Conference Transcript - ZNTL 2026-06-03

Akash Diwari, Analyst — Jefferies

Good afternoon, everyone. My name is Akash Diwari. I head our farm and biotech research efforts at Jefferies. It's the pleasure of hosting the Zentalis management team. Julie, why don't I hand it off to you for some intro remarks, and we'll get going.

Julie Eastland, CEO

That sounds great. Well, thanks again for inviting, and we're glad to be here. Appreciate the time. Xentalis is uniquely and very specifically focused on bringing a Xenassertif to the market, with our primary focus in developing this agent for patients who have cyclin E1 high protein expression in the platinum-resistant ovarian cancer setting. That's our primary first step forward, but this is an agent that has a lot of promise in a number of different ways. And today we can talk a little bit about how we see P-ROC as our first step in a journey for a Zen assertive in combination and in other tumor types. So we're excited today to get our homework done, get P-ROC in, and then think about how we can extend that elsewhere.

Akash Diwari, Analyst — Jefferies

Understood. And I definitely want to talk about moving beyond ovarian, but I actually wanted to hit on ovarian first and really on the fundamentals because you know it's interesting well not even interesting it's remarkable that there's so many new agents in development for ovarian cancer that's great for patients as well but I don't think we're thinking about hey what does that mean if we have drugs that are help you know doubling overall survival in the frontline setting what that means in kind of the refractory market the sense was always well refractory late line PROC is a smaller opportunity, and it might be today. But as these next-gen therapies get into place, there's a downstream effect that I think materially changes maybe the size of that market. Help us think through, when we think about PROC today, how many patients and how long are patients really on treatment in kind of a third or fourth line setting, and how that might actually evolve over the next five years as new therapies, particularly ADCs, get established?

Julie Eastland, CEO

I think it's a great question, and Ingmar can chime in, of course, as well. But when you think about the options for patients today in the PROC setting, you're really talking about mostly single-agent chemo or other taxanes, now some new approvals with some taxane combos. These all sort of have the same sort of therapeutic benefit in terms of being these chemotherapeutic type of agents. And so patients here typically, and in particular in a total population, see response rates that range anywhere from 4 to 13 percent when it comes to single agent historical chemo and today as they've journeyed through the setting and become platinum resistant they've already seen a lot of chemotherapeutic like side effects with neuropathy with hair loss etc they really want to see a break from that and so I think as NO offers an opportunity there for differentiation in terms of its tolerability profile but in addition specifically for patients with cyclin E1 overexpression, which typically don't do as well, here in that setting there are not a lot of agents to serve that population. I think as we see ADCs come into play, I think these are great options. We don't know how cyclin E1 patients perform in the face of these ADC all-comers, but we do see that they are a great new promise for patients, and we would expect them to move sort of up the line, creating an even larger, longer opportunity for patients and, you know, certainly a clear path in the platinum-resistant setting.

Akash Diwari, Analyst — Jefferies

And I think that's an important comment because I know, okay, maybe the conservative way to think about it is, okay, this is going to be used in a late-line, third, fourth-line setting. But you've always said, like, look, we think there could be appetite even in the second line for monotherapy. And I think a big part of that is really why, you know, we're just treating patients with the topo payload again and again and no one's really answered this question but i feel like this you know this kind of consensus that'll be adc adc adc would change if there really is topo resistance that ends up showing which i certainly think is a possibility when you look at the lay of the land and i think there's emerging data sets on this right now we have target mediated resistance we have toxin mediated resistance what are some signs that would already indicate to you that actually re-treatment with a topo payload materially drops efficacy here.

Julie Eastland, CEO

Yeah, I think, Imar, do you want to sort of address how physicians see this?

Ingmar Bruns

A couple of thoughts, right, and that are our own, and of course also what comes through discussions with investigators or key opinion leaders we have talked to. So number one, I think there's other disease indications, solid tumors you can look at, like, you know, breast cancer is one example where there's more data than an ovarian cancer where you could say that the retreatment efficacy of topo-1 ADCs is actually poor, right? And I think there's, you know, a variety of data, and it's probably not true for every molecule, so I don't want to overstate that, but, you know, the majority of it is really the payload that drives the effect rather than really the binder and the target, right? Because there's probably a single-digit percentage, and again, with some variation, of course, between the molecules there. So I really think, and that's in line with at least the conversations we had, that this is primarily driven by the payload, right, in this case.

Akash Diwari, Analyst — Jefferies

Understood. I mean, look, I think that's going to be really interesting to see how it evolves over time. Now, I think maybe the second part of this dynamic is really, we're also seeing more tolerable payloads and more tolerable ADCs. And, you know, whether it's the tubulous data, and I know Gilead's quite excited about that platform, but you have something like NAPI2B that has historically had, you know, issues, on-target side effect issues, very stable, low dose, seems to be tolerable. Our friends at ZymeWorks, you know, again, it's not just the response rate, but it's really the duration. And I can't help but think, well, why doesn't that apply to your we won and you know certainly i think there was this saga and certainly we were bullish on the opportunity we won combined with chemo and it made sense right you get the cell damage you get the cyclone e i mean there's a natural synergy there but it seemed like the therapeutic window just simply wasn't wide enough to move forward with that is that so before we even get to the adc side i'd love to get kind of a post hoc view because you have hundreds of patients with the data on this i don't think people appreciate is the perception that your we want is not combinable with chemo correct or is there nuance at that at a certain dose or with certain regimens actually there is an acceptable tolerability profile yeah I think that's a that's

Julie Eastland, CEO

a perfect question and of course we do have that data and that data was presented at ASCO just this past week in the mirror trial where we looked at combinations of a xeno plus different chemo backbones here we focused in on the paclitaxel combination there were a number of doses here across this particular combination. This was in an all-comer population in the platinum-resistant ovarian cancer setting. And I think, importantly, what we see at, I think, what is the more optimal dose of 250 milligrams of a Xeno plus the Paclitaxel standard dose, we see nice responses, 50% ORR at that dose, as well as, you know, nice duration in nine months of duration of response. Now, that's a really nice outcome for patients in this setting where Paclitaxel historically is anywhere from 25% to 30% ORR with a much shorter duration of response. So this is not a randomized trial. It's small numbers, all those caveats, but it certainly is a great signal. And it's broader than just its importance to platinum-resistant ovarian cancer. Paclitaxel, and the reason we highlighted, it is not just because of P-ROC because it also is used, obviously, in the PSOC setting. and it's a combination partner that you could imagine even in other tumor types so it really provided a nice broad basis to say yes the zeno is combinable yes you don't have to use the monotherapy dose to see that and yet you have nice addition response rates and durability so this was the promise of a we want inhibitor I think we have found that you can do that even with an agent like paclitaxel which carries its own level of toxicity but that was manageable and combinable. I think that's a basis for how we kind of see the future of additional development. And to your point, we would expect that same biological action to also be present and available in an ADC. The question really is which ADC will have the profile and will have the share in order to be kind of a combination partner in ovarian. We already see those opportunities potentially in other tumor types.

Akash Diwari, Analyst — Jefferies

Understood. Now, I remember this was kind of an investor discussion a few years ago which was like treatment related versus treatment adverse events right there is there might have been an AE but we think it was related to the chemo it wasn't related to the we won the data that you presented at ASCO was that like a full take in terms of all treatment related adverse events whether they were related to the chemo or were they related to the we won was that the cleanest cut I mean yes I remember previously there was maybe more selective disclosure on that yeah I I can't really comment on the past, but I can comment on the data we presented, but that was all of the data for both.

Julie Eastland, CEO

In there, we sort of highlighted some of the reasons why some of the patients discontinued PAC only versus and continued on with the Xeno or discontinued because of a Xeno assertive. But in the PAC discontinuations, the majority of that, quite interestingly, was I think patients' preference to stop the additional neuropathy. that they were experiencing. So, again, important to find the right combination partner. But I think we highlighted all the safety data in total.

Akash Diwari, Analyst — Jefferies

Now, and maybe just a comment on even the first-gen ADCs, because it's interesting. Like, you'll have a 30, let's say 40% response rate, and I kind of just very simplistically be like, but your PFS is double your response rate. When I look at the ADCs, I know that doesn't mathematically make sense, but it makes sense in my head. When I look at the ADCs, particularly with the immunogen first-gen compound, you know, like you saw higher response rates even in, you know, the fully receptor-level rich, but PFS didn't necessarily have that kind of one-to-one translation, even though you might have had a lower response rate. Your PFSs in some instances were better than ADCs that actually had higher response rates. Can you talk about what's going on there, right? Like, why is there maybe this difference between PFS and ORR with these ADCs that you're not seeing necessarily with the we want?

Julie Eastland, CEO

Yeah, I think I'll hand that over to Ingmar.

Ingmar Bruns

Yeah, I don't think we necessarily know the answer, right, for the ADCs, why the PFS doesn't follow. That's something that we also hear, right, the one that is approved, right, We're, you know, at least in the population that we're looking at, especially the cyclin E1, high patients where this, in prior treatment registrants, seems to be even shorter than we know it from the registrational trials, right? But what the reason really is...

Akash Diwari, Analyst — Jefferies

What do you hear in the real world, like four or five or...?

Ingmar Bruns

Yeah, I mean, I don't think I would, you know, could give you a number here on average, but there's anecdotal cases of really certainly just a few months, right? But, you know, it's not a, you know, certainly not a data set that allows the full conclusion But that's the observation we have. What mechanistically is behind it, hard to tell for us, of course, right? But we do think that there's a broader impact, potentially, of cyclin E1 overexpression, right, on outside of these mechanisms, like E1 inhibition.

Julie Eastland, CEO

It's a good question. I'm not sure there's a good scientific answer. Sometimes PFF is short, and OS is reasonably long as well. So, you know, you're getting a disconnect there as well. But that seems to be repetitive, certainly in this tumor type.

Akash Diwari, Analyst — Jefferies

I think one of the things that's unique, and this has been a discussion, I think, with your Rewon even before, which is, like, there's differences between these chemos in terms of their safety profile and then potentially even their efficacy, which is unusual. Like, I don't think investors always hear, like, you know, we work well with PAX, but we don't work well with this one. And I mean, this is even two years ago, three years ago, this was a discussion. So hitting on that point, what have you learned about synergy with WeWon and the right type of chemo? What is the right chemo to combine with? What have you learned from the wealth of data you have actually in Chemo Combo now? And then number two, how do we apply that when you think about ADC platforms to combine with? Because even within Topo, there's ways to skin the cat. You can have a high-dar, greasy target. You can have something which is more stable, site-specific conjugation and a lower dose. So two-part question. A, what is the right chemo and why? And then number two, how do we take those learnings in terms of ADC partnerships?

Julie Eastland, CEO

So I think from a chemo partner perspective, I think, one, it sort of depends on where you've studied and what that chemo agent has already shown in a particular tumor type. There's different, obviously, responses to chemotherapy, certainly in the P-ROC setting. And so, you know, you're looking for a potent agent, obviously, that has, you know, cell stress replication, cell replication stress, excuse me, that, you know, we one really is a great partner with. So you really want to make sure you're getting a lot of stress on the replication process. Maybe some of the chemotherapy agents do that better than others. But I think where you're seeing certainly in p-rock paclitaxel has one of the higher Response rates and so that could make it a very good partner Tolerability is the other side of course the equation and so you could have a great response rate But not great tolerability combination. That's not going to lead you to the best synergistic effect So I think you really have to think about how does that?

Ingmar Bruns

Chemotherapeutic agent perform within the setting and that will probably be true for ADC's do you want to add a yeah Yeah, I think specifically, I think patlitaxel or texanes in general are a good example, right? Obviously, with the effect on tubulins, right, that is a pretty effective combination for an agent that's supposed to drive cells into mitotic catastrophe, right? So we think it's really a good combination partner that's probably supported by the data that we've presented, even though it's a small number, as Julie already said. I think you can also see it for platinum, right, given the specific mechanism there, including the DNA strand breaks, right? That's, you know, certainly DNA damage and repair plays into this here, and, you know, the combination makes sense. We have focused for now on the Texanes, and I think there's, that's actually, you know, as a drug class itself, of course, right? Because these drugs in many solid tumor indications are here to stay for many years to come, right? You can, of course, look at the respective indications where taxanes still play a role, such as triple negative breast cancer, but not limited to. But we also see it, secondly, as a surrogate, right? Because, you know, there's certainly earlier generation ADCs, maybe even the topos, where, you know, there's potential for combination. And, you know, of course, when you look at the first generation payloads, then there's more obvious synergy and similarity to the taxanes here. But we can also see it with the topo inhibitors, of course, right? And then you can see drugs that are relatively close to taxanes, right? Aribulin is an example, right, is technically not a taxane, but mechanistically very, very close to this, right? And that's how we think about it. And as you said yourself, I think the most important takeaway is that if you have a partner that induces replication stress, then you don't need a biomarker selection. It's a strong statement based on a relatively small data set, but that's how it looks like, right? And, of course, that's something that needs to be confirmed. But that's, of course, giving room for a much broader perspective here for this.

Akash Diwari, Analyst — Jefferies

Yeah, understood. Now, the other thing I just want to make sure people have context is, again, there's been years of dose-finding work with your agent in chemotherapy. A lot of the data has not been published even. And so I just want to make sure. So the data that you showed at ASCO was relative to what subset that you have kind of in-house. And then number two, how confident are you that, you know, with the five on, two off, and the dose, I think you were mentioning, 250, right? Like, the pushback would be like, how do you know 250 is good enough? Like, you know, you have so much data. Are we cherry-picking here? So how confident are you that you've actually established the right dose to take in combination with chemotherapy?

Julie Eastland, CEO

So in that particular study, in the MIR trial, the combination was with PROC patients, one to four prior lines of therapy and all of the doses that were presented at ASCO were the doses that were studied in that combination with paclitaxel so you're seeing all the data from a 200 milligram continuous dose and then three intermittent doses 5-2 at 200 250 and 300 and what you're seeing there is not just the activity but also then the safety and the tolerability data of the combination across all those doses so how can you be sure 250 250 looks like the optimal dose based on that initial signal finding study it is as small as like 12 patients I think or so and so you would obviously want to expand that out but 250 does look like it's the best of those that we've seen in that trial so there would you know likely need to be you know additional expansion cohorts obviously and maybe you would study more than one dose but 250 certainly looks optimally the best dose that was in those um that particular cohort so there isn't any additional paclitaxel combination data as i mentioned there were four chemotherapeutic agents that were studied in combination and that additional data will be cleaned and it will be published we focused again on paclitaxel just because of the nature of its importance to ovarian and it's commonly used

Akash Diwari, Analyst — Jefferies

but we'll provide all that data set um in the future okay understood now um going to your monotherapy trial obviously you have a big readout coming out although that's that trial is still very much ongoing but I do find it interesting you know your MOA is one of these unique ones where like for me if your prior PARP you would be ideal to actually get your drug again because you think about dysregulation in the cell cycle typically these PARP progressing patients are actually very rapidly progressing I personally don't think you should be using PARPs really onset setting but your drug actually would be better positioned to work there so there is kind of this investor perception and certainly I think with your communications too when you look at you know the Denali data the mammoth data and kind of the same quote-unquote types of patients monotherapy FC is going to be in that kind of let's say 30 to 35 range we're talking about PFS maybe of six months but I find it interesting again you have more data internally than we do and there are ways to enrich for patients who are responsive to we one beyond just simply cyclone II and I don't know if that's fully understood right so when you think about a the right expectation for monotherapy for that phase three is that about fair 30 35 percent response rate monotherapy and PFS there and number two what could you do in terms of enriching for patients beyond cyclone II to maybe

Julie Eastland, CEO

amplify that signal yeah I'll take the first and you can think about that but you know the the selection of cyclone E1 as a biomarker I mean cyclone E1 actually drives this cancer it's not just a marker on a cell surface to direct you know a therapy to it actually is part of what drives these cancer cells so it's an important different group or different class of patients so that's important to note. So you could think about potentially biomarkers within that, but, you know, in particular, it's important that this is a separate sort of group of patients. Just to confirm, yes, we have seen ORR consistently in the platinum refractory and cyclone E1I patients as we define it based on our cutoff, and we've seen those response rates at 30% plus over a number of different treatment algorithms, meaning patients who've been more heavily pre-treated than others. We see duration of response in the five- to six-month mark, and PFS, you know, maybe slightly less than that in Denali. And so that's been pretty consistent over a number of different trials. Over, to your point, hundreds of patients, and I think the data that we presented in January 2025, which was a way to present that historical data that may not have been collectively discussed, We did that in 25 and that really is the same Denali part 1b data continues to Be the final data that you see and now we're going to be generating this next set of data in Denali part 2 Anything you want to add in our on? Other biomarkers because we've looked at a lot.

Ingmar Bruns

Yeah, I think there are you know, I don't think we can say that we explored them and in trials enough, right, so the obvious one is P53, which plays a role in ovarian cancer here, and, you know, there's a bunch of others, of course, right. I think the issue with this, if any, then, that you enrich the population further. I think we're kind of going in a different direction by thinking, you know, if you have combination partners that induce replication stress. I mean, cyclin E induces replication stress, right? So if you have a partner, we don't need a biomarker selection that's of interest, right? I know your question was, you know, how can you enrich the response rate?

Akash Diwari, Analyst — Jefferies

Let me tweak it a bit because I couldn't agree more with what you laid out. Like, for example, you look at certs, first line, and we just got the Persevered Aid at ASCO. You know, they did this cut in terms of patients who are on prior AI therapy for one year or less, right? And so you kind of, this is not a biomarker. It's more, hey, if you were on AI for at least a year, you probably had a very strongly endocrine-driven tumor. And ergo, those patients are probably going to have a bigger benefit. So it's not a biomarker, per se, as much as it's like, hey, prior line of therapy and what the patient took previously might actually set up a we want to work better, right? So, for example, if I took a PARP and, you know, I've already disrupted the cell cycle, to me, those would be patients who would actually already, you know, inherently be more responsive to your therapy. So forget the traditional biomarker, but if you're thinking about enriching for a subset of patients that would be responsive at a rate that would be higher than your historical data, is there some flexibility there on that side? Because that is where it would get interesting.

Ingmar Bruns

Yeah, there is, right? So I think one example is the Muir trial in part two where we're focusing on those patients that have progressed while on PARP inhibitors, the front line. Same is true for second line. Actually, it doesn't matter for progressives on PARP inhibitors. So we don't really know, speaking of biomarkers, why this population is biologically so distinct. It's not very well described or understood, but it is. It's a very homogenous population with a very homogenous, especially duration of response and treatment response, right? And we see that as a biomarker, and it's known that in this population the cyclin E expression actually goes up, right? When progressives on PARP, you know, have high cyclin E expression. That's something that we're utilizing. That would be one example here.

Julie Eastland, CEO

And that's an area we're exploring, right? In the second part of the Muir trial, we've combined with Bevacizumab to look at those patients who progress while on a PARP inhibitor in the first line maintenance. As they come into second line induction and second line maintenance where they're getting Bev, we're going to be adding a Xeno there to see those patients, not only to understand how they do, but there we can actually maybe measure PFS activity because it's sort of known that these patients have about a three-month PFS, so if we can see an improvement there, we not only have a nice proof of concept from a combination perspective, but also activity, and that would allow sort of expansion and thinking about how you would address these patients in first line as well.

Akash Diwari, Analyst — Jefferies

Have you guys disclosed your baseline characteristics yet for the face read?

Julie Eastland, CEO

We haven't.

Akash Diwari, Analyst — Jefferies

If we think, because again, I feel like that's a double whammy in a good way in the sense It's like, hey, you're going to have, on the comparator arm, fast-progressing patients, then number two. It's like you're preventing them from having that outcome because you're solving the issue, right? If you were to guess what percentage of patients who are these fast heart progressors would be in this trial, your ongoing phase three monotherapy trial, versus relative to what we've seen in Mammoth and Denali, any hints?

Ingmar Bruns

Yeah, I mean, it's a substantial number of patients, right? So we don't have exact numbers, but...

Akash Diwari, Analyst — Jefferies

What's the ballpark need substantial?

Ingmar Bruns

Well, a quarter.

Akash Diwari, Analyst — Jefferies

Okay, yeah.

Julie Eastland, CEO

I was going to say 30%, but yeah, a quarter to 30%, yeah.

Akash Diwari, Analyst — Jefferies

Numbers are always better. Okay, 25%, 30% of patients could be these fast-park progressors. And relative to the other prior trials, what was the percentage of those patients?

Julie Eastland, CEO

Those patients were post-park treated. So I can't say today, without looking at the data, how many of those would have progressed while on PARP or if they had to complete their PARP treatment and then receive immunotherapy.

Akash Diwari, Analyst — Jefferies

Okay, understood.

Julie Eastland, CEO

That was sort of a small combination.

Akash Diwari, Analyst — Jefferies

Yeah, understood. Very interesting. Now, maybe just on the chemo combo again, I just wanted to hit on this. Even if you look at the preclinical data, I remember AstraZeneca used to publish, they were like, look, we don't even have to give these drugs on top of each other. We can give a wee one, wait a week, and then just give something that's causing DNA damage. And so when you think about not only is 250 and 5.2 the correct dose for your wee one, but when you think about strategies to combine, what's the right regimen? Have you guys figured that out at this point, or is there still work to be done?

Ingmar Bruns

I mean, there's one thing we can say, right, that certainly the 250, since you mentioned that, is, you know, at a level where the exposure ensures target engagement, right?

Akash Diwari, Analyst — Jefferies

And you would define what? IC80? Like, when you mean target engagement, how do you define that?

Ingmar Bruns

Yeah, it's like an IC50, IC80, right? And that's clear and determined. So I think we obviously want to make sure that you have target engagement in whatever dose you apply. And that's certainly within that range. And the five-on, two-off, and that's actually pretty clear in the ESCO data that we presented, right, in comparison to the continuous dose, actually underlines the choice of the intermittent schedule, right, which, you know, just the two off days really seem to allow recovery of, you know, the undesired effects.

Julie Eastland, CEO

And I think your question's appropriate as you think about combining with other partners. You know, will you, in a three-week regimen, say with an ADC, how will you dose Zeno when you're then also receiving your ADC treatment? And I think those are things that we'll work out that we don't have an answer for. I think it does kind of depend on the combination partner, but certainly in the setting of the combination of the chemo agents, you know, Azeno was on its schedule of five days on, two days off, and Paclitaxel was on its regular schedule. So it was, you know, from that perspective, you know, it was well managed within their standard dosing schedules.

Akash Diwari, Analyst — Jefferies

Can you talk, I mean, a bit about, obviously, ovarian tons of development right now, but, you know, there is some shades that even you look at small cell, you know, Harpoon or any of the DLL3 bispecific, the T-cell engagers did not have as high of a response rate as the ADCs, but they had a durable tail. And so the idea is if you're overlapping regimens, you can debulk with an ADC and then have a tail with, let's say, a T-cell engager. There is probably a clumsy analogy I can apply here. But talk to me about, are you seeing that interest externally to partner with your drug, right? Where people are, you know, pharma partners or biotech partners are coming to your team proactively saying like, hey, you know, this actually makes a lot of sense to us. And in terms of a financial agreement, what would you need from a partner so that, you know, again, you are still capital constrained. You want to make sure you focus on that phase three. So if you were going to start with these kind of dose-finding, you know, partnerships on the ADC side, is that something that can happen this year because you're already getting enough of that external excitement? Or is the pitch, you're hearing externally, I want to see the phase-free data, we want to see what the overall tolerability profile is, and then we can discuss maybe combining it, right? Like, how do you sequence those events?

Julie Eastland, CEO

Yeah, I mean, in terms of, you know, conversations with partners, we don't specifically obviously comment on that. I will say that there is very much interest in Combining a Zenna with other agents everyone is looking to see That data and what the tolerability profile eventually looks like so I think there's interest We think that we can certainly find interest in other tumor types number one in ovarian our homework is to get across the finish line with the Zen assertive and P rock to continue with the combination with the Bevacizumab expansion trial and to think about where else we can take these combination partners and, you know, frankly, which ADC will be the winning ADC because that will be important to understand its profile and how it could combine. So I think there's interest and I think the time is maturing. To that, I don't see the start of that type of study in 2026 because I think there's just a set-up time associated with it. But certainly I think that there's interest, and financially we'll find a way.

Akash Diwari, Analyst — Jefferies

I really appreciate it. Great conversation. Thanks so much, everyone.