Everyone had a great long weekend. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining TD Cowen's 7th Oncology Summit. For our next session, we have a Q&A with Zentalis, it's my pleasure to introduce Julie Eastland, the CEO and President of Zentalis, and Ingmar Bruns, the Chief Medical Officer. Julie and Ingmar, it's a privilege to have you both here. Thank you for joining me.
Thanks, Tyler. We always appreciate it.
Of course. Before we get started with the discussion, for those of you in the audience, feel free to email me questions at tyler.vanburen@tdsecurities.com. You can also use cowen.com, but again, that's first last, and we'll do our best to get them asked before the end of the discussion. Also, as you all may know, our favorite season, which is Extel voting season, kicks off today. The TD Cowen Biotech team would appreciate your support if you feel that we've earned it. With that, we'll go ahead and get into questions, beginning with the phase I-B MUIR ASCO update. You all just reported phase I-B MUIR study data evaluating azenosertib plus paclitaxel, and we have potentially more coming at ASCO this weekend.
It'd be great if you could start with, I guess first, why you decided to explore this combination and the key takeaways that we saw from the abstract, and as well, what we could expect this upcoming weekend.
Yeah. First off, thanks so much for having us. Of course, as always, we appreciate the opportunity to provide a forum where we can do Q&A. Before I begin, as is a reminder that during today's chat, there will be forward-looking statements made. These are based on our current beliefs and assessments and may be subject to significant risks and uncertainties, so we encourage you to review our recent filings with the SEC. I want to get to, of course, your question on the phase I-B MUIR study that will be presented at ASCO. We did put out a release, and we're really excited about the combination here.
I think the reason that this was originally pursued in the MUIR trial, which is a multi-part study, the first part being combinations with cytotoxic agents such as paclitaxel, is that this really shows an opportunity here biologically to add to the already ongoing replication stress that these agents provide, with azenosertib then providing this additional benefit for these agents. We first wanted to obviously show, and we will be discussing at ASCO in a poster more broadly, four doses that were studied with the azenosertib plus paclitaxel combination. This is in the platinum-resistant ovarian cancer setting. In this combination, we are showing here that there's a demonstrated safety profile that is manageable in combination with these two agents, and especially at the potentially optimal dose of 250 mg once a day for five days on, two days off.
The efficacy here, I think, Tyler, was important in that it really showed an added benefit of these two agents together over historical benefit of paclitaxel alone. This was not a randomized or comparison trial, but just looking back at the historical data of paclitaxel in this setting. We think that this makes a lot of sense to do. It certainly does allow us to think about the broader application of azenosertib, not only in earlier ovarian lines, but also potentially as a way to think about combination in other tumor types. Oh.
I'm on mute. My bad. Thanks for that. Just to be clear, any meaningful updates or changes between the abstract and the full presentation this weekend that we should expect?
The abstract cutoff was the same for the poster as it was for the abstract. The basic takeaway message will remain the same, but there will obviously be greater detail and more context on the poster.
Understood. What other tumor types are you all most interested in beyond ovarian?
I'll turn that to Ingmar. Do you want to talk about that?
Of course. We're certainly interested in early lines of ovarian. You asked for the tumor types beyond ovarian. I think we're seeing really broad potential here based on the mode of action, and I think this data set that will be presented at ASCO, and you just discussed with Julie briefly, shows the potential. How to really go beyond ovarian cancer, especially in combination where you probably don't need the Cyclin E1 overexpression, and can combine all comer population, essentially. There's a lot of indications also based on this data set, not limited just to this data set, where paclitaxel is still one of the key backbones. Think breast cancer, think other solid tumor indication, larger ones actually, where taxanes play a role for sure. Again, that's not limited to just this data set.
We also see it as given that we're looking at a spindle poison here with a taxane combination for some of the vedotin or DM1, DM4 type of ADCs. Where spindle poisons play a role and, of course, that's a bit of a longer shot, but we've previously presented data on this as well. For us, this is really while this particular data set matters and this particular indication matters, it's really something that shows broader relevance here as well.
Okay, that's clear. Thanks for that. Let's move to DENALI Part 2. By the way, for the audience, instead of emailing me questions, you can actually submit it via the portal that you're viewing this fireside chat at. I've got a dashboard up here where I can see your questions come in, feel free to do that. Moving to DENALI Part 2 and the pivotal development program. Maybe for those who are less familiar, you could start by walking us through the design of DENALI Part 2 and the different cohorts and how it's intended to support an accelerated approval strategy.
Yeah. DENALI is a multi-part study. We are currently enrolling Part 2 of DENALI. This is designed to support accelerated approval, of course, pending positive study outcomes, and additional discussions with the agency. The study design here consists of three components. I'll call them by parts as well. Part 2A was a dose confirmation which evaluated two doses at 300 mg and 400 mg, each with about 30 patients enrolled in each dose group. Back in April, we announced that we selected the 400 mg 5:2 dose, that's five days on, two days off, as the optimal monotherapy dose in the PROC setting. The second part then enrolls all patients at that selected dose at 400 mg. This is Part 2B, and that will enroll about 100 patients between Part A and B combined, all at the 400 mg dose. This cohort is currently enrolling.
We announced in April as well that we added Part 2C. Part 2C was an opportunity really to broaden the study population, and is expected to include up to approximately 40 patients who've been previously treated with taxane-containing regimens in the PROC setting. This is really to ensure that this population aligns with the overall treatment landscape that continues to evolve, of course, in PROC, which is really great news for patients.
Thanks for that. What was adding the Part 2C cohort with paclitaxel, was that in response to regulators or KOLs and investigators or all the above?
No, it really wasn't. We thought last year as we saw some potential new entrants that there would be an opportunity here to ensure that we really strengthened the data set for DENALI Part 2 with taxane-containing regimens. Obviously, we already have patients who have prior taxane exposure in the trial, but this was an opportunity to continue to add to that some of these combo taxanes, as well as just ensuring that there was, again, a broadly representative population of patients who had the opportunity for these, what could potentially be newly approved agents. We were sort of looking ahead and thinking about what we might do here to add some additional sort of strength to the population with regard to taxane-based prior exposure.
Understood. Regarding the decision to move forward with the 400 mg five on, two off intermittent dosing regimen, can you give us more color around that, what you saw with the data set to pick the 400 mg, and if you saw significant difference in efficacy or safety between the 400 mg and the 300 mg?
Yeah. Ingmar, I'll let you talk about.
Yeah. Happy to. Yeah, Julie just outlined the different cohorts in DENALI. Just as a quick reminder, Part 2A enrolled 60 patients, where 30 patients were randomized to each of the doses. Dose groups, comparing, again, the 400 mg five on, two off, which we had seen in Part 1B already. Then 300 mg, again, intermittent schedule five on, two off. There was a pre-specified interim analysis after each patient in cohort 2A, and it had two post-baseline scans. In this interim analysis, we'd really seen meaningful and clearly differentiated response rates at 400 mg versus 300 mg. The safety and tolerability profiles were actually comparable between the two dose groups. We saw some, and that's important, encouraging improvements in a few key tolerability measures that were observed in Part 2A versus Part 1B, especially including the discontinuation rate due to adverse events.
There was, for those who remember Part 1B, pretty high. Approximately half of that was observed there, and there were no treatment-related Grade 5 events in Part 2A. Also a difference, too. While they were very rare, but what was observed in Part 1B. In summary, that's really a very straightforward decision based on the superior efficacy of 400 mg, and then essentially comparable safety profiles between the two dose groups.
Great. Thanks for that. Yeah, it's been very encouraging to see safety improve with the new studies and the new team. Kudos to you all on the execution there. I guess, as we think about the potential pivotal DENALI Part 2 readout later this year, how would you all like to set expectations for efficacy, in terms of what you hope to see to lead to approval, but also significant uptake in the setting?
Ingmar , you want to go ahead?
Yeah. The efficacy data that are in the public domain, they're of course around Part 1B, right? As you know, Julie just described, Part 2 is designed for patients with one to three prior lines of therapy in case of folate receptor alpha-high-expressing patients and mirvetuximab eligible four lines. I should say, that's, as we know, a relatively small fraction of patients around less than a 1/3. That's compared to DENALI Part 1B, which, again, was one to five prior lines, but had a median of three prior lines of treatment. We'll have to see how many patients we get, despite the more narrow eligibility for Part 2A, who just received one or two prior lines. Whether then the median number of prior lines of treatment will be meaningfully different.
If that's possible, then we might see a less heavily pretreated population in Part 2, and you may remember a quite small, admittedly, but post hoc analysis of subgroups based on prior lines of treatment that we've done, that shows that clearly fewer lines of treatment show better response and duration of response. Again, it's not a pre-planned analysis, but the results were very clear. I also want to mention that it's possible that we could end up with a patient population that's very similar in terms of prior lines of treatment to Part 1B. Also given that the treatment landscape, of course, has changed a little bit, and there we've really seen across a number of trials, as mentioned before, MAMMOTH, even the original dose escalation, a very, very stable response rate across those trials in somewhat comparable patient populations.
When you think about Well, that's very helpful color, when you think about the response rate, what do you think is the minimum threshold for response rate that you guys want to see for, again, broad uptake and approval? Is it like 30% or ±5% or?
Yeah, I think that's accurate. 30%, ±5% is fine. That's fine from a regulatory perspective. That's really the impression we get from regulators. That's also the impression we get from thought leaders and investigators globally on the trial, that they think it is definitely a meaningful improvement on single-agent therapy and chemotherapy. In terms of duration of response, somewhere between five and six months is certainly superior over what's been shown with single-agent chemotherapy. Actually, what's been shown with some of the real-world data on targeted drugs herein. We think that's really appropriate. Of course, that's from a regulatory perspective, subject to further additional FDA feedback, but that's where we see a meaningful efficacy outcome.
Okay. Will duration of response and PFS be mature enough to report that later in the year, or should we just expect top-line response rate with safety?
Yeah. The primary endpoint is of course ORR, right? That's also very clear, based on FDA's guidance here. We currently expect the top-line readout on the primary endpoint by year-end, and then we'll see how mature duration of response and also PFS will be by year-end. That, of course, depends on when the last patient is enrolled and followed up for a sufficient time. We certainly aim to characterize those endpoints as well and as we can, we'll provide the top-line readout. We may not have mature enough information on those endpoints to be able to really provide specific estimates.
Okay, that's helpful. On the safety front, I imagine, I guess you want to replicate or confirm a similar kind of discontinuation rate and rate of AEs. As we approach the readout, maybe you could walk through the adverse events of interest and that you guys are most closely paying attention to, and where you think the bar or the threshold is in terms of like Grade 3 rates to see broad uptake in the treatment setting.
Yeah. Ingmar, do you want to talk about-
Yeah, I think-
Safety profile?
Go ahead.
Nope. Just handing it over to you.
Yeah. Well, I think we really think what has been generally demonstrated and is in the public domain for Part 1 B, apart from, of course, the discontinuation rate, actually shows a very safe and tolerable profile, right? As I said, we see improvements on that, and that includes neutropenia rate, that includes discontinuation. It, of course, even though very rare events on Part 1B, and somewhat idiosyncratic, includes the G5 event, the Grade 5 events, of course. I think, in terms of where we think it should be, it is what you've seen, right? It is also compared to the evolving landscape compared to still very relevant competition of single-agent chemotherapy. It's really a fraction of the cytopenias that we're seeing, right?
We're have actually a 1/3 - 1/4 of the cytopenias, neutropenia in particular, that's being observed both with chemotherapy as well as with some of the ADCs that we're seeing here. Overall, the majority of the GI effects, so this, again, as a reminder, there's three groups. There's the cytopenias, there's the GI effects, and then there's fatigue. The effects that we see in the gastrointestinal side effects or adverse events, they're mostly low-grade, and they're very well manageable. Also that's true for fatigue. The number of high-grade events that's being observed is not as high.
We think that overall, this shows, in the dataset that's out there in the public domain, shows a very well-tolerated drug in line with, of course, the benefits of the route of administration as an oral drug, which gives tolerability and gives, of course, the independence and convenience of an oral administration. We think what you've seen with some improvements that I just pointed out is pretty much the bar we want to meet.
Yeah, importantly, this agent isn't going to layer on additional neuropathy or other sorts of therapeutic type of profile, which is important for patients who've experienced that already coming into the setting.
Well, there's some differentiators Sorry, Tyler. There's some differentiators, of course. You know those. There's no observation of neuropathies, there's no eye toxicity, there's no ILD, there's no hair loss, right? All things that, even though not super frequent, they're scary and very limiting to patients. That's not something that's been observed here, besides the groups of adverse events that I just outlined.
Yeah. Since you touched on it, there's several client questions, but two of them are related to ADCs. One asked about the preclinical data, AACR, which shows significant activity in ADC-resistant models. Another one, she talked about the ASCO data, which showed that it worked in all comers with paclitaxel, and the NCI has now expanded beyond CCNE1 amp in with T-DXd in ENHERTU combo trial. Just essentially both are asking about how you think about azenosertib sequencing post-ADCs and in the evolving treatment landscape. Maybe you could just elaborate on that a bit.
Yeah, maybe just touching base in the ovarian setting, but then we can also touch base. As you mentioned at AACR, we had a nice poster looking at azenosertib's potential opportunity in a PDX model in triple-negative breast cancer. We can talk a little bit about that evolving landscape. We definitely see here an opportunity. I want to keep in mind that the profile of this agent for Cyclin E1 high protein expressers is a biomarker-selected agent in the PROC setting. In particular in PROC, where we think this matters may not be as relevant as you start thinking about combinations or other tumor types, but certainly in the PROC, we certainly see a benefit to this biomarker-selected population. You've got an oral agent. It's not a chemotherapeutic agent.
It could potentially have combinability, and so when you think about the ADC setting that's coming potentially in the PROC, we think that that's great for patients. They have an opportunity to have more agents. Those agents that they've had coming into the setting have been primarily chemotherapeutic type of agents. Coming into the setting, they have more taxane or chemotherapeutic type of options, whether that's single agent or combination agent in terms of taxanes, and now they potentially have additional new chemo, i.e., ADCs. Our agent, of course, is specifically here for patients who have Cyclin E1 protein, so we've got an oral non-chemo biomarker-directed profile that we think for these patients that we've shown, again, at AACR, real-world data and our own data that shows that Cyclin E1- positive patients don't do as well and likely have poorer prognosis.
We see this really as a sequencing event, Tyler, twofold. One, really, we see an opportunity for patients who are Cyclin E1 high to have an opportunity to potentially respond here to the agent, where we've seen certainly enhanced and correlated responses to azenosertib monotherapy in the setting for those patients. If they progress, to go on to other agents such as chemo or other ADCs. Secondly, of course, in time, we'd love to see combinations with some of those ADC agents as we've seen in the triple-negative setting, where we see really added benefit of azenosertib with both paclitaxel and other ADC combinations. That could be also true here in the PROC setting or in the broader even frontline ovarian setting, where we think ADCs will continue to evolve into the earlier landscape.
We think there's a clear lane for azenosertib and PROC as monotherapy, and we think there's a huge opportunity for azenosertib in combination, both in ovarian and outside of ovarian.
Okay. Wonderful.
Ingmar, if you want to talk about ADC-resistant opportunities for azenosertib in triple-negative, but Tyler, we'll go where you want us to go in terms of questions.
Yeah, you could touch on that briefly. Unfortunately, we're well over time here, and we have the next session starting.
Oh, yep. We could go on forever.
Yeah, it went fast. We have a lot to discuss, but fortunately, we've still got a good amount of the year left leading up to the pivotal data. Apologize regarding the timing.
Nope.
Great discussion with you all. Julie and Ingmar, thanks so much for joining. For those listening in, UroGen is up next, starting now.
Thanks, Tyler. Have a great day.
Have a great day.
Thanks, everybody.
Take care.
Thank you.