Greetings, and welcome to the Zentalis R&D Day event. At this time, all participants are on a listen-only mode. A question-and-answer session will follow the formal presentation. For participants connected via phone, if you would like to ask a question, you may press star one on your telephone keypad. If anyone should require operator assistance during the event, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Dr. Anthony Sun, CEO of Zentalis. Thank you, sir. Please go ahead. Great. Thank you. First, I wanna thank everybody for attending the R&D day at the end of the year. This is something we've been preparing for about half a year, and we're very excited to share. First, I'd like to just introduce some of our scientific colleagues that have joined us on this call, and maybe you can give your brief backgrounds, that'd be great. Kwok, can you start? Sure. I'm Kwok Kong. I'm a Thoracic Medical Oncologist. I'm also the Director of Hematology Oncology here at NYU Langone Health. Really focusing on looking at novel therapeutics in non-small cell as well as small cell lung cancer. Great. Thank you. Anthony Letai. Hi. I work at Dana-Farber Cancer Institute and Harvard Medical School in Boston. For many years, I focused on understanding how the BCL2 family of proteins regulates apoptosis, and also how we can manipulate that to selectively kill cancer cells with drugs that are inhibitors of BCL2, BCLXL, and MCL1. Great. Ross? Hi. Ross Levine. I'm the Chief of the Molecular Cancer Medicine Service here at Memorial Sloan Kettering Cancer Center, and for many years I've focused on novel mechanisms to delineate therapeutic opportunities in leukemia, including those that target signaling epigenetics and other sort of pathways, including DNA damage. Great. Thank you, everybody. A couple things that we're gonna be trying to do on this R&D session. It's maybe a little different from others and just get a couple things off the plate. Number one, there actually will be nothing at this R&D Day about the biomarker in case people were wondering, so let's just put that out there. Number two, we're gonna try to do this in an hour. Folks that may be multitasking, you might miss something 'cause we're gonna go pretty fast. Without further ado, let's do this. Here are the forward-looking statements that folks may need to read later. Slide three really is a company overview. I think many of you that are listening on this call know the company quite well, but something that you may not know quite well is really about the integrated discovery engine, and that's really the focus of this R&D day, to give people a little bit of a peek underneath the hood of what we are doing at our science center in San Diego. Here is kind of what I've shown in our corporate deck slide about what we do best, which is merge cancer biology and medicinal chemistry together to create drugs that we think are unmet clinical needs. That's something that we've done, hopefully people will do well. I also wanna start a little bit from the past and go into the present and into the future. We started as a preclinical small molecule discovery company, and some of the probably viewers on this call are some of our early private investors, and we basically focused on chemistry. We've put a DDR oral ER degrader and apoptotic drug into the clinic, and that's where we are currently today. I think we've shared before, people in the past, really exciting data about what we have generated in the clinic, obviously in patients. There is a future, and the future really is about approved drugs, and you'll hear me talking more about some of the efforts that we are putting forward in the company to create even more pipeline products and clinical assets of value. Underpinning all of this is the point that's gonna be the force behind or the message behind this R&D day, is the integrated discovery engine. How is it that we create new drugs, that we get new targets and combination partners? How is it that we use the integrated discovery engine to derive better clinical trials because of novel patient selection or drug partners or schedules? How do we actually go into the commercial realm with better markets and new clinical indications? Underpinning all this, once again, is the integrated discovery engine, so let's talk more about it. We actually have put in state-of-the-art, for instance, X-ray crystallography into place. We are doing this in-house. We're expressing our own proteins, purifying them, creating crystal structures in an iterative structure-based drug design, and where we use our chemistry expertise to basically find better designs of competitive protein scaffold pockets. In addition, we've also integrated our genomic discovery platform, and this is some of the work that we've been using CRISPR screens, where we're doing unbiased approaches to find biomarkers, unbiased approaches to find combination partners and new targets. Here, for example, is just some data in our collaboration with Tavros Therapeutics, where you're actually seeing data generated in our labs looking at, for example, what genes are involved with WEE1 sensitivity, what genes are involved with resistance formation. Obviously, we're just listing some of the aspects of the finds here. For example, you will notice that RM1, RM2 are sensitive genes to knockout, and this is something that we'll discuss about later in the slides. In addition, we're also using machine learning, and I know this is an oft-used word for many companies, but we have actually integrated this into the company at this moment. 'Cause we believe in a multi-omics approach where we take every data piece that we have in the company from CRISPR screens, organoids, cell lines, patient response data from our clinical trials, and we're feeding it into the machine learning algorithms that we have created. We've created the data infrastructure with AWS and all the, you know, the logos that you see here to enable us to access this information to basically turn this data into knowledge and to make predictions. What is the drug combination we should use? What is the biomarker we should pick? What is the drug schedule resistance mechanism that should arise? This is actually gonna become a bigger and bigger part of what we're doing in the integrated discovery engine. In addition, we're also expanding our discovery capabilities, and we're enhancing the chemical space. There is actually a very large effort that we're doing in the targeted protein degradation space, and you're gonna hear it later today about our efforts in heterobifunctional degraders. This is an active area of further capabilities. In addition, we are also doing more in terms of organoids. Organoids are derived from patient tumor biopsies, and we're using this data to basically find and to refine our hypothesis on what works and what doesn't. This is, for example, some data in our collaboration with Tempus, where we can see that the combination of gemcitabine and ZN-c3 has great effect in an ovarian cancer organoid. Of course, we're also bringing something called BH3 profile, which is what you're hearing for the first time today, based on a license from the Dana-Farber Institute, and we'll talk more about this later in the presentation. What is this all about? Well, it starts with a patient, and it always starts with a patient, and it ends with a patient. We look at pathways, we look at genomic features, we look at places where there could be a biological effect that we could interrogate. Then we put our discovery engine to work based on all the different things that you've seen us talk about earlier today about the chemistry, the preclinical models, the CRISPR screening. We create drugs that we ultimately wanna put back into the future. We believe in this iterative cycle that is actually what we wanna do at the integrated discovery engine front. Without further ado, now let's talk about some of the data that we've been generating with the integrated discovery engine. We'll start with, of course, ZN-c3 WEE1, which is our platform program. You've heard me talk about this slide, which is, you know, talking about how a WEE1 inhibitor works, which is really about preventing the phosphorylation of CDK1. It actually also has other effects that I sometimes talk about, which is, for example, it also prevents the phosphorylation of CDK2, as you can see in the top left-hand side. There's other effects, for example, on aberrant origin firing or preventing the exhaustion of the nucleotide pools, and of course, more about the IO effects of DNA damage on cGAS and STING. I don't know, Kwok, if you wanna comment on some of these other effects about WEE1 inhibition. No, I think you covered most of it. Okay. Really exciting target, and it's gonna be really interesting to look at the combination bio therapies. Correct. This is something you're gonna see us continue to push forward with our integrated discovery engine as we learn more about the biology and its application. This is really our drug, and this is our drug in the pocket, obviously, for WEE1. What I wanna just highlight is that this is some of the work that we've been doing, for example, finding and discovering that the phenylalanine 310, where that circle is a novel binding location in the pocket for our drug as opposed to a competitor by AstraZeneca. This work, for example, is published in the Journal of Medicinal Chemistry where we can create a drug that is extraordinarily potent, extraordinarily soluble, and most importantly, we believe, very selective. For example, here in the middle is actually a kinase panel about our cells compared to adagrasib or AstraZeneca's WEE1 inhibitor. You can see we hit about five kinases of note, and of course, AstraZeneca hits close to about 40. We believe it's the selectivity profile in addition to our potency and our PK qualities that allows us to differentiate the drug clinically. Clinically, we actually have many drug programs that are currently enrolling and putting patients, enrolling patients. For example, we have our uterine serous carcinoma, we have ovarian trials in combination with chemo, we have our ongoing osteosarcoma trial with gemcitabine, but we are also happy to report today that we have actually started and initiated the predictive biomarker ZN-c3 monotherapy trial. Also happy to report that we have initiated the ZN-c3 plus niraparib trial in our partnership with GSK. In addition, we have also multiple studies ongoing in China in our joint venture with Zentera. Let's go into some more data actually, now first in uterine cancer for ZN-c3. Uterine serous carcinoma is a subtype of endometrial cancer that is actually a very onerous one. 70% present actually with metastatic disease, and as you can see here on the right side, 10% of new cases, but 40% of deaths. There really is a huge unmet need about how to treat this. On the left-hand side is actually some data that we've generated in a uterine model, where you can see the efficacy of ZN-c3 in the SK-UT-1. On the right-hand side is the fact that we've seen responses. We've seen multiple responses, in fact, in USC patients. Here, for example, is a representative scan in actually one of our patients, where you can see the abdominal lesion circled in yellow actually completely goes away in this one patient. This is an addressable population of approximately 15,000 patients in both North America, Western Europe, and Japan. Something that we think is quite amenable to treatment with a WEE1 inhibitor. Let's talk about ovarian cancer. This is data that we've generated, for example, in combination with carboplatin. As we can see here, ZN-c3 monotherapy and carboplatin are similar, but you can see the really, really nice regressions combining ZN-c3 with the chemotherapeutic. As we know, when you have the chemotherapeutic, it usually works better with ZN-c3 because when you have DNA damage from the chemotherapeutic, it sensitizes the drugs obviously, or sensitize the tumor cells obviously to ZN-c3. There is a potential addressable population of 14,000 patients here, as approximately about 25% of patients are platinum resistant and have recurrence within six months of primary therapy. There is a huge unmet need here. Here's the data that we've generated internally in combination with PARPs. As you can see here, this is an OVCAR3 line in ovarian cancer, and the green is talazoparib, Pfizer's PARP inhibitor. Obviously, the red line is our ZN-c3, and the combination has really, really nice tumor growth inhibition. We think this is something that's gonna be really exciting, and of course, we've initiated the clinical trial to look into this, as there are about 18,000 patients that might be addressable in terms of a ZN-c3 PARP combination. PARPs, as we know, are gonna be generating close to about $7 billion in revenue by 2025, and pretty much all of those patients will relapse as this PARP inhibitor is not a cure. Once again, as I mentioned before, we have initiated this study this month with GSK, and here's the study schema that people can refer to. Let's continue. Osteosarcoma. Osteosarcoma is also something of interest to us and this is some work that we chose to work with osteosarcoma and why we also chose to combine with gemcitabine. This is data on the left-hand side in regards to our sensitivity panel with our CRISPR screen. You can see that RM1 is shown there. That means tumor cells are sensitive to RM1 inhibition in combination with ZN-c3. Here's, for example, on the right-hand side, is just a preclinical data, in vitro data of combination of ZN-c3 gemcitabine in A427 cells. In other words, gemcitabine and WEE1 work well together. This has been corroborated, obviously, in the clinic. Here is, for example, some more in vivo models of this in osteosarcoma. In this case, you can see, ZN-c3 in red, gemcitabine in green, and of course, we have really nice tumor growth inhibition. This study, of course, has already started, and there's a huge unmet need in osteosarcoma. The study schema is shown here on slide 28 that people can refer to later. Let's continue now into other promising future clinical indications that we think are something that we would like to explore further. Number one, breast cancer. This is data that we always find very interesting is it's the connection about the immuno-oncology mechanisms with WEE1. We have actually seen data, for example, published, where WEE1 actually down-regulate PD-L1 expression. On the top right-hand figures, you can see, for example, trastuzumab resistance is being upregulated with these samples here with PD-L1, but that adavosertib here in this WEE1 use have actually down-regulated. In this in vivo study, you can see trastuzumab resistance being basically reversed in combination with a WEE1 inhibitor. This is something that actually we think is extraordinarily exciting. This next slide is internally generated data. I just wanna orient people here to what is happening. On the left-hand side is tumor volume, but observe that we start here in this model at 1,000 cubic millimeters, and that is not a typo. This is an extremely large tumor model before we start a treatment. In green is just trastuzumab. As you can see, it's not very effective. In red is obviously ZN-c3 with nice tumor growth inhibition. The combination which actually causes tumor regression with extremely large tumor model here. This is something that we think is quite impressive, and we think that this is a large market here, as approximately 15% of adjuvant trastuzumab patients will relapse, and there's about 60,000 patients in the major markets for this. This is data also generated internally that we here, in this case, created a PARP-resistant triple-negative breast cancer tumor model. As you can see from these IC 50 numbers, niraparib works obviously in wild type, and so does olaparib. The other DDR target drugs like ATR, ATM, CHK1, DNA-PK do not work. Once you have a resistant form of this cell line, you can see that ZN-c3 actually maintains its potency, while niraparib and olaparib obviously lose theirs in this model. You can see on the right-hand side an in vivo version of this, where olaparib no longer works, and it costs me about 27 days or so, we start treatment with olaparib and ZN-c3 together, and you can see that we can start to get regressions. This is something that's very exciting to us in the triple negative breast cancer model space. Here's more data, for example, that we've shown also in triple negative breast cancer, in this case, a PDX model of combining ZN-c3, but in this case, with niraparib. Here we're using a 5-2 regimen that actually has good tolerability in the mice, and you can see a similar story here. Really, really nice impressive tumor growth inhibition and slight regression here in combination with ZN-c3 plus niraparib. Approximately 20% of triple negative breast cancer patients harbor BRCA 1, 2, and so there is probably about 45,000 patients that may be addressable with this combination in the future. Let's go on to colorectal. Here in the colorectal side, you're gonna see that we actually have data from a clinical trial called FOCUS4-C. In this trial, it was actually adjuvant use of a WEE1 inhibitor versus active monitoring in patients that were KRAS and TP53 positive. Here on the right-hand side. On the left-hand side of the graph, you can see the progression of free survival curves actually separate quite nicely, and there's a hazard ratio of 0.35 of use of a WEE1 inhibitor versus active monitoring as adjuvant use of a WEE1 inhibitor. This is something that's quite exciting, and we wanna share with folks some preclinical data that we've generated. On this slide here is a xenograft model in colorectal cancer, and you can see in this TP53 mutant population, KRAS G12C positive, really nice single agent efficacy of our drug at various doses. Bear in mind, 80 mg/kg is approximating about the 300 mg/kg. 300 mg dose we have in the clinic. You can see a 99% TGI as monotherapy in the CRC model. Here's exciting new data that we've also generated internally about the use of a ZN-c3 in combination with a G12C inhibitor, in this case, sotorasib, which is the drug by Amgen, the G12C inhibitor. You can see here ZN-c3 and sotorasib are kind of similar in terms of its monotherapy activity, but you actually see really nice regressions in this KRAS model with the combination use of both. Once again, just clues in terms of the future potential of this drug of a WEE1 inhibitor in colorectal and in combination with colorectal drug regimens. Now let's go into IO. This is data actually that we wanna talk about in terms of interferon signaling and the IO. Kwok actually is the author of this study. Maybe Kwok, you can describe some of the results that you generated in your own hands. Sure. You know, I think the preclinical data in vivo generated in my lab as well as several other labs have shown that when you have WEE1 inhibition in a cancer cell, actually generate a pro-inflammatory response with multiple mechanisms downstream that actually secretes interferon, that actually recruit a pro-inflammatory environment such that you can actually combine this with PD-1 blockade and show striking synergistic activity. On the left is studies that were done in my lab with squamous cell lung cancer in vivo. On the right was actually a study that was just published about two months ago that shows a very similar synergy between WEE1 inhibition and PD-1 blockade. The mechanisms that they show is that WEE1 inhibition can actually reactivate the endogenous retroviral elements and actually engage a short RNA pathway that actually secretes interferon into the tumor immune microenvironment. Great. Thank you, Kwok. This is something we think is extraordinarily exciting, and there's even more data about PD-L1 actually basically inducing synthetic lethality perhaps in the WEE1 axis. Now, on the right-hand side, you're gonna see a study here done by an investigator at SITC, which shows that when you take a drug like prexasertib, which is a CHK1 inhibitor, and you knock out PD-L1, you can actually obviously increase efficacy here. That there is a connection between PD-L1 expression and synthetic lethality. This is something that we think is extraordinarily exciting and points to the future directions of where we wanna take the drug. Here, for example, on the next slide, is actually clinical data. Maybe Kwok, you can talk to this one. No, this is actually really, really exciting. This is the first human proof of concept that WEE1 inhibition, in this case in combination with cisplatin, can actually increase T-cell infiltrate into tumor immune microenvironment as well as the pro-inflammatory M1 macrophages, really suggesting that WEE1 inhibition can actually alter the tumor immune microenvironment such that it's antitumorigenic. Really exciting data. Yep, just realize that the figure on the left is actually human samples and biopsies from patients that responded to WEE1 inhibitor plus cisplatin. This is once again clinical data that we're seeing here, really very exciting as Kwok mentioned. Now let's move into the BCL-2 realm. Maybe I invite Anthony Letai, maybe you can give us a background on BCL-2. Sure. Turns out all the cells in our body have suicide programs built into them, the most important one of which is called apoptosis. This is regulated by this BCL-2 family of proteins. There are some that are pro-apoptotic that actually execute apoptosis, and this involves permeabilizing the mitochondria in the cell committing suicide. There's the anti-apoptotic proteins like BCL-2 or its cousins, BCL-xL or MCL-1. These prevent apoptosis essentially by binding up the pro-apoptotic proteins. What they do is they bind the BH3 domain of these pro-apoptotic proteins in a little hydrophobic cleft. Drugs that target this interaction, like venetoclax or other BCL-2 antagonists, are used in the clinic now to inhibit BCL-2 effectiveness. Great. Thank you, Tony. Of course, ZN-d5 is our program for BCL-2 inhibition, and here's some pre-clinical data that we've shared before. We focus, for example, on a very potent drug, but we also focus on selectivity over BCL-xL. BCL-xL is a target that you don't wanna hit because it's associated directly with thrombocytopenia. Actually on the right-hand side is a platelet toxicity assay that we have taken. We actually take patients' plasma and actually measure the toxicity of drugs basically to platelets directly. You can see the difference in terms of CTG and the leftward shift of our curves versus obviously venetoclax in terms of platelet toxicity. This is something that's very exciting to us in terms of creating a very potent drug in terms of BCL-2, one that we believe will hopefully have better safety and tolerability in the clinic. In addition, I kinda gave a clue earlier that we have partnered with Dana-Farber in terms of BH3 profiling, and this is technology that Anthony Letai has actually worked in with extensively. Maybe you can give folks an introduction on what this is. Sure. As we're making these BCL-2 and BCL-xL and MCL-1 inhibitors, a really important question is to ask, well, which diseases benefit from these different selective inhibitors of these anti-apoptotic proteins? Well, it turns out to answer that question, genetics is of very little use. For instance, AML and CLL have no genetic alterations that would indicate that they're susceptible to BCL-2 inhibition, but they are. You have to do functional studies, and you need to study the mitochondria. What BH3 profiling does is it exposes the mitochondria of whatever cell you're interested in to a standardized panel of BH3 oligopeptides that aren't really drugs themselves, but very good study reagents. Using the pattern of mitochondrial response to this panel of peptides, you can diagnose BCL-2, MCL1 or BCL-xL dependence, and we have found over decades that this is extremely accurate in identifying which diseases, and indeed which individual patients, will benefit from which of these drugs. In fact, it's this approach that allowed venetoclax to progress through the clinic and eventually to FDA approval. This is something that's very exciting, not just for our integrated discovery engine, but obviously we believe in the future for our clinical trials as well as Tony mentioned. Speaking of trials, maybe a little bit of an update. ZN-d5-001 is our first-in-human dose escalation study of our drug in relapsed refractory NHL and AML. We've dosed as of November third, 27 patients, 23 NHL and 13 in DLBCL, and we have escalated the dosing from up to 1,200 milligrams daily. Let's maybe share some initial data from this trial to folks. Here is actually just some early comparisons between venetoclax and obviously our drug. I have to put the caveat that the data is early, and in here we have 23 patients that are valuable in terms of safety and tolerability, but we wanted to make an effort to give folks an idea of how our drug is shaping up. So on the right-hand side, you can just basically notice that I'm highlighting here two red boxes, and you can see that our tolerability, just in general, is better than venetoclax. But the astute person will say, "Well, Tony, you're working obviously in dose escalation, you're including lower levels of drug dosing, et cetera, in your 23 patients versus venetoclax 106." That is true. There's also another point, which is our trial is actually on without food, and that was by request of the FDA to do this basically on an empty stomach before progressing into the fed state, which we know will actually increase AUCs. The data that you're seeing on the right-hand side is venetoclax from between 200-1200 milligrams with food, while the data on the left of this chart is 100-1200 milligrams on an empty stomach. Okay. There is a couple of things I want people to know before you say, "Okay, you got a safer drug or a more well-tolerated drug." AEs in venetoclax are not dose-dependent, and we've included here on this chart on the left-hand side in the gray, as you can just basically eyeball this, if you take a look at things of note, for example, nausea, all doses is 48%. If you look at any grade less than 400 milligrams versus 600, 900 or 1200, there really isn't a dose dependency in terms of AEs. Take a look at something like anemia, which is listed at 17%. There was actually 32% at lower doses, 18% mid doses, and 10% at higher doses. Taking a look at neutropenia, 17% overall, 18% at low doses, 24% and 12% at the mid and higher doses. As you can see, there really isn't a dose dependency in terms of venetoclax AEs, so we think that potentially that our AE profile could be a guide to how our drug perform obviously as we go into higher AUCs in the fed state. Of course, the next question folks will obviously ask, "Well, how are you doing on the efficacy front?" Let's share some thoughts on that. Number one in the top of the chart is basically a comparison once again of the dosing states between our drug and with published literature of venetoclax. Of course, once again, we are on empty stomach and venetoclax is with food. Our mean AUC at the 400 mg dose is 8.7 versus the 32.8 in the product insert for venetoclax. Realize, of course, we are doing this in the empty stomach as opposed to in the fed state, which we know will markedly increase the AUC. The unbound drug fraction of our drug, however, is at least twice as good as venetoclax, and this is based on several in vitro studies that we have conducted, and obviously by design of our drug as we try to improve the unbound drug fraction of this BCL-2 inhibitor. When we kind of think about efficacy, there are only 19 patients that were evaluable. Of the 19 patients that were evaluable, as you see the pie chart on the left-hand side, the vast majority, 11 of the 19, were DLBCL. In this population, DLBCLs, folks know, this is a very difficult to treat subtype form of non-Hodgkin's lymphoma. We see efficacy at our AUC that is comparable to what is seen by venetoclax. We've had two responses thus far, a complete response in one patient, a confirmed partial response in another patient, so at 18% ORR, which is obviously comparable to venetoclax, with a larger N. In addition, we note on the right-hand side, we do have another unconfirmed PR in follicular lymphoma at 800 mg dose without food. That was observed after this data cut, so that's why we have not included it as part of the two patients with responses thus far. Once again, we think this is a very promising efficacy that is on par with venetoclax at this early stage in our dose escalation. Here on the next slide is an efficacy snapshot. This was a patient with a 61-year-old female with DLBCL that was diagnosed in 2014 with stage four disease. Got three prior lines of therapy, including R-CHOP and even stem cell transplant, so obviously was not doing very well. Got onto our trial with 400 milligrams QD fasting and actually received a CR, complete response by the investigator with a duration of 8.5 months and ongoing since October. As you can see on this PET scan, you can see obviously the highlighted lesions obviously completely going away. The next efficacy snapshot is a patient also with DLBCL, 60-year-old male, DLBCL, stage four disease. This patient was on our 800 mg dose fasting and I just first have a warning that the figure is actually quite graphic, so for folks that we're sharing. But we wanted to share because the cutaneous lesion for this patient actually had quite a substantial response, as you can see here. The nodal disease unfortunately progressed, but as you can see, we're clearly deriving clinical benefit in this patient population. Once again, this is something I'm very excited about. Now I wanna share for the first time, our designs for monotherapy use for ZN-d5 for a potential registrational path. Maybe I'll start first with Ross. If you can describe for folks, what is amyloidosis, and what is the unmet need? Well, amyloidosis is sort of a cousin of multiple myeloma, but is quite a distinct clinical entity, where the fundamental issue really is not the malignant cells, but rather their ability to produce proteins, which then infiltrate other organs. The challenge has always been that it's a poorly understood, and more importantly, poorly treated disease. When patients ultimately, 'cause they just can't get disease-modifying treatment and go on forever, they develop all kinds of end organ complications. We really have to think of it as asking, can we ultimately develop therapies that get to the core of the disease and the biology that's driving it? The question I think in this circumstance, given the relevance of BCL-2 to the plasma cell lineages makes the antibodies, can this be used as a way to sort of cut this disease off at its knees and prevent or regress these sort of devastating end organ complications? Great. Thank you, Ross. There have been small case series, clinical case series, that have shown that a BCL-2 inhibition can work for amyloidosis. Once again, this is something that we're very excited about in working with the leading KOLs. This is an orphan disease, but this is something where obviously use of our drug could be used for a very long period of time. We're happy to report that this is a study that will be starting in the Q1 of next year in the study schema as described, and this potentially could be registrational. This is something we're very excited about as you can see, or as we progress forward into the new year. Next I'm gonna go into AML and share with you some very exciting preclinical data that we think is something that we're gonna pursue aggressively. That we've always said that ZN-c3 is something that is within the solid tumor realm, but we would like to share more. Ross, maybe first you can talk about what is AML for folks that may not be familiar. I mean, AML, for those of us that take care of blood cancers, represents really the most common acute leukemia we see in adults and really a disease that remains having a very, very horrible prognosis. You know, there are probably between 10,000-20,000 patients per year, and although we have chemotherapy and more recently other agents that have started to finally open up, that we have therapeutic options, when five years ago we had chemo and almost nothing else, we really don't have curative therapies for the majority of our patients. The challenge fundamentally is how do we improve upfront therapy, and can we develop therapies that really work after people fail chemotherapy? As you'll hear, you know, some of the early data with the first generation BCL-2 inhibitor has really been quite encouraging that this has a major role in the disease. The question fundamentally is how do we then leverage that use and develop new combination therapies that push the paradigm in general in AML, and particularly in high-risk disease? I really wanna point out that in patients, for example, that have TP53 mutations, we don't really have anything that is truly effective or disease-modifying, and we have a desperate need for new therapies and combinations that can really turn the tide in that high-risk disease. Thank you, Ross. Folks that have followed the company will know that TP53 abrogates the G1 cell cycle blockade, and so you're reliant on the G2 checkpoint, and this is what is mitigated obviously with WEE1 inhibition use. We know cells that are TP53 mutated are sensitized to a WEE1 inhibitor. Now let's go into some novel data that we wanna share for the first time. This is about utilizing a BCL-2 and a WEE1 inhibitor together, ZN-d5 plus ZN-c3. Perhaps what is not well known is that a BCL-2 inhibitor like ZN-d5 actually induces DNA damage at subtherapeutic doses. As you can see on the western blot here, you can see the increase in γH2AX in terms of the combination of ZN-d5 and ZN-c3. Maybe, Tony, you can just comment on how come we haven't really thought about this angle of DNA damage with ZN-d5 before in the past or BCL-2s in the past. Very often when we think about apoptosis, we often think about it very much in binary terms, which is a cell completely dies or completely stays alive. There's a growing appreciation that there are small subsets of cells, often, where some of the mitochondria permeabilize. Mitochondrial permeabilization usually considered the point of commitment to apoptosis, but sometimes that doesn't progress to full cell death. In those cases, you get mitochondrial permeabilization and activation of nucleases that can actually damage the DNA, and that's what increases the γH2AX. We just have better assays now to understand what some people call incomplete or mini apoptosis. We wanna basically exploit this biological phenomenon. Let us show some data in terms of what we're thinking. This is in the HL60 AML model, and something that just basically blew our minds when we saw the data. As you can see here, this vehicle, it grows quite rapidly. The blue line is ZN-d5, our BCL-2 inhibitor, and the red line is ZN-c3. Observe the doses used. These are subtherapeutic doses that we're using for ZN-d5 and ZN-c3. Despite that, we have remarkable activity at subtherapeutic doses of our BCL-2 inhibitor and WEE1 inhibitor together, causing virtually close to 100% regression. We're obviously the only company in the clinic with both inhibitors for BCL-2 and WEE1. Now let me show you more data, and this is actually patient-derived AML samples. In this case, I'm gonna share data both in vitro and in vivo. On the bottom side, in the in vitro side, were samples that were taken from AML patients. Prior to collection, you can see that the percentage of blasts in these three patients were 93.4, 62.1 and 41.1. Post-treatment, as you can see with venetoclax and Vidaza, you can see there's still quite a bit of blast left, 33%, 68%, and 32%. When we use this in vitro model to test, right, we wanted to see what happens with ZN-d5 and ZN-c3. We have virtually going from 93.4% blast to 4.6, 62.1 to 0, 41.1 to 3.6. This is remarkable blast reduction in AML patient samples on patients who have progressed on venetoclax. On the right-hand side is actually in vivo data, where we take samples from patients, obviously PDX, and place them into mice. You can see the same effect here, where individual doses of ZN-d5 or ZN-c3 have efficacy. The combination has virtually eliminated the bone marrow of any cancer cells, 99.5%. This is extraordinarily promising activity of the fact that the combination of ZN-d5 and ZN-c3 may work on patients, for example, that have progressed and become resistant to venetoclax. I'm happy to report this is something that we are putting into the clinic of ZN-d5 and ZN-c3, just kinda like when, you know, there's an iPhone announcement of, you know, iPhone 13. You don't wanna wait till next year or two years from now before the clinical study starts. We're happy to report that we're gonna be working hard to initiate this study in the H1 of 2022. This is something that we're gonna be pushing very fast, and we think this is clinically something that's very, very important to take into patients. Maybe, Ross, you can comment just on what is the opportunity and what the unmet need here is. Yeah. One comment. To me, that PDX response or the in vivo response is sort of the kind of response that gets me, an AML doc and scientist out of my chair. I wanna underscore that point, that we really, that slide and the next slide, it's kind of results that we really go, "Huh." That, you know, seeing a real human AML sample that you can clear, we don't get those results every day. I think it's time to do a trial like this. I think the point, as Tony was articulating, is that the moment is now. Like, we have many patients with AML who either aren't eligible for therapy because of their age or comorbidities, meaning intensive therapy, or they relapse after therapy. These are pressing clinical needs where we really don't have definitive, and we definitely don't have curative answers. I think ultimately, you know, the excitement here is the idea that we can bring this exciting new combination with these two drugs we hope are gonna work better together than either alone, and bring it to specific scenarios where we have pressing clinical need. We're excited to see how it does, and I will tell you that we're very excited to see patients who really, need good options get to try what we think is this great, potential option. Thank you, Ross. Let's just continue down into our pipeline. The next one, of course, is ZN-c5 or oral SERD. Folks may have been at SABCS and just wanna highlight, for example, that we had a poster presentation there. The efficacy actually has continued to improve since the mid-year update. Now we have seen a CBR rate of 44% at our what we view a potential RPTD of 50 milligrams. Patients actually that did not receive a prior CDK4/6 had a CBR of 56% in a PFS of 8.3 months. Something that we obviously think is very exciting on the efficacy front. One thing that we do wanna note is that we believe the field of oral SERDs is really gonna be differentiated on safety and tolerability. We have not seen any dose-limiting toxicities, and there have been no change in the pattern of AEs since we've last shared at the corporate mid-year update. This is something that's very exciting. Along the realm of what is exciting is how do we treat patients that are CDK4/6 resistant? If you think about the different pathways, you know, CCNE1 amplification, CDK7 overexpression, WEE1 overexpression, there is an increased dependence on G2M checkpoint, and this is something that our integrated discovery engine team members have been working on. On the right-hand side, you can see in this in vitro study just a validation that CDK2 is needed, basically, is associated with increased sensitivity to ZN-c3. We know that there are obviously CDK2 inhibitors in development, but we actually think that ZN-c3 in combination could be an answer for CDK4/6 resistance. Here is preclinical data in a xenograft model T47D. This is a model, basically, you can see that the combination of ZN-c5, our oral SERD, with our WEE1 inhibitor has really, really nice regressions. This study that we're gonna take will be initiated in 2022 of a combination of ZN-c5 with ZN-c3 for breast cancer. Something else that's new that we're gonna share next is really about the safety tolerability profile of the oral SERD and a new concern that I think people have not really pointed to, and that is bone loss and bone protection. Loss of estrogen, we know, is associated with osteoporosis, and you can see the figure on the top left about what a bone and a hip bone or femur bone looks like when it's osteoporotic. Now, we actually ran a study where we actually did ovariectomies in the mice, we treated them with drug, and then we actually did a micro-CT and look at the trabecular bone network and see what is happening to bone. What we found was quite remarkable on the bottom left-hand side, is that you can see that ZN-c5 at even the 10 mg/kg dose is actually bone protective. You contrast that with fulvestrant, and that you can see that we're actually bone protective. The micro-CT scans here on the right-hand side actually show this. You can see that use of fulvestrant actually is osteolytic and osteopenic, and that actually, when you use ZN-c5, it actually preserves the bone. This is something that we think is extraordinarily exciting, and it points well to something that people may not have really thought about in the oral SERD space, is that if we're gonna be using a drug for 5+ to even 10 years in the adjuvant setting, you certainly don't wanna be causing vertebral fractures or causing women to have bone loss. That would be, obviously, not very good. This is something we're excited about. We'll share more data as this comes in, but we want to bring it to people's attention. Let's now talk and finish up also on ZN-e4, our EGFR inhibitor. We said, as one of our corporate goals, that we'd be sharing updates from this trial, and here it is. We've enrolled a total of 32 patients. We have found our phase II dose is 240 mg. Tolerability appears to be excellent. Out of these 32 patients, we've actually only had one patient here, for instance, that had grade one skin rash. Something of note, we've also exhibited great efficacy. We had an ORR of 36% in these relapsed patients who are IO naive. Now, keep in mind, of these 11 patients, only one of them was T790M positive, and all of them had failed first or second generation EGFR inhibitors and one to two lines of chemo. Maybe, Kwok, you can comment, what is your clinical experience in terms of what would you think, these patients would do, post EGFR first, second generation, non-T790M positive? No, this is really exciting for my time. You know, obviously, these patients, especially when they don't have T790M, has a resistance mechanism. These patients have really nothing to go for them. Having a response rate of about 36% is really exciting. This is an area that's tremendous unmet need because they tend not to respond to traditional targeted therapies. Great. Thank you, Kwok. Let's move now, just in the interest of time, to our next program. We're excited to reveal our next preclinical program that we're working on, and it's a heterobifunctional degrader targeting BCL-xL. Maybe Tony, if I could have you just explain what BCL-xL is. We've talked a little about BCL-2 and anti-apoptotic protein that protects the mitochondria from apoptosis. Well, BCL-2 is generally not expressed that highly in epithelial cancer. Kwok, where it really seems to be more important in blood cancers as we've gone over. What does protect the epithelial cancers? Well, probably BCL-xL, a cousin of BCL-2 that has very, very similar function but is a completely different gene. BCL-xL is kind of what to epithelial cancers is what BCL-2 is to blood cancers. The idea is to target BCL-xL that has a different binding site with a distinct drug so that you can selectively target BCL-xL but not BCL-2. Where this will probably find its home is not so much in the blood cancers, but in the epithelial cancers, which is, of course, a much, much larger proposition. Thank you, Tony. The problem, of course, is that there is on-target toxicity, and there was a drug by AbbVie called navitoclax which showed good efficacy, as you can see on the top left-hand side. However, there was a marked issue and a direct correlation of on-target toxicity on platelets. The more you use navitoclax, the more you have problems with thrombocytopenia. You can see the numbers here in terms of thrombocytopenia across different dose regimens, even approaching up to 78% grade three-four thrombocytopenia, as you see on the bottom chart. How do we solve this problem? Well, the way we wanna solve this problem is through our heterobifunctional degrader. What we've noticed is that platelets have a different E3 binding situation. You can see on the right-hand side in VHL and cereblon, that platelets have much lower levels of the E3 ligase of choice for us. We have decided to link a BCL-xL inhibitor with our own linkers and our own degraders to target tumors while avoiding platelets. As we have seen before, the problem is on target. What's exciting about our program is that we've already generated data that we think shows the efficacy. On the left-hand side is a multiform T-ALL in vitro model, where you can see navitoclax in red and various degraders that we have constructed that have nice efficacy. On the right-hand side, you can see the difference, however. Obviously, we are degraders, unlike the red line of navitoclax, which is not a degrader. We can actually have a Dmax that is approaching 70%, which is actually quite remarkable. In addition, we have shown data that we spare platelets, which is the whole point of this exercise. If you can see in the platelet toxicity assay, navitoclax obviously quickly degrades up to even 95% of platelets. Look at our IC50s, obviously, for platelets are much higher, which is obviously, of course, by design. Our heterobifunctional degraders, we believe, is very exciting. You can see here on the in vivo study that we have on the left-hand side data that our degraders have efficacy that is similar to what navitoclax has shown. However, of course, the whole goal is that we can dose this in patients because we won't cause the thrombocytopenia. As Tony mentioned, there is a very large population of patients, both in liquid and we believe in the future, solid tumors, that will be able to benefit from this. Of course, we've seen the data that we've shown previously about ZN-d5 plus ZN-c3, we certainly think our heterobifunctional degrader could probably combine well with ZN-c3 as well. We'll be nominating a candidate next year. Let's go to the summary. We've shared a lot of information I've gone through very quickly through the slides, and we just wanna say that ZN-c3, our WEE1, which is our cornerstone drug in our pipeline, is a cornerstone in multiple treatments in many indications. Here are just some addressable patient population numbers in the major markets. Highlighted in red are some of the numbers, of course, in other markets that we're disclosing for the first time today, for example, ZN-c5 plus ZN-c3 and ZN-d5 and ZN-c3, obviously for liquid tumors. Here's a summary slide of what we've shared today at the R&D Day. We've hopefully given you a better appreciation of our integrated discovery engine. We're putting in state-of-the-art X-ray crystallography for structure-based drug design. We have a genomic discovery platform using CRISPR screens. We're using multi-omics and machine learning. We have a new degrader platform in place for enhanced chemical space. Of course, we've announced that we have a BCL-xL degrader program that will be nominated next year. We've shown preclinical data across multiple models for ZN-c3. We've shown supporting evidence for ZN-c3 in IO, and of course, we shared today that ZN-d5 and ZN-c3 opens up a whole new chapter and possibilities in terms of treating liquid tumors with our WEE1 inhibitor. We've shown that ZN-c5 is bone protective, unlike fulvestrant. We've shown today also new clinical data. We believe that the ZN-d5, the BCL-2 inhibitor, is showing promising signs of efficacy and of course, an excellent safety tolerability profile of where we are in dose escalation. ZN-c5, if you've seen in our poster, continues to maintain great efficacy and of course, we believe best in class safety tolerability. ZN-e4 has progressed to an RP2D determination. I think what's probably very exciting for most folks, we've announced a host of new clinical trials that we'll be initiating. ZN-c3 plus PARP and the biomarker studies have now started in December. We're gonna be starting a trial of ZN-c5 plus ZN-c3 for CDK4/6 resistance. Of course, we're starting our monotherapy trial for ZN-d5 and amyloidosis that will start in the Q1 of next year. Of course, something we're very excited about is the new chapter for ZN-c3 in liquid tumors in AML, and that trial will start in the H1 of 2020. Once again, we've talked about the past, we've talked about the present, but hopefully we've given you a glimpse of the future and how the glimpse of the future has all been predicated on the balance of what the integrated discovery engine has brought to us today. This is our new pipeline chart, where we've added a few updates in terms of status of trials and the BCL-2/xL degrader obviously as our new program. We've done this in less than an hour and left a few minutes, obviously for questions. Let me turn now to the Q&A session. Thank you. The floor is now open for questions. If you would like to ask a question, please press star one on your telephone keypad at this time. A confirmation tone will indicate that 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. Again, that's star one to register questions. Our first question is coming from Eliana Merle of UBS. Please go ahead. Hey, guys. Thanks so much for taking the question and the exciting updates on the pipeline. Maybe just on the protein degradation pipeline. Curious, kind of, you know, you've spoken about the risk of hook effect in the past. Curious how you're approaching that question in the protein degradation space and also kind of any unique chemical capabilities that you bring to the table in thinking about developing these novel compounds with a unique PKPD components. Thanks. Yeah. We believe the hook effect is real, and we believe that obviously that's something that will be seen in clinic, obviously if you dose higher. It's all about finding the therapeutic window of where you can dose to get obviously the efficacy that you want. Certainly we've seen from the initial preclinical data we've generated with our program within our program, that we have great efficacy at low doses. It's something we're very excited about. Yes, in our new degrader program, we do have obviously our own chemical capabilities that we're obviously not talking a lot about right now. Thank you, Eliana, for the question. Thank you. Our next question is coming from Michael Schmidt of Guggenheim. Please go ahead. Hey, guys. Thanks for taking my questions. A whole bunch of news today, so a lot of questions, I guess, but maybe just one on the SERD program. I guess the concept of it being bone protected is quite interesting. I guess you'd think the you know the bone effects would be sort of a class effect for hormonal therapies. Just curious what your thoughts are on the mechanism there. Yeah, we're working on the mechanism. We know, for example, that estrogen is bone protective, right? We believe the design of our chemical structure is different from the other oral SERDs. This is something that the people working in the oral SERD class have not focused on. It has all been about, you know, the usual efficacy criteria, but efficacy seems to be about the same across the oral SERDs. We think, once again, safety and tolerability will be the differentiation amongst it, and people need to focus on bone protection, particularly if you wanna use a drug for five+ years. We'll share more data on this, and these are ongoing preclinical work that we're doing, and we think the science is very exciting. There should be publications for this in the future. Yeah, super interesting. I guess now with the 50-milligram dose looking quite good, I guess, how do you think about launching phase III trials for the SERD program? Sure. when? That's something that we are obviously discussing internally, and we're balancing that obviously in regards to the rest of our pipeline that we have obviously to fund. This is something that we think is a great drug, and we'll give more guidance in terms of how we're looking at this. We're obviously gonna be eagerly anticipating what AMEERA-3 is going to show. We obviously saw what the EMERALD results were, but we're obviously eagerly anticipating what a better oral SERD may show with AMEERA-3. Super interesting. On the EGFR, I know that that's sort of a program where you do have a recommended phase II dose now. I mean, is that something that you perhaps could position for the Asian market, or how do you think about next steps for that program? Yeah. This is a program that we haven't really prioritized given obviously our interest in the rest of our program. But we do think it's a very nice drug, and we do think that it's a drug that would work probably best in combinations, given the fact that I don't think anybody here at Zentalis wants to run a head-to-head trial against Tagrisso. We do think that we have a nice drug. It will work well in combination, and we're exploring different ideas about how to combine. And we're in discussions also to see if that makes sense with external combinations as well. Okay. Obviously lots of activity around the WEE1 program. Yeah, I thought the IO mechanism was interesting and, you know, I guess, you know, that concept of downregulating PD-L1 expression, you know, I guess how additive would, you know, a PD-1 inhibitor combo be in that context with the WEE1 inhibitor? I think, Kwok, you're the best one to answer this one. Sure. I think there's multiple mechanisms at work here. You know, obviously WEE1 can actually, you know, cause a pro-inflammatory response that's independent of PD-L1 expression and cause release of chemokines and cytokines in a cancer cell-intrinsic manner, that recruits these good T cells, that gets further activated with PD-1 blockade. I think this is a very intrinsic, very complicated and multifactorial mechanisms in terms of how WEE1 inhibition can reactivate the immune system. I think this is a really robust area to really think about, in addition to PD-1 blockade as well as other immunotherapeutic combinations. Super interesting. Can I just throw one more in perhaps on the- Sure. On the BCL-2 program, you did. Of course. Share some data from the NHL subset that you know was quite interesting I thought. You know, were there patients with AML in the study too, and how did the drug do there as single agent? Can you talk about sort of your dosing scheme in the phase I trial in terms of the step up in dose going forward? Yeah. It's too early in the AML side of the equation because we recently just started dosing AML patients, so it's really just much too early to say on the AML side. In terms of the dosing schema, we've gone up to 1200 mg, but it's in the fasting state. What is required of us now is to complete our fed-fasted study, which we are doing. Next year we will continue to dose escalate in the fed state, which we believe will obviously improve the AUCs even more. Once again, all the data we've shared, people need to keep in mind, and this is not quite apples to apples, is the fact that we're comparing data of our fasted state versus the fed state for venetoclax, and we think our data is looking very good. Thanks so much. Yep. Thank you, Michael. Maybe time for one more question. Thank you. Yeah. Our next question is coming from Andrew Berens of SVB Leerink. Please go ahead. Hi. Thanks, guys, for squeezing me in. Really nice job walking us through a lot of programs in one hour, and also a great preamble to the call set list. Maybe one science-based question and one financial question. In regards to the EGFR program, I was just wondering if you could give us any color on EGFR activity profile against different mutations. I think you said that only one of the obviously resistant patients had a T790M mutation. Then, the financial question, maybe for Melissa, just wondering with all these programs going forward and the new programs you announced today, how we should view the cash burn and relative to your existing cash runway. Yeah. I'll start first with the EGFR program. Do we work in exon 20 is the question we usually get. You can think about us as basically a third generation EGFR inhibitor like Tagrisso, but we believe obviously with better tolerability and potentially better efficacy, but that's obviously hard to tell in a small subset of patients. Maybe the cash question, Melissa, you can handle that one. Yes, happy to. Thanks, Andrew. Cash on hand we have runway through to Q3 2023, and everything that Tony and the team have been talking about has been included and covered for in that cash burn. We're well-funded for the next couple years. Okay. Does that include utilization of the ATM? I think you have an outstanding ATM? That's not taking into account additional potential fundraising. Okay. Thanks. Great. Thank you, Andy. We wanna be mindful of people's time. We did say we're gonna do this an hour, so Tony- Wanna thank. We've got a few more analysts. Okay. I know Morgan Stanley was also online to ask questions. Okay. Maybe we can wrap up. Sure. Sure. Maybe we'll a few more minutes. Okay. Of course. Thank you. Our next question is coming from Mike [audio distortion] of Morgan Stanley. Please go ahead. Hey, guys. Thanks for taking the question. Thanks for all the updates today. Just a quick one for me. Tony, you highlighted the broad potential of the WEE1 platform across different combinations and indications. Just curious for your breast cancer, HER2 positive combo and also colorectal, you know, in terms of timing of those programs moving forward. We haven't come to a decision in terms of timing or even if those programs will or will not move forward. We just wanted to share just in this sense that, you know, this drug is a pipeline and a drug, and it's broadly applicable across tumor types, both solid and now liquid. We're giving it a lot of thought and everything is gonna be about prioritization so that we don't have an answer right now, unfortunately, Mike. Gotcha. Thanks. Another question? Thank you. I think that brings us to the end of our question and answer session. Dr. Sun, did you have any additional comments today? No. Just want to thank everybody and of course thank our three KOLs for attending today. I know they have busy schedules and obviously thank everybody for listening. Ladies and gentlemen, thank you for your participation. This concludes today's event. You may disconnect your lines or log off at this time and enjoy the rest of your day.