Okay, great. Good morning, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thanks very much for joining TD Cowen's fifth Annual Oncology Innovation Summit. For this next session, we have a fireside chat with Zentalis, and it's my sincere pleasure to introduce Kim Blackwell, Chief Executive Officer. Kim, it's a privilege to have you here. Thank you very much for joining me. Sure. Well, as always, thanks for having me as well. Of course. Before we get started, for those of you in the audience, feel free to email me any questions that you might have at tyler.vanburen@cowen.com. I'll do my best to get those answered during our session. But Kim, it'd be great if you could start by giving a brief overview of azenosertib for those who are less familiar with Zentalis. Yeah, sure. Well, azenosertib is our lead clinical asset here at Zentalis. It really is a hallmark therapeutic in the sense that the very origins of Zentalis were kind of cutting-edge medicinal chemistry against known cancer targets. Azenosertib targets... It's the 50th anniversary of the discovery of WEE1 this year, so we're kind of highlighting that. It's been a long-known, very important cancer target in that it, WEE1, when left to its own devices, creates stops within the cell cycle that allows cells normally, and cancer cells, to repair their own DNA. When you remove those checkpoints within the cell cycle process, cancer cells grow out of control, and ultimately, that leads to cancer cell death and mitotic catastrophe. Azenosertib is well advanced into the clinic. It has demonstrated monotherapy activity, and in particular, high amounts of response rates at about 31%, which is what we reported out last year, in heavily pre-treated, or what's also known as platinum-resistant ovarian cancer. So the fact that it's against a known target and has such a high amount of monotherapy activity makes us very excited about the potential of developing it as a monotherapy and getting it to as many ovarian cancer patients as possible. Wonderful. So ASCO is coming up this weekend. What more should we expect from the poster of the phase I clinical study of azeno in combination withgem in osteosarcoma, relative to the update we received, I guess, almost a year and a half ago now? Yeah, sure. So although our company's priority, one of our many priorities, is to develop azenosertib as a monotherapy, we'll be presenting data at this week's ASCO meeting, building on a fairly long, 2-3-year experience of the drug being combinable with a number of agents, including traditional chemotherapy. So the presentation at this week's ASCO is combining azenosertib with a commonly used chemotherapy known as gemcitabine for the treatment of osteosarcoma. The background of this study is that osteosarcoma is an incredibly hard-to-treat, chemo-refractory, very little response, in fact, less than 5% objective response rate disease. And the drug, azenosertib, combines very well with a number of chemotherapies. We've seen high amounts of synergy with carboplatin, paclitaxel, pegylated doxorubicin. This week's presentation really is the first completion of a dose-finding, or what we know as a phase I study, combining the drug with a highly synergistic, at least preclinically, chemotherapeutic agent known as gemcitabine. Gemcitabine is a commonly used chemotherapy in osteosarcoma, so after Adriamycin and ifosamide, gemcitabine is one of the chemotherapies that's used in a setting known as relapsed or refractory osteosarcoma. That means that local regional therapies have failed to contain the disease, and unfortunately, for the patients facing this situation, the disease is incurable and incredibly hard to treat. So the phase I poster that we're presenting declares a go-forward dose in osteosarcoma in combination, the combination of gemcitabine and azenosertib. Really, the top-level results are that the combination was well-tolerated, but compared to historical controls of single-agent chemotherapy, we saw a tripling in the event-free survival above and beyond single-agent chemo, or what you would expect. It wasn't a direct comparison. This leads to a lot of excitement in the osteosarcoma community and plans to move it into an investigator-initiated or cooperative group-sponsored study, where you would be able to look at the combination and have some sort of comparator of single-agent chemo, most likely gemcitabine, given that that's the backbone. We're really looking forward to working with the investigators to move that into the go-forward dose into the clinic and demonstrating even further the activity we saw in the phase I study. Okay, that's helpful. The... We're gonna move to ovarian and USC now, but does this update this weekend have any particular read-through to your efforts and those indications? Yeah. Well, I think the most important thing is, is at last year's ASCO, we were able to declare recommended Phase II doses in combination with carboplatin in ovarian, in combination with single-agent paclitaxel in in platinum-resistant ovarian cancer, and we had previously declared a go-forward dose with pegylated doxorubicin. So this is really the fourth declaration of combining azenosertib with a number of single-agent chemotherapy. So we've done the work to really demonstrate that the drug is combinable, with a number of chemotherapeutic agents, and that has implications, given what we're seeing, as well as the preclinical strength of the data for other disease types, for combining azeno with chemotherapy. Okay, great. So let's move to ovarian. In the second half of the year, I believe you guys have four or five data readouts. The clinical activity is ramping up pretty aggressively here. For the final phase Ia azeno monotherapy results, how many more patients will we get, and what will be new as we think about comparing and contrasting it to the monotherapy data presented at ASCO last year? Sure. So great question. High level, we have a lot of data readouts, two very important data readouts using azeno as a monotherapy in the second half of this year. As you alluded to, the first of these readouts is a phase I study, also known as 001, that initially enrolled a lot of different tumor types in a very traditional dose escalation study, starting as low as 25 mg once a day, given continuously. The study's been ongoing for a long time. What we disclosed last year is that there were over 120 patients enrolled to date, and what we actually showed as a demonstration of the dose optimization work that we have been doing is that the response rate in ovarian cancer was 31% and 50% in uterine serous carcinoma, a less common form of endometrial cancer. And I just wanna really highlight, 'cause we're gonna see a lot of data later this week, that this is monotherapy activity. So we're the only drug to have oral monotherapy activity besides the PARP class in ovarian, and we were very pleased with this 31% objective response rate. The two data readouts that you're gonna see later this year are, one, the 001, the phase I study, and the second is a study known as MAMMOTH, which has a cohort of patients treated with monotherapy azenosertib, and we can get into the details of MAMMOTH in a second. But to answer the second part of your question, which was really how many more patients should we expect to be seen in the second half, I can tell you that enrollment has been very, very robust. It really is indicative of the excitement of investigators of having an orally available drug that works as a monotherapy, especially in these hard-to-treat platinum-resistant ovarian cancer. We've enrolled all comers, meaning that there wasn't a specific biomarker, other than patients had to receive a PARP inhibitor in the MAMMOTH study. I think, you know, we're pretty excited to put data out there that really represents a significant increase in the number of patients, not just treated with monotherapy azenosertib, but also treated at our go-forward dose of 400 mg, five days on, two days off. So when you look at those two data sets, what people should expect is a significant, and significant means at least 5-6-fold more patients than what was available last year, and in particular, treated at that 452 dose, just from the 001 and the MAMMOTH studies. So, you know, I'm really proud of our team here at Zentalis. I think it really represents the collaborative spirit we have with many of the ovarian and gynecologic oncology groups. This is not, you know, gonna be a small data set. This is gonna be a pretty significant data set when you look at the sheer number of patients treated with ovarian cancer in both of these data readouts this year. Sounds great. 5-6-fold is certainly a pretty big jump. At least, I wanna be clear about that. At least. Okay. Even better. But as we think about the MAMMOTH update that you referred to, in PARP-resistant ovarian and the combo with niraparib, what do you need to see from that data readout to be confident and move that combination forward in clinical development? Yeah, so, you know, the history of the MAMMOTH study, I know you know it well, was that it started in late 2021 when the preclinical data would support that WEE1 inhibitors combined very well with PARP inhibitors. We had seen data from the historical no longer being developed AZ WEE1 inhibitor, adavosertib, which really actually showed that post-PARP, olaparib and olaparib plus adavo had similar activity post-PARP. It was a study known as EFFORT, and there was a 23% response rate with adavo alone, which is not a small response rate, especially when you think that adavo was being given five days on, five days off, so kind of a very intermittent dosing schedule, but still with monotherapy activity. The study was initiated kind of really to demonstrate that azenosertib, the Zentalis WEE1 inhibitor, could be combined with niraparib, which we now know in retrospect, probably isn't the most active PARP inhibitor in ovarian. We saw some recent data, you know, even at SGO, the gynecologic oncology meeting, that head-to-head preclinical data would say that niraparib is not as active as olaparib. But at the time, niraparib was available, and the company felt like it was a very worthwhile endeavor to try to combine it with a PARP inhibitor. So the study is not a randomized study. It is three cohorts that were sequentially accrued for women facing ovarian cancer post-PARP. The first cohort is layering azenosertib on top of niraparib. The second cohort is alternating or sequencing, so one week of azeno followed by one week of the niraparib. And then the third and most recent cohort is known as cohort three, and it is a cohort of patients that have all progressed on a PARP inhibitor that are now being treated with monotherapy azeno. And as you can kinda tell by my recurring monotherapy theme here, if you have a drug that meets, you know, an approval standard as an oral agent, as a monotherapy, that is the fastest path to get a drug to patients, to get approvals, to get, you know, all the things that you need to have a commercially successful asset. And so the third cohort is, you know, equally important to the idea of, can you combine azeno with a PARP inhibitor? We're looking forward to showing the data. The other differentiator, if you're looking at the data readouts for this year between MAMMOTH, which is the post-PARP ovarian, and 001, which is the phase I kind of dose, dose-finding study, is that great attention was paid to collecting tissue and sequential cell-free DNA on MAMMOTH. Because I do, I do believe that having that information, having an enrichment strategy that would drive up a response rate above and beyond what we, you know, even reported out on the small data set last year, is really important. So if you wanna think anything about MAMMOTH and what we're tracking, one, it will answer a question: Does monotherapy work about the same or differently than layering it than monotherapy azenosertib the same or differently than layering it on top of a PARP inhibitor? The historical precedents with adavosertib and olaparib, the AZ study, is it really doesn't add a lot to add them to. That's, that's one of the questions that MAMMOTH will answer. But then second, this monotherapy cohort with fully interrogated biomarker, that will really be incredibly supportive data for the registration-intent study we're running, which is DENALI. Okay. Yep, perfect segue to my next question on biomarkers. Denali phase II data is coming in the first half of next year, where you're enrolling patients who are CCNE1 amplified and/or cyclin E positive, E1 positive or negative. So, what do you hope to show in that trial in terms of overall response rate and duration of response when the data read out? Yeah. Well, so DENALI, as you alluded to, is a study that's specifically defined, designed to help us understand, is the response rate even higher in a Cyclin E-defined population of platinum-resistant ovarian cancer? And there's a very robust data set pre-clinically, that WEE1 works even better in Cyclin E-driven ovarian cancer or Cyclin E-driven cancers, but particularly Cyclin E ovarian cancer. And then we saw late last year, probably one of the last IIT studies we'll see with adavosertib, which is adavosertib, given as a single agent, five days on, five days off, in Cyclin E-defined cancer, certainly met what we consider a bar for an accelerated approval, although no longer being developed by AstraZeneca. We believe we have a better WEE1 inhibitor. It's more specific. It's only five kinases. So, you know, the logic is the preclinical data of Cyclin E in Cyclin E-driven cancers where azeno works even better. We have the adavo clinical experience, where adavo, given on a fairly intermittent schedule, worked, you know, with over 30% response rate and an enduring duration of response from 4-6 months. And that's exactly what DENALI has set out to prove, which is in a registration grade, registration intent study, does the drug work in everybody? Does the drug work better in Cyclin E-defined cancers? And I do believe the supporting data and this, the premise behind this, the DENALI study is incredibly strong, stronger than many studies that I've been involved in with that, within my career. And so we're looking forward to disclosing those results in 2025. Okay. Okay, let's go ahead and move to frontline, your frontline maintenance approach in platinum-sensitive ovarian or PSOC. Can you just remind us why you guys decided to make this change in the fall, and if you're currently generating data with azeno in frontline maintenance? Yeah. The basic reason, and you and I have discussed this before, that we decided to move the drug up to the earliest line of therapy for stage three, four ovarian cancer, which is also known as the first-line PSOC maintenance setting, is 'cause what we heard consistently is for patients that have finished their initial first six cycles of carboplatin paclitaxel, we need better maintenance therapy, and we need better maintenance therapy, in particular in patients who are no longer eligible for the benefits of a PARP inhibitor, which are basically patients that are not whose tumors don't harbor a BRCA mutation or are called HRP, or in the old days, we called it HRD negative. And what we heard consistently was you have an oral agent with monotherapy activity-... that we need something to, just like in the adjuvant setting for many solid tumors, we're looking for an oral therapy to layer on top of Avastin or bevacizumab. And that's exactly the intent of this study, is to really layer the drug on top of single-agent bev, which has only been shown to improve the time for recurrence by about two months, with a drug that had a median PFS of five and a half months when we reported out the initial efficacy data last year. It also enabled us to move the drug into a setting where there's very limited therapy, meaning the PARPs are no longer being given in that setting. There was a clear regulatory standard, which is, if you could improve the recurrence or the disease-free interval, some people call it the progression-free survival, by a matter of 4.5-6 months, which is exactly what our drug does as a monotherapy, that would be a blockbuster drug, similar to the way that the PARP inhibitors are being used in the first-line maintenance setting. We plan on giving some more thorough details, as well as timelines, in the second half of this year around that study and the study design. Understood. At a high level, in terms of the study design, though, is there anything you could say? I mean, I guess the obvious is it's gonna be the combination versus monotherapy, bev and, and patients in the frontline maintenance setting with a medium PFS as a primary endpoint. Is that fair to say? I think that's similar to almost all of the first-line PSOC maintenance studies. I think it's fair to say that, you know, that the drug with bev, without the use of PARP, would be limited to the HRP setting, but that's still a tremendous opportunity. We see a tremendous opportunity to move that drug up, especially as an oral agent. It plays to the advantages of having an oral drug, as opposed to... You have to remember, these women have just finished doublet chemotherapy for more than, you know, close to half of a year. What we hear consistently is one of the reasons the PARP inhibitors were so successful, even with the heme tox of the PARP inhibitor, is people want oral agents. Again, no different than any other, what we call, adjuvant or long-term setting. And so I think this design and our intent really plays to the strength of the drug, in that setting. And to answer your question, PFS or disease-free interval are regulatory endpoints that are widely accepted in that setting. Okay, that's great. Let's move to USC here in the last few minutes. Is this an indication you guys are still excited about? And, what do you need to show in the phase II TETON trial, with the azenosertib monotherapy in USC in the second half of next year in order to file for approval? Yeah, so we're still incredibly excited about the opportunity, although it's a much smaller opportunity than the platinum-resistant ovarian cancer. We've estimated the treatable patient population to be about 4,000 patients who have progressed through first-line and second-line, although now pembrolizumab and IO is being moved up into the first-line setting, so that allows us to really think about moving the drug as a monotherapy into the second line. Again, similar kind of logic, which is adavosertib given five days on, days off in the old days, and in a study known as ADAGIO old days meaning a year ago, that's why I'm laughing. In a study known as ADAGIO, you know, had a response rate that would put a drug into the accelerated approval. The heme tox in ADAGIO was was not as well-tolerated, and AZ was no longer developing the drug. We reported, again, in a small patient population, a 51% response rate in a drug that is known to be chemotherapy refractory, very limited treatment options. And so we remain excited about it. It's just a smaller commercial opportunity. But certainly, one of the things that's important to recognize is it's the same prescriber base, meaning the same doctors that are taking care of the ovarian that will build experience in how azeno works and see the drug working in their own patient population, will also have an opportunity to prescribe the drug for USC if we're successful in getting it registered. Okay. Let's move to the next indication, colorectal cancer, fairly large solid tumor indication, of course. Can you just briefly explain the rationale to combine azeno with the BEACON regimen and what you hope to see with the data update by year-end? Yeah, broad strokes, since we're short on time. When you inhibit a driver mutation, you cause what's known as replication stress, and that is the sweet spot for WEE1 inhibition. The tumors cannot keep up. The replication forks, which are part of DNA repair, can't keep up. The DNA can't repair. And if you think about this, the cell is kind of shackled. It can't repair its own DNA because you've removed the driver mutation, whether it be BRAF or KRAS, and that's exactly what you do with the small molecule inhibitors. Our drug comes along and just puts the accelerator on, causing mitotic catastrophe. So we showed, you know, even at this year's AACR, very strong preclinical data in combining azenosertib with a KRAS inhibitor. The colorectal study that's partnered with Pfizer is really based on very strong preclinical data, combining azeno with the BEACON regimen, where tumor regressions were occurring, where most of the people working in that field said, "We just don't see tumor regressions in these BRAF CRC." As you know, BEACON has a lot, there's a lot to be desired in that it, the duration of the benefits to patients is really only a little over four months. We saw an opportunity to develop a zeno in combination with highly synergistic molecularly targeted agents, without really layering on top of drugs that have combinatorial heme tox. That really is strong preclinical data, no overlapping tox, is really the premise for why we're excited about combining the drug, not just with the BEACON regimen, but with other molecularly targeted agents. Okay, very helpful. We're up on time, but I have to ask one last question. Since you have a phase I readout for azenosertib plus ZN-d5 and relapsed refractory AML by the end of the year. So maybe we could just give a brief, a few lines on what you expect to see with that update. Yeah, again, phase I, dose escalation study, you know, no overlapping tox, hypothetical overlapping tox with a BCL-2 and azenosertib, very unmet need population. Preclinical data showed a lot of synergy when you think about it. You know, apoptosis is programmed cell death. That's what BCL-2 inhibitors cause, and our drug just contributes to cell death by speeding up cell cycle. So very strong preclinical data, unmet need, lots of enthusiasm from the investigators. Not molecularly defined, at least the way that enrollment has been included, and so we, you know, look forward to sharing those results in the dosing later this year. Okay, wonderful. Kim, thank you very much for your time. It was a very interesting discussion, and thanks to everyone for logging in. Thanks again, Tyler.