Hey, everyone. Thanks for joining us here. I'm Matthew B. Biegler. I'm an analyst here at Opko. I cover Zentalis. Always a pleasure to be here with Julie Eastland, CEO, and Ingmar Bruns, CMO. Guys, welcome. You're new-ish, I'll say, to this story. You've got a track record of turnarounds stories, though, Julie, most specifically coming up, Harpoon. What was it that interested you about joining Zentalis?
Well, first off, thanks, Matt, for having us, and we always appreciate the attention and the coverage. It's a great question, and I'll answer that. I think the same reasons that I looked at Zentalis as a great opportunity, I think Ingmar did as well, and we joined together in the fall of 2024. What we really saw here was a very large body of data, clinical data and preclinical data, but certainly the clinical data that supports azenosertib as the first oral non-chemo treatment here for this biomarker-selected population in the PROC setting.
The results that we've seen to date really demonstrate a meaningful benefit for these patients with response rates over 30% and approximately six months in terms of duration of response. You know, this in the context of single-agent chemo, you know, non-platinum setting, where you see single to low double-digit response rates, a very short duration of benefit there for patients today. A high unmet need, an agent that we have that we think is differentiated and needed in this setting, that's really been well-characterized over hundreds of patients in terms of its tolerability and safety profile.
Again, you know, we think there's a clear opportunity here to improve the opportunity for patients in this setting who've seen nothing but chemo coming into this part of their journey.
I would agree. I mean, you mentioned large body of data. I think by my notes, I have over 500 patients treated as a monotherapy or in combination. You've tested dozens of different dosing schemes and schedules, clear activity in patients that have failed all other options. I guess my main question, and I think probably all investors' questions, is: What needs to happen to finally get azenosertib across the finish line and approved?
A perfect question, you know, and the main question, right, that I think Ingmar and I were thinking about in 2024, that we executed on starting in 2025, That's really focusing this pipeline and the opportunity for this agent to get to patients. By doing so, really designing two studies. First, the DENALI trial, which is a multi-stage clinical program. We're in Part two of that DENALI trial, That Part two is designed to be potential accelerated approval pathway for azenosertib in these PROTAC Cyclin E1-positive patients. That is a trial that is ongoing and enrolling.
We provided an update at the beginning of the year that we completed the first part of the DENALI trial in terms of enrollment, which is the dose lead-in portion. We continue to enroll in that trial and expect to have about 100 patients at the selected dose to read out the study by year-end, and that would potentially serve for accelerated approval. Of course, the agency has been very clear on their advice for accelerated approval pathways, and that is the importance of having a confirmatory randomized trial to go alongside that.
We announced at the beginning of the year that the now-branded ASPENOVA trial, which is our phase III confirmatory study against single-agent chemo, will support full approval in the same setting, so same population. What is going to get this to patients is going to be these two trials, first, for accelerated approval in the U.S., and then, shortly following on thereafter, full approval with the phase III, randomized confirmatory study.
Makes sense. I still do get-- I think probably the primary pushback I get lately on the name is, you know, PROTAC, obviously great for patients. There is more competition now. You're seeing some ADCs targeting Folate receptor alpha that might work regardless of the biomarkers. I think the biggest question on investors' minds is, like: Is accelerated approval still an outlet for you? Yeah, I mean, make the case for us why you think that is, and if you want, you know, you can include, you know, some of your interactions with the FDA in terms of what they have said.
Sure. I think that's a, that's an important, you know, last point. Maybe I'll start with, you know, FDA interactions and, you know, sort of talk about some of the areas where we think, you know, we've had those conversations with the agency to align around the accelerated approval pathway that was done in 2024 when the DENALI trial was first designed. In addition to that, you know, of course, we had discussions with the agency around the ASPENOVA design for Phase III, and at that time, of course, had discussions that DENALI could still serve for accelerated approval.
I think we have consistent team, and certainly Ingmar can talk about that, but the FDA has been, you know, a great team. They've been consistent, they've been responsive, we continue to believe that should the data support these pathways, obviously, in the setting, that are registration pathways to accelerated approval is something that we certainly have got in alignment with the agency on at this point. In terms of why it should matter in the market, let's remember that patients have had multiple rounds of chemotherapy coming into this setting, the standard of care really still is chemotherapy, whether it's single agent or whether it's combinations, and ADCs effectively are chemo regimens just in a targeted approach.
They all require IV infusion. Here you have a lot of patient time in the chair, and you don't have an opportunity here for convenience, and again, for a non-oral regimen. azenosertib really hits the mark, importantly, both in being a non-chemo option and a break from chemo for patients, you know, taking away some of the tolerability effects and the short duration. For agents like ADCs or for chemo, we really want to give another opportunity here for patients to have something that we know correlates to this biomarker-selected population, which typically has been shown to not have as favorable prognosis as the total population.
We also don't think that ADCs are an or in this setting. We think it's an and we certainly welcome the fact that patients are gonna have multiple agents in which to help them through their journey, and that azenosertib alongside, and importantly for this biomarker-selected population who may not do as well, is gonna be an important part of the treatment regimen. That ADCs are certainly a great option to come back to chemo for patients after they've had a lot of chemo. Eventually, we've seen preclinical data where we have nice combination effects with ADCs and azenosertib. This is really an and, not an or.
Got it. I mean, just in terms of convenience, as an oral, all-oral option, it seems to me like this would be a kind of a quality-of-life benefit. I mean, I think every single treatment up to that point would've been actual time in the chair, which is no fun for anyone that has cancer.
That's right. I mean, Ingmar can talk about this, and certainly patients that we talk to, this is really a key area of, you know, differentiation that's important to them. You know, Ingmar, you've said before, it can take an entire day out of a patient's life, and when you get into this stage, some of these chemo is weekly. You know, every week you're traveling and preparing and sitting in an infusion chair. This is, you know, really an important opportunity for patients to, you know, have a better quality in terms of convenience for treatment.
Yeah. Ingmar, do you wanna add anything to that?
I think I just reiterated, right? You know, none of these patients, unfortunately, will be cured, right? Quality of life and convenience is a really big factor, of course, you wanna extend the quality of life. I think, you know, responses and, you know, sufficient duration of response does that. You also don't wanna, as Julie already said, you don't wanna spend a day, which it always turns out to be in a hospital setting, right? You know, weekly is, of course, extreme, but it's true with, you know, paclitaxel . That's, you know, actually the cadence then.
Even with, you know, alternative, newer, treatments who are infused, you end up with a full day, right? Every two weeks, every three weeks. That's also, if I take a loop back to, you know, your previous question, around the FDA support, I think that's what they... You know, I don't wanna speak for the agency, of course, but, you know, I think that's what they really clearly see is that there is a need for an oral, convenient, treatment option that really gets to the patients where they are. Most of these women, of course, are a little older, and they're probably not living right next to the next cancer center.
This really brings a lot of additional quality of life while still being efficacious, and in the end, of course, actually, relatively well-tolerated for an anticancer drug.
Yeah, I agree with that. I do get questions on kind of the extent of your regulatory interaction. You know, just maybe even over the past 12 months, to the extent you can tell me, it's clear you've got buy-in on the ASPENOVA design confirmatory trial. Do you still need to meet with the agency to kind of iron out the recommended Phase II dose for the Part 2B of the DENALI trial? Is that kind of the last checkbox we're waiting for here?
That's an important checkbox, obviously, to get the data from Part 2A of the DENALI trial, which is the 2-dose randomized portion of the trial. Certainly, you know, if that is still, of course, enrolling in both dose arms, even though we have sufficient patients to analyze those two doses, we're just, you know, letting the patients' data continue to mature, as we get that dose selection. You know, if there's any ambiguity there, then obviously a conversation's gonna be important, but we think that that will be clear, and that we will, you know, obviously have information going to the agency, and that is something that we will do, before we have sort of a public view on our dose.
We wanna make sure we have sort of full confirmation internally and with the agency as we move forward.
Is there plans to inform the street when you have selected that dose for Part 2B?
We do. We will.
Gotcha. In terms of gating factors, I mean, it sounds like right now you're kind of recruiting and over allotting patients into both doses before you hit that gating factor, and then you can enroll and recruit just in that single dose, right?
Yeah. I think Ingmar always says it really well. There's gonna be a minor inefficiency here as we enroll in the arm that won't go forward. What it does do is it allows us to continue to enroll in the select dose that would go forward, we're looking to get to about 100 patients, of course, in that trial, to serve as the basis. Patients from Part 2A and from the balance of the enrollment after dose selection will collectively serve for the FDA filing, for the NDA filing. Important that we, you know, speed is always, you know, important to us, and doing it in a way which, you know, we know is in a quality way for patients.
Certainly, you know, nothing more important than the time value of money, right? To get the drug to patients here as quickly as possible.
Do you anticipate a real clear difference in terms of the 400 and 300 mg dose in terms of both safety and efficacy? I think I remember, yeah, maybe it was from the PARP inhibitor setting, where you also tested both doses, and it looked like there was definitely a marginal efficacy advantage to going higher at 400. Didn't really seem to sacrifice a lot in safety either.
I think that's right. Ingmar, do you wanna kinda just revisit that data? 'Cause, the integrated analysis we presented at the beginning of 2025.
Yeah
really helps to answer that.
You're right. There's, you know, marginal differences on the tolerability side, right? There's slightly more pronounced AEs on the heme side, a little bit more GI, but it's relatively minor. We also think that, you know, with a different approach to, like, trial management and supportive care, that those improve over what you've seen in the past. In the integrated analysis, there is a pretty relevant difference in delta in the overall response rate, right? That's why we actually, you know, embraced the fact that we had to do the dose confirmation here, because we've never, in the same trial, of course, compared both doses, right? Because it is, a, you know, a cross-trial comparison.
The short answer is yes. The safety and tolerability should be very comparable. We expect, of course, a difference in the efficacy based on prior data, but that remains to be seen, and we'll have the answer fairly soon.
Talk a little bit about the biomarker, why you think that Cyclin E1 overexpression is a good biomarker, and you're looking at both amplification and overexpression. I know there's been some translational studies in the past where amplification, definitely patients with CCNE1 high amp, like, do worse, a worse prognosis. I don't see it as much on the IHC, but maybe, you know, you've tested this in so many patients at this point, like, is it a kind of a data-driven decision?
I think this is a super important point, because gene amplification certainly drives Cyclin E1 overexpression. But we've also shown that there's a substantial number of patients who don't have gene amplification, but do have high Cyclin E1 protein expression and do correlate to response. We don't want to miss patients just because we're looking at gene amplification. Keeping in mind that sometimes other transcription factors lead to Cyclin E1 protein expression, as well as the inability of the protein to degrade, slower protein degradation, other transcription factors, and gene amplification can drive Cyclin E1 protein overexpression.
It really is the protein expression levels, which are measured with the IHC assay, and the cutoff there is determined based on a substantial number of samples that were derived retrospectively from clinical studies of azenosertib in the PROC setting, including our ZN-c3-001 dose escalation trial, the MAMMOTH trial, and of course, the DENALI among others, but that data really drives the rationale as to where that cutoff should be in correlation to meaningful responses, and it includes patients both who are amplified and patients who are not CCNE1 when amplified.
That is why it's important, because physicians, we don't want them to miss patients who could potentially benefit simply because they're looking at just gene amplification as a marker. Important to test all patients to see if their protein expression levels for Cyclin E1 really correlate here as a potential opportunity for azenosertib to benefit that patient.
You think you've done enough work at this point to validate the biomarker in terms of both, like, cutoffs for IHC and for amplification?
Yeah. The data to date has been retrospective, obviously. The DENALI trial now is a prospective screening, and a lot of that data, of course, in 2024, was shared with the FDA. We've done a lot of work there, like I said, several, you know, 100 samples looking at that cutoff. The validation is always done in these registration trials, and that's what the prospective, you know, selection of the patients based on the IHC will provide the necessary regulatory sort of validation. We certainly feel from a clinical perspective, that there is a lot of data to provide validation across multiple studies, seeing that cutoff, being selective for responses. It's not just one data set and one study, it's really across a collective set of studies that we're seeing that.
If we just focus on DENALI, the first part, let's say around 30% ORR, a little bit higher, around six month DOR, I'm assuming that's kind of what we're thinking for the bar for part two. More importantly, though, you know, this drug went on clinical hold for reasons we don't necessarily need to get into. Do you think actual ORR and DOR can improve? Because I feel like a lot of patients were, you know, subsequently lost follow-up after the drug went on clinical hold. I'm wondering if with the more mature data from part two, it would actually look better.
Yeah. Ingmar, do you want to approach kind of the bar as well as how we see.
Yeah.
- you know, changes in DENALI part two?
Yeah. As a first, I think we agree with the bar, right? You know, there is certainly precedence, you know, in PROC with mirvetuximab, but there's also the feedback that we're getting from our investigators or, you know, KOLs in general. That, you know, excitement is there with, you know, a response rate around 30% and, you know, the duration of response around, I think, five to six months. As you know, we've shown in an analysis that there's even above six months in 1B with 6.3, which, you know, is pretty exciting. That's, of course, that we're, you know, something that we're hoping to see again. Yeah, to your question, if it can improve, it's true.
There was some disruption here by the partial hold. But I think what's more important even, we had a chance to really apply lessons from, you know, the prior trials, right? Also, after having a chance to analyze them and, you know, have a bit of a deep dive on the data where possible, right? So we certainly clarified and streamlined the use of supportive care. All the recommendations or mandates for supportive care are very clear, very clearly visible. That was truly important and will make a difference, right? I think the main point is really closer trial management, not because the drug is particularly toxic.
We really don't think that, despite the history, and I think the data we're seeing confirm that. Every trial where there's limited experience, you know, as you know, there's always sites, if you expand your footprint there, that I've never seen the drugs, have no experience, and, you know, you can, of course, do SAEs and try to educate them, but in the end, the learning process is with the drug, right? Treating their patients. Initially, toxic or not, right, even a very well-tolerated drug like azenosertib benefits from closer trial management, right?
Yeah.
When you follow the data, you know, have an eye-level relationship with the investigators and the sites, and you oftentimes see that, you know, there's any potential deviations in the supportive care or anything around the patient, and you reach out and alert them, right? Given that we have very extensive experience with hundreds of patients here, this is also, you know, very well accepted. Actually, you know, the sites, appreciate that.
Yeah, honestly.
So, uh-
It's a great-
Sorry, go ahead.
I would say, it's actually, you're prompting my next question, which is on safety. I wanna talk a little bit more about that, cause and I wanna push back on some of the notion that I hear that this drug is just inherently too toxic. Cause when I look at, for example, like the salvage chemo arm of MIRASOL, I mean, it looks pretty consistent in, I think as I know, might even look a little bit better in terms of like dose reductions and discontinuation. Kind of like how are you thinking about the safety profile of the drug?
Yeah, I appreciate the question. I think, you know, as I said a couple of times, I actually think it is despite the history and, you know, this overhang based on the hold and actually manageable and quite well-tolerated drug, right? Especially if you compare it to alternatives, both experimental as well as standard of care. You know, there are some metrics there that, you know, are a little bit misleading in our opinion. It's too early to provide the proof, but we're really convinced that some of the metrics we've seen, like discontinuation rates, in one B, they're in an unfortunate way, an overestimation of things because.
Then again, comes back to, you know, the approach of trial management and oversight. Now, whenever there's something that doesn't seem right in the EDC or any reporting that doesn't seem logical or obviously wrong, every day our clinical scientists.
Grade AEs were categorized. If you look at discontinuations that were protocol-defined AEs, you know, here we're in the high single digits, which is definitely in line with other novel cancer agents. You know, there's a lot of, you know, in addition, we're not dealing with neuropathy, hair loss, and other sort of related items that maybe chemotherapy does. I think you're spot on, and this is the one area, which is why I think it's worth spending the extra minute on.
With just Aspenova, the confirmatory trial, the design from a high level, it looks a lot like Mirasol, which obviously led to the full approval, of mirvetuximab. Any, like, really kind of like high-level differences that you think people should be aware of?
Yeah, Ingmar, you want to go ahead with the ASPENOVA design?
Yeah. We do agree. You know, it looks like MIRASOL because that's still, you know, the valid approval path for PROC here. The only difference, of course, is that we will select for Cyclin E1 positive patients, which I think is particularly interesting because they're, you know, believed to have really poor prognosis and poor outcome from any treatment, actually. It will also be very interesting to see the control arm with single agent chemotherapy, right, side by side. The other difference is that the trial has an adaptive dose randomization run in.
That's really something to accelerate things. It already helped to accelerate the conversations with the agency to even get started on the phase III. you know, it's also an option that in case we have not selected a dose from DENALI, when we initiate, then we can, you know, nonetheless start the trial. The majority of the evidence is still expected to come from DENALI, if not all. We can basically enroll the adaptive part, we cannot enroll it at all, or we can enroll a few patients with the majority, again, of the evidence coming from DENALI.
Makes sense. The last question I have, which I think is a really interesting question, though, is, you know, of course, the first thing investors do is they look at MIRASOL, they look at how the salvage chemo arm performed in that, and then they do a cross-trial comparison to DENALI Part 1B, and they're like, "Well, DENALI doesn't look that much better." Is the MIRASOL control arm a good proxy? These are FR Folate receptor alpha positive. These are not CCNE1 high patients, and I feel like CCNE1 high patients tend to have a worse prognosis. Would you agree?
Yeah. There's no difference really that has been demonstrated between the Folate receptor alpha high and all comer population. We do think it's a good proxy. However, you know, as mentioned already, you know, with the Cyclin E positive patients certainly demonstrated for Cyclin E or CCNE amp patients have poorer prognosis on center of care chemotherapy. Therefore, I think, you know, the expectation is, given that overall, we think there's no disadvantage of using protein expression versus amplification, as Julie already explained, we're expecting poorer performance of the control arm here on the trial even.
Yeah. Awesome. I think we're pretty much out of time, but thank you so much, Julie and Ingmar, for walking us through this story. I think it's gonna be a really, really exciting year for the story, and obviously a very, very pivotal one as well. Thank you for spending the time again.
Yeah, good to see you. Thank you so much for the invite.
Absolutely.
Thank you for having us.
Thanks, everyone, for joining.
Have a great day.
Thanks.