Greetings. Welcome to Zentalis Data Review KOL event. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. You may submit a question via the web at any time by using the Ask a Question feature on the left side of your screen. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. Please note this conference is being recorded. I will now turn the conference over to your host, CEO, Dr. Tony Sun. Tony, you may begin. Great. Thank you for the introduction, and welcome everybody to the Zentalis AACR 2022 Investor Event. I'm joined here today with our special guest, Dr. Katie Moore. Maybe, Katie, you can help us out by just giving a little bit of your introduction by yourself. Great. Thank you so much, and good afternoon, everyone. I'm Dr. Kathleen Moore. I'm a Gynecologic Oncologist at the Stephenson Cancer Center in Oklahoma City, where I serve as the Associate Director of Clinical Research and Director of Phase I Clinical Trials for our cancer center, and I'm very excited to be here today. Great. Thank you. Maybe first we have to obviously have the forward-looking statements and disclaimers, and then of course, let's go through today's agenda. We'll be focusing the majority of our time on obviously the WEE1 update, which we're very excited to share. We'll have a little bit of updates, obviously on the oral SERD and the BCL-2 programs as well. Just as a reminder, we are a company with multiple assets in clinical trials. We have four programs in the clinic, ZN-c3, ZN-c5, ZN-d5, and ZN-e4. We also have a degrader program that's obviously in preclinical development. Without further ado, let's just obviously go through just as a brief background on what a WEE1 inhibitor is. A WEE1 inhibitor basically prevents double-stranded DNA break repair by inhibiting the G2/M checkpoint. By doing this, you can actually send cells into apoptosis by inducing them to have double-stranded breaks and then going into mitosis without proper, obviously, cell cycle arrest. Our design of a WEE1 inhibitor or ZN-c3 was optimized through our structural biology work in looking at this pocket, and people, please refer to the JMC Paper, which we published late last year, talking about the improvements we've made in terms of targeting this pocket. Here is a slide about our selectivity, and this is probably something that we're very proud about of having the most selective WEE1 inhibitor in the clinic and something that we think in general is obviously a very differentiated clinical profile. Let's first go through the Uterine Serous Monotherapy Update. I'll just give the first heads-up. This will actually be a very short update 'cause we are embargoed, and we're actually not able to share the information until obviously Funda, Dr. Funda will be presenting the data on Monday during the oral symposium. Just so you know, as a background, of course, uterine serous carcinoma is a very serious condition. 10% of new cases, however, about 40% of deaths. In our study, we'll be looking at a very heavily len/pem treated patient population, lenvatinib and pembrolizumab. Maybe Dr. Moore, you can give your thoughts on, you know, what is it like to use len/pem in patient population and what's it like to treat post len/pem. Sure. I'll address those in kind of order. I think the first thing to say is that I agree with you. For uterine papillary serous carcinoma, it's an incredibly aggressive tumor. The one thing I'll point out to this audience is that uterine cancer, in general, is the only solid tumor increasing in incidence and mortality in the United States, and largely driven among women who are underrepresented minorities. This is an incredibly high-priority group of patients to develop better therapies for, and UPSC is a great place to start. We really were in a bit of a hole once you were post-paclitaxel and carboplatin in the advanced or recurrent setting with really monotherapy chemo being our best option, with an expected response rate at best of 15% of very short duration. Lenvatinib and pembrolizumab, that approval really did change that landscape. You know, we see upwards of a 30% response right now, which is fantastic, and we're grateful for that drug development. It's a hard regimen to use, though. You know, specifically in patients with mismatch repair or with microsatellite stable or mismatch repair proficient tumors, which are uterine papillary serous. You know, these are not your microsatellite- high tumors. That's who's gonna be getting len/pem. It's tough. You know, you really do have to individualize for patients. There's rapid onset hypertension, quite a bit of fatigue, and then the diarrhea that all requires mitigation strategies and dose modifications to try and keep folks treating with good quality of life so that they can benefit from that agent. You know, I have to be careful because we're grateful for that opportunity to actually have something that works better than 15%, but it is not easy to use, and requires quite a bit of attention to maintain, compliance, and long-term use. We can do it. It's just that there's a lot of room for something as equally as effective and better tolerated. Post len/pem space, I think we're still kind of evolving there. You know, the clinical trial that was done really does not have a lot of patients post len/pem receiving additional therapies. You know, it's less than 30% go on to receive an additional line of therapy. Why that is kind of remains to be seen in upcoming studies. Really the truth will be from kind of real-world evidence, big registries, to really see the sequential use of subsequent therapies post len/pem, what that looks like in a generalized population outside of clinical trials. We're kind of anxiously awaiting that. This is a new approval, so we don't have that. Patients can be pretty beat up, is my experience. It's a tough act to follow sometimes. Great. Thank you. Thank you, Dr. Moore, for that. Stay tuned. Obviously, we'll be sharing more information on Monday on that presentation. Let's go to the next section, which will be about the chemo combination of ovarian cancer, where we're very excited to share, obviously, new data in this first case of combination therapy with ZN-c3. Platinum-resistant refractory ovarian cancer is a large unmet need. And maybe once again, Dr. Moore, you can just briefly talk about the unmet need in this space and you know, what are the options. Sure. Platinum-resistant ovarian cancer. Unfortunately, most patients, the vast majority of patients will eventually develop platinum-resistant ovarian cancer. We do have maybe a cure rate of 15% for women with advanced, high-grade serous is what I'm talking about, ovarian cancer. The vast majority of patients, despite explicit chemosensitivity in the front line with platinum-based chemotherapy and surgery, you know, patients can enjoy long periods of time off therapy. Eventually, all of those tumors develop resistance to platinum. Once patients have received bevacizumab, just like my last comment, we're in this sort of monotherapy chemotherapy world of gemcitabine or pegylated liposomal doxorubicin or topotecan, where the response rates, from a generous estimate, would be about 15% again. There's a very high unmet need to continue to develop active, well-tolerated agents in this population, because especially in patients, I just want to make this point, just because a tumor has become resistant to platinum, especially if it's been like two or three platinums, that tumor will still respond to things if we find the right things. You know, ideally we would cure women, but until then, we can cobble together these meaningful progression-free survivals with these novel, well-tolerated agents and keep pushing out overall survival. High unmet need to keep developing in this space is women will receive many lines of therapy in the platinum resistant space as long as we're developing effective drugs. They don't receive those when we don't have effective drugs for them. This will always be a high unmet need for our patients until we cure this thing. Great. Thank you. Of course, we've looked at ZN-c3 in combination with chemotherapy in preclinical models. As you can see from these charts, it's actually highly effective with ZN-c3, whether it's paclitaxel, doxorubicin, carboplatin, or gemcitabine. The basic two-hit hypothesis still holds, which is you damage the DNA with the chemotherapy, and then you prevent its repair with ZN-c3. This is something we were excited about, obviously, to take into the clinic. In our O2 study design, we actually explored four different chemo combinations, PLD, carboplatin, paclitaxel, and gemcitabine. Due to the late arrival into the protocol of gemcitabine, we only have data right now for the first three combinations, and we will be enrolling patients soon in gemcitabine, and we'll share that data in the future. Here are some of the baseline characteristics of ZN-c3 O2 study. As you can see, just a couple of things I wanted to point out. There were 14% platinum refractory patients in the overall population of 56 patients. We had 46%, obviously with prior bevacizumab and about 14% obviously prior PARP use. One thing I did want to point out is that this was a very aggressive phenotype, given the fact that 100% of patients became resistant refractory between the first or second line. Maybe Dr. Moore, you can talk about like this aggressive phenotype where they so quickly became resistant or refractory. Yeah. I mean, this is really an interesting group of patients on this particular study for platinum-resistant ovarian cancer. A lot of times in early drug development, we're enrolling women whose tumors have become resistant, maybe third or fourth or fifth lines. They've kind of been these responder phenotypes like I was talking about earlier, where you can keep finding something that hits that tumor's Achilles heel, so to speak. You may see higher response rates. When tumors are resistant right off the bat, especially here, you'll see over 50% of patients in this study were resistant in the first line, primary platinum resistant. We have not done well there despite a lot of effort in this space. These are very resistant tumors, very high unmet need. Honestly, if we were developing a therapy that reliably hit high response rates in this line of resistance, which is about 20% of patients with ovarian cancer will have this primary platinum resistant phenotype. That is, you know, in a clinician's mind, kind of a home run sort of therapy. 'Cause it's been a bit of a, I hate to use the term graveyard 'cause I think it's disrespectful, but it's been an area of little progress in that first line. Plus, most of these patients have received prior bevacizumab, so they're out of the AURELIA label, which is the one thing that might benefit a little bit. So this is a very interesting early phase study population, very resistant. Great. Thank you. Some of the questions we've always been asked is, well, what should be the expectations for efficacy? I always point people to three studies. One was the AURELIA Study, which Dr. Moore just mentioned, which was a randomized phase III study of chemotherapy plus Avastin, where they looked at the combination chemotherapy physician's choice arm of PLD, paclitaxel and topotecan. Of course, in this patient population, which did not include platinum refractory and obviously did not include Avastin. There was an 11.8% overall response rate. That once again is kind of the best-case scenario what, you know, chemotherapy can do in this platinum resistant. As Dr. Moore mentioned, we do actually have much sicker population in our study. We have, obviously, your study, the Dr. Moore study that was published in CCR, which was a combination across four different chemotherapy regimens, just like ours. There was actually an 11%-33% range of efficacy, and I've excluded the high-dose CT arm, which we'll explain later, which was not as well tolerated. We'll get into that, and Dr. Moore will obviously talk about her study later. The Lheureux Lancet study, this was actually, we believe, the best-conducted study. This was a phase II double-blind placebo-controlled randomized study where in the platinum refractory patient population, in combination with gemcitabine, they generated a 23% response rate, 6% for just chemo alone. What was most remarkable to me about this study was the fact that there was an improvement in median overall survival. Not just PFS, overall survival, where there was almost a doubling of survival up to 11.4 months. The hazard ratio was 0.5, and the P value was statistically significant. We've always been amazed by the study that was run by Lheureux, where she generated a 23% response and almost doubled survival. Of course, that's how we kind of view, you know, the landscape in terms of expectations for efficacy as we ran our study. Of course, when we generated our 30.2% overall response rate, we were obviously very excited about it, with a disease control rate of 86%. If you actually excluded the refractory patient population, our response rate would actually go up to 33%. Let's look now at the spider plots. This is a spider plot of patients, obviously in the entire study. Right off the bat, when you take a look at this, you can basically see, wow, there's really good disease control rates. There are patients that go out even up to a year in terms of stable disease or partial responses. Also, the other thing I would point out is just the depth of responses that we see. As you can see, a huge clustering of patients between 50%-60+% in terms of tumor reduction. The study is early still, so we are not able to calculate a median PFS or a duration of response or, right now, or duration on therapy because we just need, obviously, a few more patients to. You know, the trial to be going on a little longer. But something, Dr. Moore, I was hoping you can talk to is that your experience. When a patient, you know, has a response, you know, when you ran your study with a WEE1 inhibitor, do these patients, you know, bounce off and progress right after or, you know, right after response are pretty stable and continue to benefit? In my experience, in our study, that was a kind of multi-arm study. When patients responded, and even in the monotherapy studies that I've been involved in, when patients respond to WEE1, they tend to be durable responses. We'll talk about this, I think, with adavosertib. There was quite a bit of dose optimization and individualization, especially in the combination. You had to sort of get through that period. It wasn't a response and then a bounce back up. You know, they responded, and then they stayed on for really clinically meaningful periods of time, which is why really in the gynecology community, we're very excited about WEE1, 'cause we know it works. We just need to figure out how to use it. Yeah, drug works for a while. You know, if we take a look at some of these patients, here was a 52-year-old female with stage 3 ovarian cancer and got carboplatin paclitaxel and then got carboplatin doxorubicin. As you can see, this patient actually never had a response. After a dose, obviously, of our drug with paclitaxel, experienced a 56% confirmed partial response. Here actually is that scan of this patient, and you can see the liver lesion markedly reduced, obviously, in the red circle. Here is another patient on the trial. That was a 72-year-old female with stage 4 ovarian cancer, and this patient actually had two rounds of carboplatin paclitaxel and obviously never had also a response as well. This patient went on to have a confirmed response of 46% overall and actually had a really, really nice decrease in the tumor markers as well. This, as you can see in the scans, was also a patient with a large hepatic lesion that obviously completely went away. We were quite obviously impressed with this. When we actually break down the study further in terms of the overall 30% response rate that we engendered, we see something that's actually quite remarkable for us, which is we had lower response rates with PLD, but we had really remarkable response rates with carboplatin and paclitaxel. 46% response rates with carboplatin and 63% with paclitaxel. Maybe, Dr. Moore, I'd like to hear your experience of what you saw with PLD, 'cause we always had obviously a lower response rate with PLD. I don't know what were your thoughts on PLD in general in this patient population. Well, I mean, this is really consistent with my data, our data. It's not just my study, of course, it's the team. With our data, with adavosertib, and we did the same thing, we had a gemcitabine arm as well. It's interesting to me, and I can't quite explain it, why the PLD combination just does not seem to be synergistic. We saw the exact same thing. Just really no signal there. Very strong signals for both paclitaxel, which again is a little bit counterintuitive, given the mechanism of action, at least from a cell cycle standpoint, but very high response rates with carboplatin. I think this is, you know, this study, it's smallish numbers, but they're very consistent in terms of the synergy that you're seeing in patients with you know, relatively refractory resistant tumors to re-treat with carbo. I mean, that's quite striking. Maybe, Dr. Moore, you can just comment just a little bit more because in your study in PLD, you actually had a 33% response rate in the low-dose WEE1 arm, and then, actually a lower response rate in the high-dose WEE1 arm with the PLD. What was your decision, actually, to enroll less patients and actually stop enrollment in PLD despite making the 33% response rate that you saw on the low dose? You know, there were some tolerability issues, and some other things that aren't quite in the public domain that came up that made this combination less attractive, PLD in particular. Okay, great. Okay, thank you. Let's go on to look at the data even further, right? This is the study, obviously, in the PLD arm. What you notice, of course, is that, you know, we actually had the most refractory patients. I should say, all the refractory patients in the evaluable population in the PLD arm is annotated, obviously by the Rs as you see here. That you can see we did have responses and actually very deep responses in these patients. There's obviously still a fair bit of patients that are ongoing. We had an excellent disease control rate of 83%. Then if you take a look at the carboplatin arm, the data gets even better. Here we have a response rate of 45% as you see here. You can see that just really deep responses throughout and a really, really nice disease control rate that obviously is continuing in many patients. Then finally, in the paclitaxel arm, you can see actually the most impressive results, which is we had a 63% response rate in this patient population and with a 100% disease control rate, and many of these patients are obviously still ongoing in the trial. This is obviously an arm that we're quite excited about in addition to the carboplatin arm. When you look at these efficacy studies kind of across the board as we label it here, you know, we talked about the AURELIA study, which Dr. Moore mentioned, which is the 11.8% response rate of chemo alone in an earlier study that was less fit. You know, that is kind of maybe the best-case scenario that did not include platinum refractory. You also had the Lheureux study published in The Lancet, which had the 23% response rate, which did include platinum refractory patients. Then maybe Dr. Moore, you know, you had a lot of responses, obviously ranging from, once again, 11%-33%. You did have this one arm of 67% with, you know, carboplatin with high-dose adavosertib. Mm-hmm. Maybe you can just comment in terms of, you know, the tolerability of the trial overall and particularly in that arm- Mm-hmm. with the high response rate. Right. I mean, the response rate here was remarkable. It wasn't so much high dose, it was just repeated dosing of the three days, right? The C1 arm, we just gave the adavosertib right around cycle 1, day 1, like normal. In C2, we did repeated dosing each week of the three days. Cumulatively a higher dose with a very high response rate. But you know, and it's published, so I can say it's you know, significant issues with hematologic toxicity that made it challenging to try and generalize that particular regimen you know, outside of phase I kind of trained centers with a lot of oversight. The hem tox was really the deal breaker for that particular regimen. Of course, you guys have seen the data that we've shared. We had lower responses with PLD, and so this will actually not be an arm that we'll be going forward with, but we're obviously quite excited about the carboplatin paclitaxel arms, which showed incredibly high obviously response rates. When you now have to couple, obviously the other side of the equation, which is safety and tolerability. When you take a look at this tornado plot here, you'll notice a couple things that are very interesting, which is, you know, this is just obviously, you know, for chemo combination trial, we believe is well tolerated. You'll also notice a couple things for people who follow the company in terms of a couple parameters. Most notably nausea. What we found that was actually quite striking is that our nausea rates at 55.4%, mostly Grade 1/2, was actually lower in combination with chemotherapy than actually in our monotherapy. We believe that's actually due to the premedications that physicians are used to giving with patients with obviously chemotherapy, which obviously does well for our drug as well. The analogy I like to tell people is, you know, if you're not feeling so well and seasick and about to, you know, have emesis on a boat, it's kind of late to then take the Dramamine. You want to obviously take the Dramamine before you get on the boat. Same analogy here, why we believe nausea and GI rates have actually markedly improved. When you look at the tolerability and the hematological toxicity of our drug versus adavosertib, and this is something we just kind of put together, you know, in terms of cross-trial comparisons between Dr. Moore's study, the Lheureux study, and our study. You'll see that for severe treatment-related Grade 3 or higher, neutropenia rates were better. For anemia, were markedly better. For thrombocytopenia, were markedly better. This is all done obviously with continuous dosing. You also notice the same trend with GI tolerability. So nausea were roughly about the same. Vomiting were slightly better than, you know, Dr. Moore's study. Then obviously, diarrhea for severe Grade 3 were actually much better. This is something that we're quite heartened by, that, you know, this is a trial that's showing that in combination that we can be well-tolerated for use. Of course, like we have always noticed that people who follow our story is that we're doing this on a continuous dosing basis. You know, this is obviously not the dose that the AZ drug has chosen, which is with less in frequency. But maybe, Dr. Moore, it'd be helpful to just get your thoughts in terms of, you know, what's it like treating patients with complicated regimens such as, you know, days one through three, eight through 10 kind of regimens. I think, you know, our patients are very interested in oral regimens, number one. They're very interested. They wanna be like patients on breast cancer. Although our agents are so much different. Oral regimens are of great interest, but, you know, they, the more complex the regimen, you know, sequenced dosing, days on, days off, you do run into some challenges with compliance and, you know, drugs don't work if patients don't take them, either because of toxicity or because it's just a complicated regimen. I think the more streamlined and simple that dosing can be once daily without sort of complicated calendars that they have to maintain just helps overall with compliance and safety and efficacy. Great. Thank you. I just wanted to kind of summarize this section up by saying, well, how do we look at efficacy in the story of tolerability, which we think are the two primary axes for this drug's development? This is something that we just put up in terms of saying, "Let's see how this drug does." Right? We have efficacy, obviously, on the y-axis based on response rate, and we have tolerability using this surrogate of serious neutropenia Grade 3 or higher. You know, Dr. Moore mentioned, of course, that, you know, she got excellent, really amazing phenomenal response rate of 67%, but it did come with a neutropenia Grade 3 of 75%. Of course, in The Lancet Lheureux Paper, you had a lower response rate, 23%, and also still, obviously a high 62% neutropenia grade. Paclitaxel was 29% with a 53% neutropenia grade. When you compare that in terms of this cross-trial comparison, we can generate 46, 63% response rates with markedly better, so far, neutropenia of 33% or 24% in our regimens. Once again, given the data that we saw for ZN-c3 plus PLD, that's not a combination that we look forward to taking forward, obviously, in future registrational trials. In summary, you know, this is something that we're super excited about, and we'll give obviously more, you know, data in terms of what we wanna do in a randomized phase III study that we would plan. We would likely choose, obviously, one of the other arms where we're generating 40%, 50%, 60+% response rates in combination versus perhaps a physician's choice of patients with PLD, carboplatin, paclitaxel and some combination. Stay tuned. There'll be future development plans that we will share. Next update. This is on the oral SERD, and this is something that we wanted to share with everybody. We wanted to give an update in terms of our efficacy data with CDK4/6. Something that we did see in terms of the study with palbociclib and abemaciclib was that our response rates were lower than what we wanted in terms of in combination with palbociclib and abemaciclib. We actually figured out why first we were quite surprised, was that we were seeing DDI, and actually in combination with ZN-c5 with abemaciclib, even up to a 67% decrease. As I think I've spoken to many investors, this is not a direction that we wanna take forward in combination with CDK4/6. We think the PARSIFAL trial is a difficult one to overcome for anybody who wants to combine with an oral SERD. Just as follow-up, our tolerability was excellent, and everything in here was consistent with what you would see in combination with the CDK4/6 inhibitor combination. In our thoughts in terms of a future potential adjuvant trial with a strategic partner, we do wanna say that we do not see any identifying relevant interactions with ZN-c5 with any of the 50 most prescribed drug lists. In fact, we actually took a look at cholesterol levels in patients as a surrogate, obviously for patients taking atorvastatin or Lipitor. As you can see here, the patients taking our drug had actually no differences or changes, obviously, in their cholesterol level. We do not believe there will be any significant DDI with commonly used drugs or for that matter, with ZN-c3 in our future combination study. Here's an interesting study that we want to update folks on, which is something we believe in bone protection. If you're gonna be using an oral SERD drug long term in the adjuvant setting where a patient potentially could be using a drug for up to 5+ years, we've been showing something that's quite remarkable. ZN-c5, as you can see in the green circle, is bone protective. Now we've actually tested in a separate study. Remember, this is an interim look, and the study is still ongoing. That Roche's drug, AstraZeneca's drug, Eli Lilly's drug, Sanofi's drug, and Arvinas's drug actually show marked bone loss. Maybe, Dr. Moore, you also treat, obviously, patients in this setting and just wanna get your thoughts on, you know, is bone loss, you know, severe bone loss, significant bone loss, you know, an issue in patients in this population if it's used long-term in adjuvant? Oh, absolutely. I mean, this is you know, we are watching, doing DEXA scans, putting patients on bisphosphonates, you know, doing all of the things to try and prevent adverse skeletal events, you know, in our patients, especially those that are already at risk for bone metastases by virtue of the type of cancer that they have. When you're using something that you know is destroying bone, but you're also controlling their disease, it sort of adds all these layers of complexity onto the treatment regimen. Eliminating that risk of bone loss while maintaining an effective anti-hormonal therapy for hormonally driven tumors, I think is sort of a. What's the word I'm looking for? You know, it does differentiate this sort from others. More to come, I think, but. More to come. This is obviously an interim look, and we'll update this slide as this animal trial obviously continues and finishes. The next few slides are actually just preclinical updates and clinical updates. First, just a quick one on our BCL-2 program, ZN-d5. We are, of course, pushing this program forward in monotherapy and amyloidosis, and as people follow the press releases, we are currently enrolling patients, and we announced that we actually dosed our first patient, so it's very exciting for us. Just as a reminder, there has been trials done in the clinic of BCL-2s in this amyloidosis population, and we just wanna point to the fact that response rates are extraordinarily high. If you have the t(11;14), which is in the majority of patients with amyloidosis, you can see up to an 82% response rates and long-term survival is, you know, at 3 years 90% or so. This is something we're super excited about. This trial is ongoing, and we'll share data, obviously, after we enroll more patients. The next section is something that I'm also personally very excited about, particularly in the science, so please make an effort to look at our poster at that AACR if you're there in New Orleans. We're gonna be showing more data about a new concept in biology that we call CAMPRO, and CAMPRO stands for Caspase-Mediated Proteolysis. Let me just walk you through these 2 charts, and then you'll kind of understand what we're talking about. On the left-hand side is just what does it look like to treat with a BCL-2 drug alone, such as with ZN-d5? On the x-axis, you'll see that's BCL-2 inhibitor sensitivity. Obviously, on the upper right-hand section, in BCL-2 driven sensitive tumors with high concentrations, you're gonna get apoptosis, and we know this obviously to be primarily in liquid tumors. If the tumor is not sensitive to BCL-2, you obviously get low apoptotic activity, and of course, you have low concentrations, you're obviously gonna have also limited activity as well. What's really novel is that we have found that at sub-apoptotic concentrations, there's actually DNA damage, there's actually damage to multiple proteins, particularly with DNA damage repair proteins. That when you actually decrease the concentrations of ZN-d5, apoptosis is actually not driven by the usual apoptotic pathways, but there's actually more pathways being lit up in regards to proteins and protein degradations, particularly in the DDR pathway. When you combine that with a WEE1 inhibitor, you get really marked effects. Let me explain this maybe with some charts that just show this. Here is just showing that the combination of a WEE1 at low doses here, this is at IC30, you're seeing WEE1 activity, WEE1 being degraded, RRM2 being degraded, et cetera, and obviously more gamma-H2AX signaling, DNA damage. When you try this, for example, in an AML model, you'll notice that ZN-c3 at a lower dose has little activity. ZN-d5 at actually the quarter of the normal dose has modest activity, but the combination of the two actually almost has complete regressions. Yes, we are excited about the fact that our ZN-c3 WEE1 program could also indicate for liquid tumor activity. Here in this next slide is just something we shared before at R&D Day, that we've actually tested this in venetoclax samples, where these are patients who have 68%, if you just look at this, the chart on the left-hand side, there was a venetoclax patient that had 68% blast after two months of venetoclax treatment. We actually cured that in, obviously, in vitro model to 0%. We worked in the PDX model. The new data is what I'm gonna show in the next slide. Well, if this CAMPRO hypothesis works, how does it work in other tumors, perhaps even solid tumors? This is truly exciting. What you're seeing here is activity of our drug ZN-d5 and ZN-c3 in small cell lung cancer, triple negative breast cancer, non-small cell lung cancer, and even in neuroendocrine prostate cancer. This is truly remarkable and showing activity in tumor indications that are obviously BCL-2 insensitive, and that the combination has fantastic efficacy, which we believe is due to the CAMPRO hypothesis. Here is another slide where we actually decide to use Navitoclax, which is obviously a drug that's more focused on BCL-xL, at one-third the normal dose, and combining with our WEE1 inhibitor, we get great efficacy in the ALL model. This is something that we believe may be universal in terms of using. Well, not universal, but across many different solid and liquid tumors alike with this CAMPRO hypothesis. Let me summarize this up in terms of what we shared today. We've shared obviously a lot of data. Stay tuned obviously for our activity in UPSC and the oral presentation Monday. We've shown, of course, really excellent chemo combination data that we're excited about, showing upwards of 46%-63% response rates with excellent tolerability. We've shared an update obviously on ZN-d5, where our decision is not to pursue a CDK4/6 combination, but we showed the presence in terms of saying this could definitely be a great drug to use in the adjuvant setting. Of course, we shared a little bit of an update of BCL-2 in terms of all the exciting things that may be engendered with a CAMPRO hypothesis. Our milestones are here. There's some checkbox obviously in terms that we've shared here today. That is the end of the presentation, and now we're going to the question and answer session. Please, we can do questions. If people have questions, please call or you can send it via chat. Thank you. At this time, we will be conducting a question-and-answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. As a reminder, you may submit questions via the web by using the Ask a Question feature on the left side of your screen. One moment please while we poll for questions. Our first question is from Mike Ulz of Morgan Stanley. Please proceed with your question. Hey, guys. Thanks for taking the question. Maybe a few quick ones for Dr. Moore. Just in ovarian cancer in terms of the different chemos that are used, is there a particular one that's favored over others? You know, we still really, somewhat incorrectly, but we're still locked into these platinum sensitive, platinum resistant cues. If a patient's tumor is considered to be likely sensitive to platinum, we're gonna reuse platinum until platinum doesn't work again, with or without a partner. Once a patient becomes, or once a tumor, pardon me, becomes resistant to platinum, you know, that tumor has progressed on the prior platinum or very quickly after, then it's this sort of series of monotherapy chemos. I think that probably the favored monotherapy regimen is weekly paclitaxel based on several studies, not just AURELIA now, where you will see response rates about, depends on the population, 20%-25%, for that particular agent. It is probably our most active monotherapy agent. Topotecan has 0%-6% response. PLD is, you know, 11%-13% with or without bevacizumab, so really poor. Weekly paclitaxel is probably our most effective regimen. What people select is really based on shared decision with the patient, because a lot of patients come out of first or second-line therapy with significant neuropathy. It's very common. The use of weekly paclitaxel is very limited there. A lot of patients don't wanna lose their hair again. There's reasons why it's not universally selected, but it probably has, I would say, 40% of the market for first platinum resistant use, and then the other two are divided up. Does that answer your question? Yep, that was helpful. Maybe just one more question, and then I'll hop back in the queue. Just given your experience with adavosertib and the early data we're seeing so far with the Zentalis combinations, you know, what are the key points of differentiation in your view? Is it really the safety? Or do you see other areas where you- Yeah, I think it's the safety. Right now, you know, it's. I think I have a lot of experience with adavosertib, and I was very fortunate to be involved and then lead the most recent study. Number one, it works. Targeting WEE1 is a great target. It works. I've seen it work. We've been kind of desperate, honestly, in drug development to get WEE1 figured out so that we can get it to patients in a safe way because it works. My experience with it has been that it works, but it's been difficult to use, and you have to be all over the hematologic parameters and then dose, modify, and hold appropriately, depending on, you know, if I'm using a monotherapy or a combination sort of regimen. I've been involved in both. I'm very pro WEE1 targeting, as are many of us that have used the drug. I think thus far, the efficacy data, and I haven't seen the uterine data yet either. It's embargoed to me as well. The efficacy data thus far looks very similar to what I presented in the combo arm and what Stéphanie Lheureux from Princess Margaret has presented. We feel at least at this point, it's at least as good, you know, and maybe it's better as a next gen. The safety profile does look significantly different. Those hematologic toxicities look very different to me. My antennas are up for this being the way we can move it forward. We need some more patients. I'm excited to have another agent in this for this target. That's helpful. Thank you. Our next question is from Akash Tewari of Jefferies. Please proceed with your question. Hey, guys. A few if I may. So look, for the treatment adverse event table that you showed, what was the median follow-up? For Dr. Moore, would you feel comfortable at this juncture saying the Zentalis compound seems to have a better safety profile than the AstraZeneca chemo combos? And do you feel like the safety profile that we've seen early on is acceptable in a real-world setting? Next question. It looks like one of your ZN-c3 plus carboplatin standard or stable disease patients on the 300 mg dose is very close to becoming a PR, which would push the response rate to 54%. Can you give any details on that patient? Have we seen that patient's lesion size shrink or grow from their last scans? Then lastly, there seems to be a big difference on the response rate when we looked at confirmed and unconfirmed responders. I think you mentioned this earlier, but I'd love to get more color, Dr. Moore. Can you comment on your confidence on whether these unconfirmed responders will eventually be confirmed responses and when we would get that update? Also what happened to the 13 patients that were not evaluable for efficacy? Thank you. Okay. Akash, I didn't actually write all this down, you know, try to- I'm so glad. The follow-up in terms of the adverse events was in a January cutoff. It's from the start of the trial up to January of this past year. In terms of the 13 patients that were not evaluable, the vast majority, I believe 9, 10 of them, were simply because of the fact that they hadn't had a follow-up scan yet, so it's just not able to even obviously evaluate, or they did not have obviously evaluable disease. We had about one patient come off because of consent. They chose not to continue with the trial for unclear reasons. Those are the main reasons in terms of why we did not put those into, obviously, the evaluable bucket. I'm not certain, of course, specifically on which patient right off the top of my head in carboplatin that you said that was, you know, getting closer to even a response. But we feel awfully good that there are so many patients that are getting close to a response and doing very well. Yes, we believe in the high response rates we're seeing, particularly in the carboplatin and paclitaxel arms. Dr. Moore, maybe I remember to reverse the questions in reverse order, but maybe the first one I think I'll repeat for folks who is what is your belief in whether these patients that had an initial response will later be confirmed and continue to benefit? We always have to see. You always have to, I've made some predictions about things that have been wrong, I have to couch that. Based on my experience with the data, you know, once you started to see tumor reduction, you know, on that first scan, usually that was an indicator that that patient was gonna benefit from ongoing treatment with the WEE1 kinase inhibitor. My experience is in combination with chemotherapies. With that sort of background, I would say my expectation is that many of these unconfirmed responses would be confirmed. We really did not see patients respond and then pop right back up with a new lesion on the next CT scan, in my memory or very often. The spider plots for our study look very similar. We had longer follow-up, of course, 'cause it's an older study, but patients really stayed on for a while. I do think that when you're seeing responses, they're going to be durable, and we can expect continued responses. I mean, I'll just say for our C2 arm, which was the one that had a lot of heme toxicity, so we have to keep that in mind. The median progression-free survival was 12 months. Patients stayed on for a while when they responded at some hematologic cost. If we can work that out, which I think we can here, then we're really going to be onto something for this population of patients. Dr. Moore Anthony Sun, can you just- Go ahead, please. Yeah, just a follow-up. Dr. Moore, you had mentioned that the 67% response rate you had seen in the AstraZeneca study, the tolerability just wasn't acceptable in a real-world setting. The chemo combo data you've seen so far, and specifically on the Grade 3 AE, do you think that is acceptable in a real-world setting? Thank you. Yeah. I think that it's getting closer. You know, I think it's more in line with what, you know, we can manage. You know, oncologists, junior oncologists, medical oncologists, we're a smart group, and so, you know, we can manage a 20%-23% rate of greater than Grade 3 neutropenia. You'll notice there wasn't quite as much thrombocytopenia, which we saw more of on my study, and that was probably more the concern. You know, I can live with, and a patient can live with, having a Grade 3 ANC as long as it's not complicated by fever, holding dose, and coming back up in dose mod from there. Really big drops in platelets do put patients at risk in a different and significant way that makes those sorts of therapies hard to generalize. It's hard to give a patient something. It's like the same thing we saw with niraparib in the early days when everyone's getting flat dose and you had someone at risk of walking around with 10 platelets. You know, that's just not okay. They had to do a lot of re-looking at the data to figure out the individualized starting dose, right? It's all about sort of figuring out how best to dose patients and modify so we don't have those risks. I think this is closer to what I think would be as acceptable than what we saw on my study. Thanks so much. Akash, you had some other questions, but I'm just forgetting it, unfortunately. If maybe you wanna repeat for Dr. Moore? No. You know what? I think we hit 'em. Yet again, I apologize for all the questions. This is very helpful. Thanks. Okay. Our next question is from Michael Schmidt of Guggenheim. Please proceed with your question. Oh, hey. Thanks for taking my question. Just maybe one more on the tolerability. I mean, it sounds like this is, you know, better tolerated than the AstraZeneca combo, Dr. Moore, based on what you said. I guess worth highlighting perhaps how it compares to just chemo alone and I'm also wondering about some of the DLTs that have been seen in the 200 mg dosing cohorts as well, and how you feel about those and perhaps Tony about selecting a recommended dose to those. Well, I can comment on versus chemo alone. I mean, I think that certainly when you add anything to chemotherapy that has linear activity, you're gonna increase some of the toxicity. It is gonna have more associated adverse events than chemotherapy alone. I think the important point is, can we mitigate those toxicities in an acceptable way so that patients are getting the benefit of the combination, and maintaining good quality of life, and able to sort of go about their business and feel relatively good, like we've done with PARP inhibitors. Those were hard to use initially, and we all figured that out. You are gonna have more hematologic toxicity. You're probably gonna have a little bit more nausea, although we see far less of it with combo than we do with monotherapy. These are things that as we put more patients on these trials, and kind of see how they do, we're gonna develop the mitigation strategies that allow us to use these drugs safely, in the right populations, so they can get efficacy. Hopefully, that answers your question. I think we just can't be blasé about, oh, there's, you know, it's no added risk. Of course, there's some added AE, but if we can mitigate it safely and at good quality and acceptability to our patients who are the most important people that are not in the room here, then that's a winning combination in my mind. I don't know about the dosing question you just asked, so you'd have to refer back to Tony. Yeah. Just in terms of dosing questions, Michael, we can say that we're actually continuing to do dose escalation, actually. The doses that we are working on are actually not the final doses. We do expect potentially the results could improve as we increase dose, but we just obviously have to monitor obviously the AE. We actually have not picked an RP2D with our key combinations yet. Okay, got it. You know, just conceptually, when you think about the sort of synergistic effect with DNA-damaging chemotherapy here in ovarian cancer, I guess, does that lead through to other indications too, perhaps, where the similar concept could be applied? Yeah, I would think so. I mean, I would think so. This is one of the few examples. Again, it's like PARP inhibitors, where ovarian kind of led the way with just amazing results. We had the halo effect for BRCA-associated breast cancer and prostate and pancreatic cancer now, where those benefits are good but not as great as ovarian. It's one of the few examples where we've led the way. I think this will be another example, where we're gonna set the standard, and then probably start looking at it. Makes sense to me in breast cancer, triple-negative breast, but it probably makes sense in several other tumors as well. There's certainly preclinical data to justify that. I would think there could be a great deal of a halo effect, especially if we figure out a biomarker for this at some point, which is beyond the point of this call. But I think that there's quite a few tumors that would benefit from WEE1. Yep. Breast being top on my list, but ovary for now. Ovary and UPSC for now. Let's get those approved, and then we'll branch out. All right. Great. Well, thanks for taking the questions. Of course. Thank you, Michael. Have a great weekend. Okay. Our next question is from. Oh, go ahead, please. Sorry. Our next question is from Eliana Merle of UBS. Please proceed with your question. Hey, guys. Thanks for taking the question. I was just wondering if you could give any more color on maybe the genomic profile of the responders and any trends in terms of mutations, or predictors of response. In particular, anything notable or pretty similar to what we saw with adavosertib, with the ovarian, you know, kind of thing with, you know, KRAS and TP53 as well as being predictors as well as BRCA of response. You know, are we seeing something similar here? Then I guess just for, you know, Tony and Melissa, I guess how should we think about the potential, you know, pivotal study or, you know, the potential clinical trial strategy going forward in ovarian? I guess, would you enrich for any particular patient population? How should we think about this in relation to the, you know, PARP combo study that you also are running? Thanks. Okay. All right. I was scared you were gonna ask another question I was gonna forget all in my head. Let me start off first with the genomic information. We actually do not have all the genomic profiling done yet, so that's a work in progress. We haven't shared that data. Obviously, we've gotten the late end of these patients and from prior published literature, it's also a heavily TP53 mutated population. Stay tuned, but I don't think we're gonna find anything new or different than what has been previously published. In terms of a regulatory strategy of this drug combination, I think it's actually getting pretty clear in my mind, which is, you know, we don't like the PLD arm, obviously, but we will choose ZN-c3 plus, let's call it Taxol or carboplatin. Then we will compare that combination of choice to a physician's choice, and that could include PLD, you know, topotecan or carboplatin or whatever that the physicians may want to do. We think that would be a pretty well-received trial, and we think the chance of success with that be extraordinarily high because obviously you've seen the response rates that we've generated. Ellie, I'm forgetting one of your questions. Oh, I'm sorry. I think your one question I forgot, Ellie? Sorry. Yeah, sorry. You're breaking up a little bit. Yeah. I was asking about just relative to the PARP combo and like, I mean, how you're thinking about the strategy in combo with PARP and ovarian relative to the strategy in combo with chemo and ovarian. In ovarian, we're gonna be looking at refractory patients that had become resistant to prior PARP, so we're trying to resensitize them. We think that would be a very interesting population, as obviously there's a lot of PARP patients out there. That's something that trial is obviously ongoing and enrolling. Stay tuned for that one. We'll share data, obviously, when that is obviously more mature. Before we take the next caller, I do wanna pick up Andy Berens' questions, which are actually on the chat. I just wanted to. Andy, these are answering your questions. First question is, did any of the refractory patients respond? As you saw on the total chart, all the refractory patients actually ended up in the PLD arm. No, they did not respond. That is a tough population to work with. Next question is, what metrics on duration of treatment can you give? When will you have confirmed response rates? We shared the spider plot to illustrate the point is that the duration of treatment is just too early to calculate, since a lot of our patients, obviously, are early. Too many patients would be censored in that data cut. But we will share that data, obviously, as the trial data emerges and matures. That's the same for the confirmed response rates. We'll share more data, obviously, as further on when the trial matures. Next question from Andy was, is there any physiological rationale for better responses with taxane? Good question. We are looking to advance that question in the preclinical realm. We have some ideas as to why it may be, and we'll share with that more in the future. We think it has to do with some of the DDR proteins that are being affected, but we'll share more of that in the future. Okay? Time check. Do we have time for another caller? Yes. Our next question is from Bradley Canino of Stifel. Please proceed with your question. Great. Thanks for squeezing me in. Thanks for the data update as well. Tony, I'd just like to start and ask the rationale for enrolling these more aggressive patients into the trial. You know, it's encouraging to see the equivalent to better response rates with the tolerability in them, but how did you balance that with the potential benefit you would have had of a more comparable data set in the like for like patients to the adavosertib trials? Can you also talk about the ZN-c3 dose interruptions in the trial? For dose interruptions, we're actually gonna have that data in the UPSC presentation that Funda will give. Stay tuned on that, on the dose interruption piece. You know, the dose interruptions we think were low in this trial, and we'll share more data when it obviously matures. It's just a little bit too early for us to share on that too. There's obviously more mature data on that question on Monday, so please stay tuned for that. Your other question is why do we choose to go for a more aggressive phenotype? We didn't have to enroll refractory patients or more aggressive phenotypes. You know, we wanted to see what this drug can do, and, you know, we wanna make sure that we can go for an unmet need and we think we've knocked it out of the park here, showing extraordinarily high response rates with good safety and tolerability. That's what we wanted to do. We wanted to ask the hard questions. Okay. I appreciate it. Thank you. It is a very similar patient population, actually. Well, a little different to adavosertib. Adavosertib was primary platinum resistant, so they had to have recurred after their first platinum within six months. They were allowed up to four lines of therapy. Here they just had two. It's still similar, just so you know that. Got it. Similar, but not the same. Appreciate it. Thank you. Yeah. Okay. Is there another question? We have one final question from Matt Biegler of Oppenheimer. Please proceed with your question. Oh, hey, guys. Thanks for squeezing me in. Thanks for the event. This one actually does fail on Andy's prior question, but I wanted to ask Dr. Moore if there is any maybe working hypotheses on whether or why certain forms of chemo might work better with WEE1 than others. Perhaps it depends on the form of DNA damage induced or something. I guess maybe what I'm trying to get at, is there any reason to be maybe even more hopeful for the gemcitabine combo, which you're now enrolling? Thanks. Yeah, that's a great question. I think we're gonna get some more data from at least the, it was not mentioned maybe as clearly earlier, but the gemcitabine arm is gonna really pick up here. We're gonna get quite a bit more data with gemcitabine. As was mentioned earlier, Stéphanie Lheureux's work, Dr. Lheureux's work was pretty striking for gemcitabine in that randomized phase II. When you think about it preclinically at least, gemcitabine is your most obvious choice because you're inducing replication stress with gemcitabine, that's kind of how it acts. If you bring in a WEE1 inhibitor or even an ATR inhibitor or something at that G2/M checkpoint, especially in a tumor that at baseline doesn't have a lot of replication stress at baseline, you can kind of synthesize or be synergistic with gem. Gem, like, should be the poster child for combination. It's just been really heterogeneous in terms of the studies to date other than Dr. LaRue's. It wasn't awesome in my study. We'll see what it looks like here. That being said, sometimes the things we think work in, you know, on paper in mice, when we put them in people, we see very different things. Like, I would not have predicted the strong synergistic signal with paclitaxel. You heard Dr. Sun say we'll kind of talk about that mechanism in the future. We saw very similar in my study. It was sort of puzzling as to why that would be synergistic. Then the carboplatin probably goes along with the same idea as gemcitabine, although far less replication stress induction and more, I think, just causing DNA damage that then just cruises through that G2/M checkpoint unrepaired and leads to, you know, mitotic catastrophe and collapse. Which one of those pairings is the best for tumor response is hard to predict at this point because they all look pretty good. Truthfully, we may learn over time that it's tumor specific, and we may pick the chemo we use with WEE1 based on a replication stress score is one example, or a molecular marker to someone's question earlier. I think we still are learning a lot about which is the best combo, or can you just do physician's choice of these three, you know, and have sort of an agnostic combination. That's a possibility, too, which would really make this very generalizable to different populations. We have to learn. There's a lot of theories and a lot of small patient numbers, with the exception of GEM, which has the most. This study will, I think, give us quite a bit more information on how we move this forward and in whom. It's like a non-answer to your question. Sorry. Thank you. Great. I think those are the last questions that we have. So once again, we will wrap up here. Just wanna thank everybody for their interest in listening. Hopefully, this was educational and informative. Stay tuned as we obviously continue to press the programs. Once again, thank you for the time. Yeah. Thank you for joining us. This concludes today's conference. Sorry, go ahead. I was just saying we're good. Let's wrap up and give everyone some time back. Dr. Moore, thank you for joining us. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation, and have a great weekend.