Lights are strong. Yep. All right, good morning, everyone. Thanks for joining us on day 3 of the Morgan Stanley Global Healthcare Conference. I'm Mike Olszemer, the biotech analyst here, and it's my pleasure to introduce Kim Blackwell, CEO of Zentalis Pharmaceuticals. Just a reminder for today that the format is a fireside chat. But before we get started, I just need to read a quick disclosure statement. "For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative." And with that, Kim, thanks for joining us today. Maybe I can just turn it over to you for a brief background on Zentalis, and then we can get into some Q&A. Sure. Well, thanks for having me. For those of you who are brand new to the story, Zentalis has been around for a little over eight years now. It was a company that was founded on best-in-class chemistry and proceeded to put four very exciting drugs into the clinic and demonstrating proof of concept. Where the company has evolved to now is we have a lead clinical asset that targets WEE1, a critical protein in driving cell cycling in cell cycle modulation. It's known as azenosertib. It was previously known as ZN-c3. This year has been a really exciting time for us as a company because, right at ASCO this year, we demonstrated that azenosertib, as a single agent, had a 36.7% confirmed objective response rate when given on an intermittent dosing schedule of 5-2, which basically means the patients swallow the pills Monday through Friday and have the weekend off. At least that's kinda how I would think of it if I was a patient or a prescribing doctor. That's how I would describe it. Pretty blown away with the 37%- Mm-hmm. -confirmed objective response rate in heavily pretreated ovarian cancer patients and a subtype of endometrial cancer known as uterine serous carcinoma. What we know about these two disease entities is that their hallmark is that they are all, P53 mutation for the most part, both ovarian and USC. They also have high amounts of genomic instability, either characterized by something we call HRD, which is also a marker sensitivity of PARP inhibitor, and they're also pretty chemo-refractory, both USC and then at least the ovarian cancer patients that we enrolled in the study were also, had progressed on multiple, over 5 lines of median therapy. So, I was a practicing doctor for a long time, and to see that kind of 36, rounding up, 37%. Mm-hmm ... objective response rate with an oral agent as a monotherapy was very, very exciting. Now, the drug had had demonstrated monotherapy activity previously in the high, low, low to mid-20s, not high,% range. But we really did the work that we needed to do to really make certain the dose that we're moving forward in our registration intent studies was the right dose, resulting in the highest amount of activity, and also was the best tolerated. Knowing that with an oral agent, you are going to have to make certain... I'd say it quite simply, the patient has to swallow the pill- Mm-hmm. -for it to work. And that was all of the work that we did, really, from the time I became CEO of the company in late May of 2022- Mm ... to this ASCO disclosure. By doing that dose work, we feel like we can move quickly. There's nothing super quick in drug development- Yep ... but quickly because we know the patients where the drug works, we know the dose, and we actually know what good looks like. Yep. Can you maybe, you talked about the improvements in efficacy with dose optimization. Maybe you can also talk about, you know, what you saw on the tolerability side as well. Yeah, sure. So again, the goal of what we call dose optimization was to take a drug that could be given every day at 300 milligrams and ask the question: Could we drive up exposures? And almost all, if not all, of the small molecule inhibitors I've ever worked with, exposure drives efficacy. And so what we were seeing was adequate exposures, we were seeing monotherapy activity, and we were seeing incredibly well-tolerated drugs. But I thought there was room, our scientists, us as a company, thought there was room to drive up those exposures even further. But what we see in most cell cycle modulating drugs is that the marrow needs a tiny break. And so that's the whole idea behind the intermittent dosing schedule, is by giving a 5-2, we were able to drive up the exposures of the inhibitor in the tumors, but at the same time, maintain that tolerability. And what we saw from switching from a 300 continuous to a 400 5-2, was not only increased activity, increased exposures, increased Cmax, which we knew both Cmax and AUC were gonna be important drivers of efficacy from all of the preclinical models, is that we saw this increase in tolerability. And what it meant was less dose reductions by giving the weekend off, the two days off in the intermittent dosing schedule, and no dose, no dose discontinuations, which was, you know, again, a very important parameter of what we were looking. We saw a slight increase in Grade 3 for anemia. It went, I don't know what the continuous off the top of my head, but it was 11%, very acceptable anemia rate. We saw neutropenia also in that same range, but no febrile neutropenia. So really, we accomplished what we set out to do, which is to drive up efficacy by driving up exposures and maintaining what we already knew to be the case, which was the drug was very well tolerated. Yep, makes sense. Can you just talk a little bit about the competitive landscape in terms of other WEE1s in development and how you're positioned? Well, the good news is we're way ahead- Yep - by years. We wanted a target that, as a drug hunter and a drug developer and a clinical trialist, I've been tracking for a long time. There was a drug known as adavosertib being developed initially by Merck and then subsequently by AZ. I was lucky enough to have treated patients on that drug when I was a practicing trialist, and I knew the drug had, the target was a very valid target. I also knew you had to have a highly specific inhibitor. The adavosertib compound hit 13 kinases at pretty high levels. We hit 5. Adavosertib is no longer, at least the public disclosure of AZ, as adavosertib is no longer being developed. That means we have the opportunity to be the first WEE1 inhibitor for the treatment of solid tumors. There are other people working in this space because I think when adavosertib was phased out or discontinued and we were coming up behind it, I think people lost sight of the fact that WEE1 is a really important cancer target. In fact, I frequently ask people, like, "What are your favorite three targets in cancer?" I think it had been around for a while, and what limited our ability to go after it in the clinic was highly specific inhibitors. And that's where this, it was almost a perfect storm at Zentalis because we had the medicinal chemistry to push a highly focused, highly specific WEE1 inhibitor in the clinic, and that's why we're ahead. Yep. We think we have best-in-class chemistry, but more importantly, we can be first. There are other companies that are working in this space. The chemistry is not simple. And that's all I'll say about that. Yep. Sounds good. Maybe we can just go back to the monotherapy dose optimization. You characterized the data that you shared at ASCO, and you're planning to provide an update later this year. Maybe talk a little bit about that and, you know, what's the goal there? How should we be thinking about that data, and how much updated data will we see? Yeah. Well, first of all, I'm really proud of the work that we got done from roughly the early fall of 2022 to the disclosure. The intent of the dose optimization work was not to say, "Here's the efficacy of our drug using an intermittent." We were able to do it because the drug's very active. But the goal during that 9 months between when we declared we were gonna do more dose work and the ASCO disclosure in June, which was about 100 days ago, give or take a couple of days, even though it seems like a long time ago- Right ... it was only about a little over 100 days. What we had committed off the dose optimization is, we're gonna show you what it looks like to give the dose, the drug at higher levels on an intermittent and how that affects exposure, because we think that's important in driving monotherapy activity. And we were able to do that. We didn't just do it in ovarian and USC. We did it in all comers, very heavily pretreated, phase I population. And so then we took that funnel down to what is the activity of the drug at the new dosing in USC and ovarian. So we ended up with 13 ovarian and six USC patients. The median follow-up was short, and that's why we committed to updating the public, the street, by the end of this year. It's only been over 100 days. The data cutoff was June second. It's September thirteenth. We will... We're committed to meeting that milestone. Really, the most obvious things are either longer follow-up in the same patient population. I've publicly disclosed that that study remains open and is accruing patients, so that means there's patients going on today, and we made a conscious decision to do it because there was such a demand to keep the study open, given the activity that we were seeing. So it's more patients, more time. We continue to work very hard to understand where this drug especially benefits patients, and in the general term, that's a biomarker strategy. Mm-hmm. And we're committed to understanding that more- Yep ... especially in the landscape of WEE1 inhibitors, in particular, the historic adavosertib, where they have demonstrated that in tumor types like HRD-positive ovarian, like Cyclin E overexpressing ovarian, WEE1 inhibition worked really well. So the update is not gonna be three more years of follow-up. Yep. It is a committed update to provide longer follow-up in the population, and then who knows what else we're able to present, and we're committed- Yep ... to meeting that between now and the end of the year. The goal is just to kind of confirm sort of what we're already seeing? The enduring benefit to patients. Gotcha. Okay. If we just stick with monotherapy still and maybe talk about the path forward here. You're gonna give the longer follow-up later this year, and just how are you thinking about the strategy going forward and the different cancer types you plan to pursue? Yeah, First, our perception is the fastest path to registration is developing the drug as a monotherapy, where you're not having to layer it on top of other agents. And given the activity we've seen as a monotherapy, we think we can be successful in developing it as a monotherapy. And those two registration intent strategies are to develop it in ovarian cancer, a study known as 005 or DENALI, as well as a similar but different gynecologic malignancy, which is Uterine Serous Carcinoma. That's a study known as 004 TETON. Those two studies represent registration intent and what I perceive as the fastest path to registration. During the call around ASCO, we committed to striving towards an NDA in 2026, and we believe both of those studies would support that, statement and goal. Can you give us a sense of when we might see data from those, or is, or is this, you know, stay tuned, kind of? Yeah. So we've committed to updating the timelines around those studies by the end of the year. Okay. Maybe we can shift to your chemo combination data. You had an update at ASCO as well, and there's some promising- Yeah. Data there, so maybe walk us through. So it's very exciting, and I'm a very impatient person. Mm-hmm. So monotherapy is the fastest path to registration with this drug, and given the activity, we believe we can be successful there. But the chemo combinations were super exciting, too. Mm-hmm. And for those of you that aren't familiar with this study, it was by far the largest phase I study I've ever been involved in and enrolled over 100 patients, and I think at the time of the presentation, we had enrolled, like, 108, something like that. It was 4 chemo backbones, all dose escalation. So even though it was over 100 patients, it was still a phase I dose escalation study. And I'm still pretty old school. phase I, to me, means you're finding the dose of combining a drug with chemotherapy, and we did that with the exception of gemcitabine, which I disclosed we were still pursuing a recommended phase II dose of combining azeno with gemcitabine, which we're committed to doing given the preclinical synergy between gemcitabine and azeno. But then we were able to ask because of the sufficient number of patients, is the drug working better or worse than historical controls of chemotherapy alone? This was a platinum-resistant population of ovarian cancer patients, heavily pretreated. Three-quarters of them had received bevacizumab, and I think a little under half had received PARP inhibitors. The most promising results were those that we saw around paclitaxel, where we have a recommended phase II dose, over 10-month PFS. With carboplatin, which, again, these were patients who had progressed within six months of receiving a platinum agent, that's the definition of platinum-resistant, a 7-point-something-month PFS in combination with platinum. We were seeing a 35% response rate in combination with gemcitabine, but again, disclosed that we hadn't declared a recommended phase III, phase II, jumping ahead, phase II dose. All three of those were really exciting efficacy endpoints in the context of being able to safely combine azeno with chemotherapy. The other part of the update at ASCO was early data around cyclin E, and that was in part driven because the science is quite strong, that in cyclin E-positive tumors, WEE1 inhibition appears to work even better- Mm-hmm. -than in non-characterized Cyclin E tumors. The KOLs had, in the GYN onc world, were very familiar with the Cyclin E story. And in fact, as part of our presentation, we showed data, meta-analysis of over 5,000 patients, showing that if you have a Cyclin E-positive ovarian cancer, you do worse with chemotherapy alone. That was like, almost like an accepted fact amongst the GYN onc community. It was an accepted fact a decade ago when I was working on Cyclin E and breast cancer. We're trying to revive that, and it's important because, it's important because our drug inhibits CDK2, and the preferred partner of CDK2 is Cyclin E. So that was the background between... B- for the analysis of Cyclin E status and benefit from azeno chemo, meaning Cyclin E positive versus Cyclin E negative. What we saw was a hazard ratio of 0.3 for the benefit of azeno chemo combinations in Cyclin E positive. This data was not presented in isolation. There is. You talked about competitive landscape. Debio actually presented data on their WEE1 inhibitor in combination with carboplatin. Very small numbers, but saw a similar effect, this huge benefit in Cyclin E positive for their WEE1 inhibitor in combination with carboplatin. The science is very consistent around this story, and I guess I'll just finish with, so great activity. Yep. Strong science that says there's maybe a subpopulation that benefit even more from WEE1. The activity was good enough, and it didn't matter what cyclin E is, just to be clear. The tolerability was absolutely good enough. We declared we're moving it into earlier lines of ovarian cancer... But then we have this cyclin E strategy, which I think enables us to think about who gets even higher benefit than unselected, and more importantly, scientifically predicts patients who do not do well with chemotherapy alone. And in ovarian, that's particularly important because if you're gonna have to go up against chemo versus chemo plus your drug- Mm-hmm. We've seen a lot of activity and declarations in this space over the past, since ASCO, at least 3 phase 3 that I'm aware of. Yep. It helps me define and design studies where the comparator arm patients are not benefiting from the standard of care. And we continue to work... I'm sure this is one of your questions. Yeah. We continue to work very hard to accumulate and interrogate the cyclin E story as it relates to the activity or drug, not just as monotherapy, but also in terms of designing studies. Yep. Maybe you can talk about taking that chemo combo data and how you use that to inform your phase III design. Yeah. So what we declared and committed to, and are committed to, is moving the drug up into what I call, in the simplest of terms, earlier lines of therapy for people who aren't following the ovarian space. It's also referred to as platinum-sensitive ovarian cancer, and it's a space where the practice or management of ovarian, as you get diagnosed, you get 6 cycles of carboplatin, and then you wait. Sometimes you get bevacizumab, sometimes you get a PARP inhibitor. But for all practical purposes, over 80% of those patients, their cancers come back, even with optimal surgery and chemotherapy. We declared we're moving the drug in combination with single-agent chemo off of the ASCO phase I data that we presented with GOG, into that space. We call it platinum-sensitive, but it's not first line. It's second line platinum-sensitive. We have really three critical reasons why we believe we can be successful going up against standard chemo. One, we saw high efficacy and great tolerability in the study results that we presented at ASCO study we call 002. The tolerability in itself would make us believe that it would, we could win against two chemos, because we're a chemo plus a well-tolerated targeted agent. Mm-hmm. Number two, the study design included monotherapy maintenance. So you get your 6 cycles in the second line of chemo, or chemo plus Azeno, doublet chemo versus chemo plus Azeno. But then you stop again. That's the practice. We have a drug that's very well-tolerated and active as a monotherapy and can be given as a maintenance compared to placebo after the 6 cycles of treatment. And then the third is related to the cyclin E, which is, we know cyclin E positivity predicts worse outcome to chemotherapy. We showed historic data. We're, again, continuing to accumulate data to help people understand why cyclin E predicts chemo resistance. And we defined eligibility criteria as the 60%-70% of ovarian cancer patients that have cyclin E positivity, because we know that predicts a worse outcome, not just PFS, but overall survival with chemotherapy combinations. Those are really the three reasons why we felt very confident we could move it up into earlier lines of therapy. What was not said was, do we have plans to move the chemo combination into the PROC setting? This means we declared we're moving the chemo combination into earlier or PSOC second line. We have a robust plan to develop it as a monotherapy in very heavily pretreated PROC. How the data we presented at ASCO would inform how we're designing studies in the PROC, we haven't disclosed. Okay. The phase III P- Sorry about the aggressive hand gestures, but that's the three buckets of ovarian. Yeah. Like, the early kind of chemo-refractory, platinum resistant, still treated with chemo, but still treated with chemo, but could you do better than chemo alone? Mm-hmm. Then, what we'll call very heavily pretreated, that's where we're seeing really high activity, is more than five lines of therapy. It's what led to the ImmunoGen approval in a patient population that's actually much less patients than what we would- Mm-hmm ... what we perceive we could benefit. Yep. So that's kind of the three, the spectrum without any slides. Yep, makes sense. Just back to the phase 3 PSOC trial design, have you gotten any feedback from the FDA yet? Or if you haven't, are there any areas where you can foresee some pushback potentially, or is it a pretty straightforward? Yeah, we haven't disclosed we're in active dialogue with not just the FDA, but it would be a global registration, global intense study, given the excitement we have around the drug. And we own all rights, all global rights now. So we are working very hard to design and enroll a study that would lead to a global approval strategy. In terms of the chemo that you select for the combination, what's the latest thinking there? Would it just be one, or could it be multiple? Yeah. So we have disclosed this. It was actually part of the ASCO presentation and the call deck. We see exciting activity with carboplatin. Again, we call it platinum-sensitive ovarian cancer, so that would be the logical- Mm-hmm But we're very excited about the paclitaxel, and what our global KOLs are telling us is that they want the optionality to either use carboplatin or paclitaxel. So the study design that would make the most sense would be to look at both of those within the PSOC setting, have an early futility or early, not so much efficacy futility, but tolerability and some futility, and then move forward with just one chemo combination. And there are definitely some efficiencies in just doing that in one study as opposed to sequentially. Yep, makes sense. We've got two and a half minutes here. Maybe just quickly on maybe your ZN-d5 real quick. Sure. So, we're committed to meeting our milestones around our BCL-2 inhibitor, ZN-d5. The two milestones, the, the drug's in clinic. We've been excited about using it as a monotherapy in AML, again, in patients, you know, in a good way. And that is an absolute unmet need, with no really available approved therapies past the first-line setting. Other BCL-2 inhibitors have demonstrated activity in AML but have not pursued a label. And so we have an actively accruing, and we're committed to showing the clinical data we've generated in AML thus far. It is a Phase 1/2, so I'm just trying to set expectations that, you know, it's, it's early, heavily pre-treated AML patients. And then, we're really kind of reinvigorated by some of the science behind the ZN-d5 azeno combination, in part because we have a very clear plan around azeno as a mono in ovarian and in USC. We have a very clear plan around chemo combinations that we think extrapolate above and beyond ovarian cancer. And we didn't talk a lot about it, but we're combining it with other molecular targeted agents like RAF inhibitors, where we see high amounts of preclinical synergy. So it makes sense that maybe if we have the preclinical rationale to combine it with our own BCL-2 inhibitor, which we do. BCL-2 inhibitors cause DNA damage. It's part of the apoptotic process, and that's what BCL-2 inhibitors do, is induce apoptosis. We see preclinical synergy in AML models, and we're running that clinical trial, and we're committed to at least updating the status. I can't remember exactly what we committed to, but updating the information available by the end of the year in that. So... It kind of strategically makes sense. We're all in with azeno as a monotherapy. We think because of its broad mechanism of action, it will benefit patients outside of the gyn malignancies, but that's more of a step two than a near-term goal. Yeah. Okay, great. We're just about out of time, so why don't we end it there? Thanks so much, Kim. Appreciate your time. Yeah, thanks for having me.