of concept setting there, And, you know, how does that tie into the whole, you know, ovarian cancer kind of ecosystem?

Yeah, so that is an expansion of Xenocertif plus Bevacizumab in the second line maintenance setting. So their patients typically have about a three-month PFS with Bevacizumab. And so we're looking both for safety combination. We're also looking for a signal there that can be then really applied across first and second line maintenance because these are patients who've progressed while on a PARP inhibitor, come into second line induction where they get paclitaxel, and then come into the maintenance setting where they get bevacizumab. So we see this as a life cycle management opportunity for Zen Assertive, and you'll see some upcoming data at ASCO where we combine in the Muir trial with paclitaxel as well. and you'll see clinical data there showing the combination of a Xenoplus pack which can be very useful not just in the setting of ovarian cancer but potentially as proof of concept in combination with cytotoxic agents that might be useful in other tumor types as well. So we're really excited about the data coming up.

Great and I think that's all the time we have left. I want to thank Julie for being here and on behalf of the whole Wainwright team congrats on all the progress thus far and we look forward to future updates.

Thank you. We're excited. Thanks, you guys, for listening. Appreciate it.