Afternoon, everyone. My name's Akash Tewari. I head our Pharma and Biotech research efforts at Jefferies. It's a 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. That sounds great. Well, thanks again for inviting, and we're glad to be here. Appreciate the time. Zentalis is uniquely and very specifically focused on bringing azenosertib 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. Today, we can talk a little bit about how we see PROC as our first step in a journey for azenosertib in combination and in other tumor types. We're excited today to get our homework done, get PROC in, and then think about how we can extend that elsewhere. Understood. I definitely want to talk about moving beyond ovarian, but I actually wanted to hit on ovarian first and really on the fundamentals because 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. I don't think we're thinking about, hey, what does that mean if we have drugs that are doubling overall survival in the frontline setting, what that means in the refractory market? The sense was always, well, refractory and late-line PROC is a smaller opportunity, and it might be today. 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 a third or fourth-line setting, and how that might actually evolve over the next five years as new therapies, particularly ADCs, get established. I think it's a great question. Ingmar can chime in, of course, as well. 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 have the same therapeutic benefit in terms of being these chemotherapeutic type of agents. Patients here typically, and in particular in total population, see response rates that range anywhere from 4% to 13% when it comes to single-agent historical chemo. 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. et cetera. They really want to see a break from that. I think azenosertib 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 up the line, creating an even larger, longer opportunity for patients and certainly a clear path in the platinum-resistant setting. Understood. 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. You've always said, "Look, we think there could be appetite even in the second line for monotherapy." I think a big part of that is really we're just treating patients with a topo payload again and again. No one's really answered this question, but I feel like this consensus that it'll be 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 retreatment with a topo payload materially drops efficacy here? Yeah. I think, Ingmar, do you want to. Yeah sort of address how physicians see this? A couple of thoughts, and that our own and, of course, also what comes through discussions with investigators who are key opinion leaders we have talked to. Number one, I think there's other disease indications, solid tumors you can look at. Breast cancer is one example where there's more data than ovarian cancer, where you could say that the retreatment efficacy of Topo1 ADCs is actually poor. Right? I think there's a variety of data, and it's probably not true for every molecule, so I don't want to overstate that, but 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. I really think, and that's in line with at least the conversations we had, that this is primarily driven by the payload, in this case. Understood. Look, I think that's going to be really interesting to see how it evolves over time. I think maybe the second part of this dynamic is really we're also seeing more tolerable payloads and more tolerable ADCs. Whether it's the tubulins data, and I know Gilead's quite excited about that platform, but you have something like NaPi2b that has historically had on-target side effect issues. Very stable, low dose seems to be tolerable. Our friends at Zymeworks, again, it's not just the response rate, but it's really the duration. I can't help but think, well, why doesn't that apply to your WEE1? Certainly, I think there was this saga, and certainly we were bullish on the opportunity of WEE1 combined with chemo, and it made sense. You get the cell damage, you get the cyclin E1. There's a natural synergy there. It seemed like the therapeutic window just simply wasn't wide enough to move forward with that. Before we even get to the ADC side, I'd love to get a post-hoc view, because you have hundreds of patients worth of data on this that I don't think people appreciate. Is the perception that your WEE1 is not combinable with chemo correct? Is there nuance, that at a certain dose or with certain regimens, actually there is an acceptable tolerability profile? Yeah, I think that's a perfect question, and of course, we do have that data. Yeah. That data was presented at ASCO just this past week in the MUIR trial, where we looked at combinations of azeno 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, I think importantly, what we see at, I think, what is the more optimal dose of 250 mg of azenosertib plus the paclitaxel standard dose, we see nice responses, 50% ORR at that dose, as well as nice duration in nine months of duration of response. Yeah. 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. 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 highlight it is not just because of PROC, because it also is used, obviously, in the PSOC setting. It's a combination partner that you could imagine even in other tumor types. It really provided a nice broad basis to say, yes, azenosertib 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. This was the promise of a WEE1 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 see the future of additional development. 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 a combination partner in ovarian. We already see those opportunities potentially in other tumor types. Understood. Now, I remember this was an investor discussion a few years ago, which was treatment-related versus treatment adverse events. There might've been an AE. We think it was related to the chemo, it wasn't related to the WEE1. The data that you presented at ASCO, was that a full take in terms of all treatment-related adverse events, whether they were related to the chemo or were they related to the WEE1? Was that the cleanest cut? Yes. I remember previously there was maybe more selective disclosure on that. Yeah. I can't really comment on the past. Yeah I can comment on the data we presented. That was all of the data for both. In there, we highlighted some of the reasons why some of the patients discontinued paclitaxel only. continued on with azeno or discontinued because of azenosertib. In the paclitaxel discontinuations, the majority of that, quite interestingly, was, I think, patients' preference to stop the additional neuropathy that they were experiencing. Again, important to find the right combination partner, but I think we highlighted all the safety data in total. Yep. Perfect. Now, maybe just to comment on even the first-gen ADCs, because it's interesting. You'll have a 30, let's say 40% response rate. I just very simplistically be like, "Your PFS is double your response rate. When I look at the ADCs, and 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 saw higher response rates even in the folate receptor alpha-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? Yeah. Why is there maybe this difference between PFS and ORR with these ADCs that you're not seeing necessarily with the WEE1? Yep. I think I'll hand that over to Ingmar. Yeah, I don't think we necessarily know the answer for the ADCs why the PFS doesn't follow. That's something that we also hear. The one that is approved, where at least in the population that we're looking at, especially the cyclin E1 high patients, where this in prior treatment regimens seems to be even shorter than we know it from the registrational- trials. what the reason really is. Interesting. What do you hear in the real world? Like four, five, or. Yeah, I don't think I could give you a number here on average, but there's anecdotal cases of really certainly just a few months. Oh, wow. Okay. It's certainly not a data set that allows the full conclusion here, but that's the observation we have. What mechanistically is behind it, hard to tell for us, of course. We do think that there's a broader impact, potentially, of cyclin E1 overexpression outside of these mechanisms, like WEE1 inhibition. It's a good question. I'm not sure there's a good scientific answer. Yeah is short, and OS is reasonably long as well. You're getting a disconnect there as well, but that seems to be repetitive, certainly in this tumor type. Understood. I think one of the things that's unique, and this has been a discussion, I think, with your WEE1 even before, which is there's differences between these chemos in terms of their safety profile, and then potentially even their efficacy, which is unusual. I don't think investors always hear, "We work well with Pacs, but we don't work well with this one." This is even two years ago, three years ago, this was the discussion. Hitting on that point, what have you learned about synergy with WEE1 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? Number two, how do we apply that when you think about ADC platforms to combine with? 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. Two-part question. A, what is the right chemo and why? Number two, how do we take those learnings in terms of ADC partnerships? I think from a chemo partner perspective, I think, one, it sort of depends on where you've studied- What that chemo agent has already shown in a particular tumor type. There's different, obviously, responses to chemotherapy, certainly in the PROC setting. You're looking for a potent agent, obviously, that has cell replication stress that WEE1 really is a great partner with. 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 PROC, 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, of the equation. Right. You could have a great response rate, but not great tolerability combination. That's not going to lead you to the best synergistic effect. I think you really have to think about how does that chemotherapeutic agent perform within the setting, and that will probably be true for ADCs. Do you want to add a. Yeah, I think specifically, paclitaxel or taxanes in general are a good example, right? Obviously with the effect on tubulins, that is a pretty effective combination for an agent that's supposed to drive cells into mitotic catastrophe. 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'd also see it for platinum, given the specific mechanism there, including the DNA strand breaks. Certainly DNA damage and repair. plays into this here, and the combination makes sense. We have focused for now on the taxanes, and I think that's actually, as a drug class itself, of course, because these drugs in many solid tumor indications are here to stay for many years to come. You can, of course, look at the respective indications where taxanes still play a role. Sure such as triple-negative breast cancer, but not limited to. We also see it, secondly, as a surrogate, because there's certainly earlier generation ADCs, maybe even the topos, where there's potential for a combination. Of course, when you look at the first-generation payloads, then there's more obvious synergy and similarity to the taxanes here. We can also see it with the topo inhibitors, of course. Then you can see drugs that are relatively close to taxanes. eribulin is an example. It's technically- not a taxane, but mechanistically very close to this, and that's how we think about it. 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. Of course, that's something that needs to be confirmed. That's, of course, giving room for a much broader perspective here for this. Yeah. Understood. 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. I just want to make sure. The data that you showed at ASCO was relative to what subset that you have in-house? Number two, how confident are you that with the five on, two off, and the dose, I think you were mentioning 250. The pushback could be like, "How do you know 250 is good enough? You have so much data. Are we cherry-picking here?" How confident are you that you've actually established the right dose to take in combination with chemotherapy? In that particular study, in the MUIR trial, the combination was with PROC patients, one to four prior lines of therapy. All of the doses that were presented at ASCO were the doses that were studied in that combination with paclitaxel. You're seeing all the data from a 200 mg continuous dose, and then three intermittent doses, five, two at 200, 250, and 300. 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. How can you be sure 250 looks like the optimal dose based on that initial signal finding study. It is as small as 12 patients, I think, or so. You would obviously want to expand that out. 250 does look like it's the best of those that we've seen in that trial. There would likely need to be additional expansion cohorts, obviously, and maybe you would study more than one dose, but 250 certainly looks optimally the best dose that was in that particular cohort. 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. We'll provide all that data set in the future. Okay. Understood. Going to your monotherapy trial, obviously, you have a big readout coming out, although that trial is still very much ongoing. I do find it interesting, your MOA is one of these unique ones where, for me, if your prior PARP, you would be ideal to actually get your. Again, because you think about dysregulation of the cell cycle, typically these PARP-progressing patients are actually very rapidly progressing. I personally don't think you should be using PARPs for a 1L setting. Your drug actually would be better positioned to work there. There is this investor perception, and certainly, I think with your communications, too, when you look at the DENALI data, the MAMMOTH data, and the same quote, unquote, "types of patients," monotherapy efficacy is going to be in that let's say 30-35 range. We're talking about PFS maybe of six months. I found it interesting, again, you have more data internally than we do, and there are ways to enrich for patients who are responsive to WEE1 beyond just simply cyclin E. I don't know if that's fully understood. When you think about, A, the right expectation for monotherapy for that phase III, is that about fair, 30%, 35% response rate monotherapy and PFS there? Number two, what could you do in terms of enriching for patients beyond cyclin E to maybe amplify that signal? Yeah. I'll take the first, and you can think about that. The selection of cyclin E1 as a biomarker, cyclin E1 actually drives. this cancer. It's not just a marker on a cell surface to direct a therapy to. It actually is part of what drives these cancer cells. It's an important different group or different class of patients. That's important to note. You could think about potentially biomarkers within that. In particular, it's important that this is a separate group of patients. Just to confirm, yes, we have seen ORR consistently in the platinum refractory and cyclin E1 high patients as we define it based on our cutoff. We've seen those response rates at 30% +. over a number of different treatment algorithms, meaning patients who've been more heavily pretreated than others. We see duration of response in the five to six month mark and PFS maybe slightly less than that. in DENALI. That's been pretty consistent over a number of different trials. Over, to your point, hundreds of patients. I think the data that we presented in January 2025, which was a way to present that historical data. Yeah may not have been collectively discussed. We did that in 2025, that really is the same DENALI Part I-B data continues to be the final data that you see. Now we're going to be generating this next set of data in DENALI Part II. Anything you want to add, Ingmar? On biomarkers? other biomarkers? Mm-hmm. Because we've looked at a lot. Yeah, I think there are. I don't think we can say that we explored them in- trials enough. The obvious one is P53, which plays a role in ovarian cancer here. There's a bunch of others, of course. I think the issue with this, if any, if you enrich the population further, I think we're going in a different direction by thinking if you have combination partners that induce replication stress, cyclin E induces replication stress. If you have a partner, we don't need a biomarker selection that's of interest. I know your question was how can you enrich the response rate even more so. Actually, let me tweak it a bit because I couldn't agree more with what you laid out. For example, you look at SERDs first line, and we just got the PERSEVERE data at ASCO. They did this cut in terms of patients who were on prior AI therapy for one year or less. 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. Ergo, those patients are probably going to have a bigger benefit. 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 WEE1 to work better. For example, if I took a PARP and- Yeah I've already disrupted the cell cycle, to me, those would be patients who would actually already inherently be more responsive to your therapy. Forget the traditional biomarker. 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? That is where it would get interesting. Right. Yeah, there is. I think one example is the MUIR trial in Part II, where we're focusing on those patients that have progressed while on PARP inhibitors. could be frontline. Same is true for second line. Actually, it doesn't matter for progressors on PARP inhibitor. We don't really know, speaking of biomarkers, why this population is biologically so distinct. It's not very well described or understood, it is. It's a very homogeneous population with a very homogeneous, especially duration of response and treatment response. We see that as a biomarker, and it's known that in this population, the cyclin E expression actually goes up. When progressors on PARP have high cyclin E expression. Yeah. That's something that we're utilizing. That would be one example here. And- That's an area we're exploring. In the second part of the MUIR trial, we've combined with bevacizumab. Right to look at those patients who progressed 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 azenosertib there to see those patients, not only to understand how they do, but there we can actually maybe measure PFS activity. it's known that these patients have about a three-month PFS. If we can see an improvement there, we not only have a nice proof of concept. Yeah from a combination perspective, but also activity, and that would allow expansion in thinking about how you would address these patients in first line. Very interesting. as well. Have you guys disclosed your baseline characteristics yet for the phase III? No, right? We haven't. Okay. Again, I feel like that's a double whammy in a good way, in the sense 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 PARP progressors would be in your ongoing Phase III monotherapy trial versus relative to what we've seen in MAMMOTH and DENALI? Any hints? Yeah. It's a substantial number of patients. We don't have exact numbers. What's the ballpark in a substantial? Well, a quarter. Okay. Yeah. I was going to say 30%, but yeah. All right. Yeah. A quarter to 30. Yeah. Number's always better. Okay. 25, 30% of patients could be these fast PARP progressors. Okay. That's right. Relative to the other prior trials, what was the percentage of those patients? Those patients were post-PARP treated. I can't say today. Without looking at the data, how many of those would've progressed while on PARP, or if they had to complete their PARP treatment and then receive? Yeah monotherapy. Yeah. Okay. Understood. That was a small- Yeah combination. Yeah. Understood. Very interesting. 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 WEE1, wait a week, then just give something that's causing DNA damage." When you think about not only is 250 and five, two the correct dose for your WEE1, 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? There's one thing we can say, that certainly the 250, since you mentioned that, is at a level where the exposure ensures target engagement. Right? You would define what IC80 when you mean target engagement, how do you define that? Yeah. It's like an IC50, IC80, right? That's clear and. determined. 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. The five on, two off, and that's actually pretty clear in the ASCO data that we presented, in comparison to the continuous dose. aligns the choice of the intermittent schedule, which just the two off days really seem to allow recovery of the undesired effects. I think your question's appropriate as you think about. Yeah combining- Chemo. Yeah. with other partners. Will you in a three-week regimen, say with an ADC, how will you dose azeno when you're then also receiving your ADC treatment? I think those are things that we'll work out that we don't have an answer for. I think it does depend on the combination partner. Certainly in the setting of the combination of the chemo agents, azeno was on its schedule of five days on, two days off, and paclitaxel was on its regular schedule. From that perspective, it was well managed. within their standard dosing schedules. Understood. Can you talk a bit about, obviously, ovarian, tons of development right now. There is some shades that even you look at small cell. Harpoon or any of the DLL3 bispecific, the T-cell engagers did not have as high of a response rate as the ADCs. They had a durable tail. 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. Talk to me about, are you seeing that interest externally to partner with your drug? Where pharma partners or biotech partners are coming to your team proactively saying, "Hey, this actually makes a lot of sense to us." In terms of a financial agreement, what would you need from a partner? Again, you are still capital-constrained. You want to make sure you focus on that phase III. If you were going to start with these kind of dose-finding partnerships on the ADC side, is that something that can happen this year because you're already getting enough of that external excitement? Is the pitch you're hearing externally, "I want to see the phase III data. We want to see what the overall tolerability profile is, and then we can discuss maybe combining it." How do you sequence those events? Yeah. In terms of conversations with partners, we don't specifically, obviously, comment on that. I will say that there is very much interest in combining azeno with other agents. Everyone is looking to see that data and what the tolerability profile eventually looks like. 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 azenosertib and PROC, to continue with the combination with the bevacizumab expansion trial, and to think about where else we can take these combination partners. Frankly, which ADC will be the winning ADC- because that will be important to understand its profile and how it could combine. 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 setup time. Yeah associated with it. Certainly, I think that there's interest, and financially, we'll find a way. Understood. I really appreciate it.