... I think we'll get started here with the next Fireside discussion. So my name is Derek Archila. I'm one of the senior biotech analysts here at Wells. Very excited to have Zentalis Pharmaceuticals with us for the next discussion here from the company. We have Julie Eastland, CEO and President, as well as Ingmar Bruns, the Chief Medical Officer. Thank you so much for joining us.
Yeah, thanks for having us. Appreciate it.
So, Julie, obviously, it would be great to understand kind of your vision for the company here as you've kind of taken the role over, as CEO, and just really try to understand kind of the priorities for the next 6 - 12 months.
Yeah. Thanks. Thanks. And again, thanks for inviting us to the conference. We always appreciate an opportunity to talk about Zentalis and azenasertib. So certainly a priority for us over the next six to 12 months is going to be moving our registration-directed studies to a conclusion. And that is the DENALI study studying azenasertib in patients who have cyclin E1 protein overexpression in the platinum-resistant ovarian population.
That is our first indication and the first place we're going to go. We've made a very clear and strategic decision to focus the company to get to an answer as a first indication for azenasertib. It has a lot of opportunity outside of that, but it's obviously enrolling our trial. It's managing and understanding how we need to educate the market, being a first-in-class agent here, a non-chemo oral option for patients in this setting that don't have that. So a really unique opportunity for physicians and patients to have a different experience, and especially for this biomarker selected population.
So that is our focus, both market education, enrollment of the study, just clinical execution, and then, of course, you know, continuing to meet with the regulators to ensure that we have sort of a clear path to accelerated approval, and the start of our phase III confirmatory study. So a lot to focus on-
Sure
... for the next 12 months, but all focused on azenasertib and cyclin E1 overexpressers in platinum-resistant ovarian cancer.
Got it. Maybe taking a step back, if we go to, you know, kind of this, the mechanism and then the differentiation between, you know, the legacy adavosertib and, and azeno. You know, I guess, what do we know today, and ultimately, what else do we need to know in the future based on some of these trials, you know, in terms of that differentiation and really driving that home, you know, with, with not only just the investor community but also with the physician community?
Yeah. Maybe I'll just start broadly and talk about the differentiation of azenasertib to what's available, and I'll let Ingmar speak to sort of the adavosertib/WEE1 space. But certainly there is a clear differentiation here with a small molecule oral agent, as I mentioned, a non-chemo option, where standard of care for these patients is non-platinum chemo, which is just more chemo that they've already experienced.
So, we think this is not only an opportunity from a molecule differentiation perspective for patients, but then also the high correlation that we've seen of azenasertib to outcomes for the cyclin E1 over expressers consistently on our historical trials is a very meaningful basis, a clinically active agent that has a population of patients that have a high unmet need.
So from a differentiation perspective, we're talking about a biomarker selected population, has no targeted therapies available to them, and we have very clear correlation of azenasertib response in this patient population. So we think a good basis, obviously, to create an opportunity for patients and an opportunity for Zentalis. And maybe I'll let you speak to our adavosertib question.
Yeah. So I think we do think that based on the data that are in the public domain for adavosertib, there is a differentiation, certainly a differentiation based on the schedule, also, you know, the dose and exposure we can reach. Much more patient and provider-friendly schedule with a five on, two off, and you know, the higher exposure, which we believe correlates with efficacy.
But there's also, of course, with all the caveats of the cross-trial comparison, you know, there's a differentiation, our view on the key adverse events for the toxicity profile for the class, right? Mainly, of course, some cytopenias, as well as you know, which is probably more relevant, the GI toxicities, which can be managed well. But, clearly there's an advantage, again, with these cross-trial comparisons for azeno.
Gotcha. So maybe shifting to just talk about DENALI and the 1B. So I guess, you know, what should we expect from that data? What, again, ultimately driving some decisions, too, around dose. But I guess, you know, how, what should we kind of interpret from that data set when we get it?
Yeah. So the DENALI trial was a multi-part trial, is a multi-part trial.
Right.
In part one B, that data we did present earlier this year that looked at response rates, both in the total population as well as in those patients that met the proprietary cutoff for their cyclin E1 overexpression, and what we saw there was very meaningful ORR compared to standard of care chemo, a doubling, almost tripling of response rates, for a patient population that is known to have poorer outcomes, even standard of care chemotherapy, which ranges response rates between 4% and 13%, may not even be that advantageous for these patients. We'll find out-
Mm-hmm
... in our phase 3 confirmatory study, but there is literature out there that does show that these patients don't do as well. So we know from a basis, just even in DENALI part 1B, at four hundred milligrams, five days on, two days off, that we have a very clinically meaningful and relevant response for these patients and duration of response for these patients. So in Part 2 of DENALI, which is the single arm registration study, there are two components to Part 2.
Part 2 A and part 2 B. In part 2 A, we're running the initial dose confirmation, Project Optimus, comparing three hundred milligrams and four hundred milligrams, five days on, two days off. This is really part of what we need to do as part of the sort of Project Optimus completion for dose confirmation. We have significant data at both of those doses across multiple historical studies, but running those two doses in comparison in the same population is a standard requirement. I think importantly, in conversations with regulators, we don't want to delay our march to accelerated-
Mm.
-approval, and so DENALI Part 2 is what's called a seamless design, so we won't stop enrollment as we complete and select, the dose, and we talk with the agency. We'll continue to enroll, and once we've had a conversation with the agency, around the dose that's being selected, we'll drop that dose and complete the patient enrollment, to get to about a hundred total patients at the selected dose for all of part 2 for purposes of registration filing, so this is really a way for us to, be mindful about timing and to be expeditious in the execution of DENALI Part 2, so we expect that data, which is prospectively screening patients who have one to three prior lines of therapy, unless they have mirvetuximab, then that can be four prior lines of therapy.
But this is a prognostic selection of patients based on our proprietary cutoff of an IHC assay looking at cyclin E1 expression. And so we're now prospectively screening and enrolling just those patients that meet that biomarker-selected criteria.
Gotcha.
We expect to see hopefully similar or better responses than what we've seen historically over many studies of single-agent azenasertib at these doses for this patient population. And a lot of that data, again, we presented in January of this year. It is available as a rebroadcast on our website, but we're highly encouraged that we're seeing consistency of that across clinical studies. We certainly expect to see that here in DENALI Part 2.
What do you expect in terms of the differences between the 300 and the 400 dose? I mean-
Sure.
Would that be material? I know you're saying you have to kind of do it, so, like, but is there really gonna be, like, material differences there? And I guess the other question from, I guess, our standpoint is, you know, do we have to wait for data, and, you know, until the very end, or, you know, even with the dose that you drop, could you show some of that data just to give us a clue of, like, you know, how things were looking? And again, if they're not very different, then maybe, you know, a little bit of a clue there.
Yeah. I'm going to let Ingmar-
Yes
... talk about the first part.
Okay
which is the difference between three and four hundred, but we'll come back and tell-
Okay
talk to you about when we expect to share data and why.
Yeah. Let me start by saying we, we do believe that, exposure correlates with efficacy and response rate in this case, right? But, we also starting from a point where one has to say, 300 milligram, as Julie said earlier, wasn't in DENALI Part 1B, so it's a, it's a cross-trial comparison of a relatively small number of patients. And we believe in this cross-trial comparison that the, tolerability and safety is broadly comparable, but, the efficacy seemed higher in 400 milligrams, right?
And clearly, with a difference of, 10%, in the ORR. But the 300 milligram, cohort, in this case, was also more heavily pretreated, and again, with all the caveats of small numbers and a cross-trial comparison, right? So we do think it's a true opportunity, right, to compare them head-to-head and in this kind of gold standard, randomized, prospective, fashion here in that case. And we'll see which one wins. We do believe that 400 is our primary dose of interest.
Okay.
Right? But at this point, I think we're also seeing this as an opportunity to compare that side by side.
Yeah. And I think importantly, three hundred is an efficacious dose. I mean, in again, the earlier-
Yeah, that's true.
... studies, more heavily pretreated patients, we're talking about mid-twenties. In terms of response rates, that's a doubling of standard care. You know, we're at 400, again, in the cross-trial comparison, we're seeing ten basis points higher in response rates, so sort of mid-thirties. And so we'll see, as Ingmar said, how that bears out in the same population in a one to three line of prior therapy setting. And importantly, though, we know it's efficacious, and so it's great to have an opportunity to have multiple doses that we know patients can benefit from.
I think our preferred dose from the data that we have historically appears to be 400, and again, that's the whole point of this is to compare them side by side. I want to get to the question you asked about data. We've made it very clear our next data milestone will be top-line data from all of Part 2 of DENALI, that's part A and B together. And the reason for that is because we've agreed to this seamless design to be able to move quickly. And so all of the patients from part A and from B will become part of the filing dataset. So to stop and provide data in the middle of the trial could mean that we end up, you know, penalizing ourselves-
Yes
... or delaying, you know, our ability to enroll this trial, I think, in a quick fashion. But of course, we will select a dose. We will have conversations with regulators, as you imagine, and there may be messaging in the marketplace about that selected dose, and our future plans. So, we'll continue to provide updates as we go along. But clearly, we all know that that dose selection is something that, you know, we will have FDA conversations with when we're at that point.
But we haven't provided guidance there, and right now we don't expect data in the marketplace from a clinical data perspective until we get to top-line data at the end of 2026. If we can find a way to do that and not bias the trial, boy, we're all open to it. But I think, the important part is, speed, and preserving that clinical data set for accelerated approval.
Gotcha.
Even more general statements-
Yeah.
Sorry to add that, right? Even more general statements will be meaningful, though, because there's an IDMC involved, right? So basically, if we disclose that dose has been selected, then you need to assume that, you know, this is meaningful in terms of efficacy as well as-
Yeah.
Tolerability.
That's right. Yep.
Maybe just in terms of trial enrollment and kind of, you know, current investigator enthusiasm around this, I mean, obviously, like I said at the beginning, there's been some fits and starts with WEE1. Like, you know, does it seem like that it's enrolling quickly? And also, is the enthusiasm still high, you know, for this mechanism?
Yeah. I'll just speak to the study is on track for enrollment and for our stated data guidelines. So I think we can say with a pretty enthusiastic perspective that we're on track and enrolling. And then Ingmar gets to speak with investigators on a regular basis, and certainly, I think what we're hearing back, Ingmar, is that physicians are super excited. Again, the premise remains the same. A non-chemo oral option for patients in this population is still an option that is highly sought after.
Nothing's changed with that. If you like the profile of azenasertib in 2023, you're going to like it today because it hasn't changed from an opportunity perspective, and physicians, I think, remain very optimistic about that. Ingmar, you want to-
Yeah, that's really the feedback that we're getting, right? I couldn't say it better. You know, the support is there. There's a lot of enthusiasm, and frankly, without disclosing any numbers here, it's very active in terms of the screening activity.
Yep.
Gotcha. So maybe the broader strategy with the azeno in terms of, like, where you want to take it. And ultimately, I think one of the key components that we had always heard, you know, about WEE1 is, you know, is it combinable? Right.
Mm-hmm.
Like, again, particularly back with the adavosertib.
Mm-hmm.
So I guess, how do you kind of feel about combinability and then ultimately, you know, future Zentalis combo trials?
Yeah. I think for starters, just taking a big step back, looking at this molecule historically. You know, this molecule's been in over 700 patients, either a single agent or in a combination setting, and so we have a really well-characterized tolerability profile or safety profile for azenasertib. I think that's not as appreciated, that it's really there's a lot of experience with this agent.
Of course, in combination, you want to make sure that when you're combining, you're combining because there's either standard of care or there's a synergistic effect, and you're looking, of course, at ways to manage the tolerability profile of both agents in combination. So there's been in our 002 study, a number of arms of combination, not only with chemo agents, but also we are currently doing combination with bevacizumab in earlier lines of ovarian.
That's sort of a dose escalation combination. And, you know, we believe, and from what we've seen in the past, that it is certainly able to be combined with other agents. And the question really is: is what's the right landscape and the tumor type? I would say secondarily, and I think importantly on everybody's minds, are ADCs, so I'll say it. And certainly, we have a lot of great preclinical data that we presented over the last year in combinations with multiple ADCs, regardless of payload, whether that's TOPO1 or microtubule inhibitors, where we see a synergistic effect with with azenasertib.
And that creates a incredibly broad opportunity in a number of different tumor types where ADCs are playing a role, not just in ovarian cancer. And so we see that as a future opportunity from a clinical setting perspective. And then, I'll just say lastly, maybe not as talked about typically, is on some ongoing investigator-initiated studies, looking at combinations with standard care in HER2-positive tumors, as well as in triple-negative breast cancer.
So again, an opportunity in other tumor types, and if we see signals there, and combinability there, that certainly would be an area we want to continue to expand on. And again, it's about resources. We've been very deliberate to focus our resources on getting the next big milestone for azenasertib, which is get it to market. And then we will continue to explore the opportunity to allocate capital, if we have it, to expand on some of these signals that we may see. We think there's a real opportunity for azenasertib, well beyond cyclin E1 high expressers in ovarian cancer.
Gotcha. And then maybe, you know, just kind of talking about, so when we get to the end of Denali, and you report out data, you know, I guess, what do you think is going to be, you know, clinically meaningful? I mean, the bar seems pretty low, but I guess, you know, what do you think gets physicians excited, and ultimately, how do you think this gets adopted into the practice? Like, where do you think it starts to fit into the treatment algorithm?
Yeah. I think the historical data gives us a really clear understanding of what is a reasonable bar, as well as other analogues that have already been approved. You think of mirvetuximab data in this setting, and we've already seen sort of a meeting or exceeding of that bar. I'll let Ingmar talk about, you know, sort of the physician use, placement of this in the treatment paradigm.
Yeah, and, and Julie already alluded to it, right? So we've seen 35% ORR and, you know, as reported as per the SGO presentation this year, 6.3 months of MDOR, which, you know, with the time of the data cut ongoing patients, so kind of subject to change. But that's strong data, and that has been perceived as such, right? So that's really the feedback that we're getting.
So from investigators, if we, you know, have a new site contact, which, you know, over recent months, I had plenty of, some of them see the data or see the data as a reminder, and they're super excited about that because it really is a game changer for what it is.
And, you know, we see this in the light also of some earlier, ADC data, as you just mentioned, right? Where the OR is maybe a little bit higher in the 50% range. But that, of course, comes also with some additional baggage on the, safety and tolerability, and then eventually, as happy as we are for patients, for sure, in that setting, you know, to me, they're all one drug, right? Because, as we see, there's TOPO1 inhibitors and TOPO1 inhibitors.
Mm-hmm.
I think that's really what drives-
Which is really more, you know.
What's kind of driving the resistance, right?
Gotcha. So I guess, you know, when you think about the opportunity, like the market opportunity for Zentalis in this specific population of patients, again, where do you think that kind of lands? And ultimately, this would seemingly be not, you know, this is kind of like more of a beachhead situation.
Yeah.
So, like, again, how do you kind of view the longer-term opportunity after-
Yeah
... you know, again, maybe you have more resources to further develop?
Yeah, really a very, you know, nice correlate that's already out in the market. So just to reset, you know, our cutoff of cyclin E when protein expression is such that we believe 50%, at least, of the PROC setting would be benefited or would be eligible for azenasertib, and that's 50%. We'll see how that bears out. We think that's a pretty conservative but appropriate allocation of the market opportunity. Mirvetuximab with folate receptor alpha high has about 35% of the market opportunity in PROC. So we're talking about a slightly larger market opportunity overall.
When we look at the enthusiasm of the uptake of a biomarker-directed agent with the folate receptor alpha population, and we look at the analyst or other estimates of peak sales there to be about $2 billion, which, you know, gives them credit, mirvetuximab gives them credit for not only PROC, but maybe potentially some PSOC. But nonetheless, that's a pretty meaningful opportunity, where we think we have at least that or better, with a larger opportunity in the marketplace. So, you know, I think we see a very viable, valuable beachhead.
And then when we think about expanding it to earlier lines of ovarian, when we think about using the agent in combination, even with ADCs in later lines of ovarian or ADCs in other tumor types, you know, we really get into a much larger, sort of opportunity for azenasertib. Which I think has been the promise of a WEE1 master regulator of cell cycles. It should be applicable across a number of different tumor types. We still think that's relevant. We just need to allocate our resources so we get to an answer and then expand from there.
Gotcha. And again, you guys have been presenting, you know, the data along the way here, obviously, big read out, obviously, DENALI, but is there anything that we should be expecting, you know, in the next, you know, six to nine months, in terms of just other key learnings or, or anything else that's kind of incremental ahead of DENALI?
Yeah, we've we will, of course, talk about, as we mentioned, some of the regulatory and the clinical updates around DENALI, but also around the phase III, which will be, you know, enrolling, obviously, to ensure that we can meet the guidelines that are required for accelerated approval and to get full approval. We have some other studies that we've run, and as we look at that data, we will provide updates to the market. We did promise an update to the market on our TETON trial, which are our USC indication, our uterine serous carcinoma indication.
And so, you know, these are signal finding studies and should they warrant further, you know, sort of value attributes, meaning allocation of capital, then we'll look to see how we can do that. But I think we really want people to focus in on where we're spending our capital, where we're spending our focus, and what is the real opportunity for valuation here for patients. And therefore, for Zentalis is, in this initial indication. We can't keep spreading our-
Yeah
... resources too thin. We've got to get to an answer.
So I guess, you know, kind of based on your conversations, like, where do you feel like the story is, like, underappreciated? Like, is it basically it's kind of, you know, following the story for a while, there's kind of a maze of data, there's a lot of different things that have kind of happened-
Mm-hmm.
... over the years. I think you've done a good job kind of cleaning up the narrative-
Mm
... making it very succinct and telling, you know, this is where we need to focus.
Yeah.
But I guess, like, where do you feel like, you know, people may still not get the story in terms of, is it the safety? Obviously, there was a partial hold back in the day. Like, so I guess where you think that occurs right now?
Yeah, I think it's a really good question, and we have worked really hard specifically to create a really clear strategy and narrative about where it's going, and I will tell you just from feedback, from conversations we have, that is greatly appreciated, so I think that was an area where people wanted to just understand which lane we're swimming in, and how we're going to get to the end of the pool, so I think that's been very, very valuable, and that we know that we have the resources to get there with a runway beyond that, so I think all of that is actually speaking to interest in the molecule and in the company.
Of course, because there is an overhang around the clinical hold from last year, and that overhang really was around the fact that people needed to understand what caused that and why the FDA lifted that hold without any modification to dose and schedule. That, that communication, which was, maybe not done as complete last year, is what we've been working on to help the market understand why the FDA saw what Ingmar and I saw and Haibo saw before we came into Zentalis. Sort of the totality of this tolerability data that actually looks you know, quite promising.
And of course, responses in this population, which are very meaningful. So we see, again, a therapeutic index, this molecule that's really attractive. And what we need to do is help people to understand and see that data. And then, you know, of course, I think as we enroll the study and get to dose confirmation in Part IIa, I think that will be meaningful to investors as well. Do you have anything to add?
Yeah, just to the, I mean, you mentioned the clinical hold, maybe.
Sure
Provide a little bit more color around that as well, right? I think Julie already said it. I think it comes really down to lack of communication in the past, right? Because the FDA, for that matter, Julie mentioned the seven to eight hundred patients treated. They had never seen the totality of the data, right? And, understandably, when those two deaths occurred, where, you know, I think the company made the right decision to err on the side of caution and saw them related or attributed them as related. But, you know, there's certainly alternative explanations for that as well, right?
But for that matter, not having seen the data, the FDA decided to put the program on hold, but then, as Julie said, lifted it without any request for change, which is pretty much, I would say unprecedented, but rare, right? And so I think that's really what this is, right? And it still is a bit of an overhang because, you know, it's the whole situation without the nuance and the context around it.
Yeah. So we're working to help clarify that, and I think, you know, the, again, in January, when we did a company webcast and presented the historical data, we also talked about the situations around those events that led to the clinical hold. It provided context around the patient situation. And so if people have time to go back and listen to that, it's worthwhile to kind of understand these are very different situations that had a lot of confounding factors to them.
Nonetheless, a Grade 5 event is a very serious event. And I think what it really, Ingmar saw as an opportunity was to come in and look at measures in which we can again, that's why I talk about medical education, how we can educate the physicians and the sites about the supportive measures they can provide to patients. Really, you know, an oral agent that you send home, you know, send your patients home with a pack of pills, is not the same as surgery or sending them to the infusion center.
It's an opportunity to help physicians understand how this agent works, how they need to manage their patients, and what are the supportive measures that they can use, which are very common if you think about ADCs, with 45% Grade 3 neutropenia in some cases. We have 12% Grade 3 neutropenia. It should be managed in terms of hematotoxicities, as long as we have kind of the education and the tools. A lot of that work we've put in place, and Ingmar's group has done a great job in that. So we, you know, are working to have a different, obviously, outcome.
Gotcha. And I guess, you know, as you think about, you know, future development plans, I mean, how much is partnering or, or at least collaboration around azenasertib?
Yeah.
You know, there was a lot of interest around WEE1. You know, is that still the case, you know, given some of the data?
Yeah, I mean, I think there is a lot of interest around WEE1, and the totality of the data certainly is in favor of agents that target WEE1, and we know that there's earlier companies with other agents targeting WEE1. The way we sort of think about partnering is certainly a philosophy of does it bring as an asset to a broader group of patients and faster or faster? And so we're certainly interested from that perspective, just in terms of lead indications, that we will always listen to ways in which we can do things larger and faster.
When it comes to expansion opportunities, I think there's a real interest in thinking about some of the ADC combinations or other combinations where there may be some interest in partnering, of course, you know, certainly from our side and potentially, you know, from others, as well. So, again, I think we're climbing out of that 2024 penalty box. You know, what's true for the medical community, the investor community, is likely also true for the strategic community.
So as we continue to develop and march this forward and meet regulatory and clinical milestones, I think we'll continue to think about what's the right vantage point to think about getting that additional support, either with our lead indication or importantly, with other abilities to franchise, as an asset.
Maybe this last question, just in terms of like, you know, maybe just tee up some of the milestones beyond Denali. If there's anything else that we should be focused on, you know, in terms of just internal or external, you know, catalyst, you know, with WEE1 or azenosertib.
Yeah, I think, you've talked about most of them. You know, it's the end of 2026 for top-line data for accelerated approval. It's going to be conversations with the agency around the phase III design and then the initiation, of course, of the phase III for supportive measures. And then outside of that will be any signal finding or data that we present in these other settings, which, you know, we will determine when we see data, what and where to present. But certainly, we won't be shy in sharing information as it comes along the way.
But I think this is really a clinical and regulatory, sort of story, for the purposes of getting to accelerated approval in this setting. Those are probably the biggest milestones that people care about: dose selection, phase III design, and accelerated approval, top-line data.
Are there any-
They're pretty big.
Like, external catalysts that you're tracking from, like, competitive, like looking at competitive landscape?
Yeah, you know, I think people are rolling along. Let's take ADCs as a bucket. You know, those are coming, you know, note, TOPO1 ADCs are probably gonna be used in the marketplace. So somebody's gonna probably win that race, and we think that's great for patients, and we also think that's an opportunity for azenasertib in combination, because we've seen synergy there. We also think it's important to make sure that this patient, this biomarker-selected population that doesn't do as well, gets a drug that we know correlates to outcomes first.
It's important because the longer you wait, the less effective every therapy is going to be in the line, you know, further down in the lines of therapy. So, you know, positioning azenasertib is important when it comes to looking at the future landscape. But it's not an either/or, it's an and opportunity. And then for other agents that are coming along, you want to talk about Corcept, which obviously had recent data and is on its path for accelerated or potential full approval?
Yeah. So we think, of course, you know, in the same vein, we're happy for patients, for additional treatment options here. But we also, you know, have a couple of questions around the registration path and how fast this will be, of course. And then, lastly, and probably most importantly, how many patients want to be retreated with chemotherapy, especially, you know, nab- paclitaxel has largely the same profile as paclitaxel, and those patients already had it, right?
They, you know, many of them have neuropathy, hair loss, things like that. And, you know, how attractive, in that case, the combination, and, you know, to a certain extent, that's probably also true for a pembro combination.
I think at the end of the day, they're all chemo options that are coming along, whether they're in the new form of chemo option in ADC or in this combination. Really, what will set azenosertib apart is this being a non-chemo option. That's certainly an important part, and it's oral, so convenient, non-chemo, you know, multiple potentially efficacious doses to help physicians manage patients' treatment over their cycles.
I think we're good there. Thank you much.
Thank you for having us.
Thanks. Great. Thanks, really.