All right. Good morning everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here, and it's my pleasure to introduce Kim Blackwell, CEO from Zentalis Pharmaceuticals. Just a reminder, format for today is a fireside chat. But before we get started, I just need to read a quick disclaimer. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, we can hop right into Q&A. Kim, thanks for joining us today. Thanks for having me. You've been CEO now for about four months. Maybe to start, you can talk about what you've learned so far and sort of what your key priorities are. Yeah. Going forward from here. I see the role having been on the board for a little over two years, right after the company had an IPO. Cut to the chase, the things I've learned is we're sitting on an amazing chemistry platform. The company put four drugs in the clinic in seven years, just a remarkable feat in itself. The purpose of the company is really to take small molecule, apply amazing chemistry, and get it to the right patients who will benefit from those small molecules. It's a space that I know well, having worked in it over 20 years in many different roles. Fairly impatient person, so love the idea that you can take known targets, engineer optimize small molecules, and get them to patients as quickly as possible. I've learned about the power of a chemistry platform. I had known it before I came to this role as CEO. I know it even more now. I also know that we're sitting on two amazing assets that are in the clinic, that are benefiting patients in the context of our clinical trials, and the work that needs to be done around both of those molecules is quite clear to me. And then the third thing is we have this amazing team of people who get up every morning and say, "How do we get the drugs to patients as quickly as possible?" I think the first chapter of the company has been how do we get chemical moieties, drugs, therapeutics into the clinic. I think the, I'll call it the pulse change, but in a good way, not fatal pulse change in any bad direction, is really the next chapter of this company, which I will lead the company into, which is incredible drugs, in particular the WEE1 and the BCL-2 assets, and demonstrating the data sets that we need as quickly as possible in order to get the drugs where they need to go, which is to lots of patients or the other fancy word is to get them approved. Yep. Makes sense. You've also made some recent pipeline changes, so maybe you can highlight some of those. At this point, should we expect any more changes in terms of the pipeline? Sure. I'm 140 days into it. Again, chapter one of the company was really, can we throw this amazing chemistry platform against known cancer targets. Two of the first examples from the early days of the company included an EGFR inhibitor small molecule. The principle behind that drug was dial out wild-type CL rash, highly effective dial-up efficacy against EGFR mutants. The second agent to enter the clinic was our SERD, an ER oral degrader. Again, beautiful example of dialing chemistry, making small molecules more effective in inhibiting their target, and in this case, also degrading the target. The landscapes around both of those disease entities, EGFR mutant non-small cell lung cancer, as well as ER-driven breast cancer, you know, those are challenging landscapes. The most important thing that drove the decision is we got a drug with legs on it against WEE1 that has broad applicability. This is not a mutationally driven target. This is cells undergoing high replicative stress, which is a fancy way of saying that transition break from G1 to S has been removed. Cells driving towards DNA synthesis. Any cells in that state, and chemotherapy can cause that state as well, should then basically enter into a mitotic catastrophe or die when we take the second break off. This is not a novel concept. It's what we do every day when we give PARP inhibitors to patients. Different targets. This idea that something is a vulnerability within cancer cells, and in this case, the strongest data for WEE1 inhibition is in cancers who have lost the G1S break. I've been using a lot of car analogies for some reason lately. That leads to replicative stress. There's lots of things that do that. P53 mutation, that is the master regulator of that G1 to S phase transition. When that's gone, that break is gone. Cyclin E1 overexpression. Cyclin E1 amplification. When you have high amounts of CDK2 and Cyclin E bound together, and lots of things cause that, you lose that G1 to S break. Our drug is on the end of the cell cycle, and it takes cells that are thinking about dividing, are trying to repair any DNA. That's the catch-up spot. Probably more science than most people need this early in the morning. You take that break off, it's not a lot different than what we're doing with PARP, right? Yep. BRCA protein not working, one vulnerability gone. PARP, another vulnerability. You can't repair the DNA. Although different biology, I think the strategy, the broad applicability, the ability to define patient populations that are enriched based on the biology. In the case of PARP, it's BRCA and HRD. In the case of WEE1, besides giving it on top of drugs like chemotherapy that cause replicative stress, you can imagine a world where mutationally driven cancers have high amounts of getting from G1 to S. You can imagine a world where that break is removed. We've disclosed strategies in osteosarcoma, uterine serous carcinoma, and high-grade serous ovarian. All three of those diseases are basically defined by P53 loss as a very foundational genomic alteration. Pretty excited about the not let's do a thousand things. You can already see I've deprioritized two assets. Yep. That also had lights on them. Really going deep and wide on the opportunities that our WEE1 asset has. Yep. You mentioned the broad applicability of WEE1 across USC and osteosarcoma, et cetera. Then in the past, you've also highlighted sort of this biomarker strategy. I don't know if you can sort of give us a little bit of sense of where you are there or how you're thinking about that. Yeah. The biomarker strategy is a monotherapy play, and again, it's to use the PARP analogy. You really kind of initially saw the signal you wanted to see with PARP in the BRCA mutant. Then it got expanded to tumors that can't repair their own DNA. We have not disclosed the biomarker. We hope to do so in the near future, but it is a monotherapy play in a specific population of patients. Gotcha. Maybe we can talk about a competitor in the field. Recently, AstraZeneca decided to discontinue development of their WEE1 and just wanted to get your thoughts there, and how that sort of translates into your thinking with your program. Yeah. This might be a little peculiar for me to say, but Adavo was a good drug way before its time. It's very rare when you see a discontinuation announcement that the head of R&D says, "But WEE1 remains a really great target." I think Adavo was a kinase inhibitor that hits 13 kinases. Again, our molecule is much, much more specific, and its earliest days of development were really to prove the power of the chemistry platform. Dial out what you don't want. That eight kinase difference is like worlds apart, including kinases that can contribute to myelosuppression, at least the biology of it. We obviously don't have head-to-head comparisons. The Adavo story is one that we have followed very closely but was developed, in my opinion, like we developed chemotherapy or to be quite honest, because I was involved in the process, the way we developed PARP in the early days. The way you develop chemotherapy is you do a dose escalation, you treat a set of patients. You say, "Did anyone have excessive toxicity? Okay. Not." Then you bump it up. I know everyone in this room knows that. That's probably not how small molecules should be developed. Activity is driven by exposure. They can give their drug their recommended phase II dose. I don't quote me on that, is we give it 10 days out of 21 days, and that was almost certainly derived based on tolerability. We can give our drug continuously. We've got 2022 tools to really help understand not only the exposures you need, are you achieving those exposures, but also what percent of patients are you getting that in? That's critical if you're gonna combine the drug. We have several dose escalation studies that are ongoing, including the chemotherapy combination in ovarian. We can give the drug continuously. I think that CHEK1, even before the announcement, we had differentiated ourselves in terms of tolerability, and my opinion is, we have a more specific kinase inhibitor. You can develop it more like a monoclonal antibody. It's not a monoclonal antibody, but when you're only hitting such a few number of kinases, the drug development strategy and the ability to drive up the exposures you need against your cancer target is much easier than if you're hitting 13 kinases. It, again, really underwrites the power of the chemistry platform. You know, that drug, because of the number of kinases it hits with a high amount of effectiveness, puts it in many other pan kinase inhibitors that have come before it. Mm-hmm. That ultimately were approved, but then when you wanted to expand its indication, they were limited because they were hitting so many kinases. Yeah. Makes sense. Just beyond Adavo, are there other WEE1s in development, you know, that you keep an eye on as well? Well, we're way ahead. We're a marathon ahead. I'm not a runner, but it seems like we're way ahead, and we're gonna stay ahead. There is one other drug in the clinic. They've disclosed at ASCO this year a very, complicated development strategy going slow. The kinase inhibitor by a company called Impact. To my knowledge, there's no other WEE1s that are currently being developed commercially. Adavo, most of the data that we've seen recently are investigator-initiated studies, and so we'll continue to follow that space. With AZ's announcement, they've created. I've said this, they've not only created a lot of green space, they've actually paved a beautiful long runway of where WEE1 inhibition should work, especially if you have a better WEE1 inhibitor and can give it continuously. Yep, makes sense. You talked a little bit about this earlier, but the data at the AACR meeting earlier this year, chemo combos, you tested a couple different combinations and gave us an early look there. Maybe you can share at a high level your interpretation of the data. Yeah. Well, we stand behind the data that was presented at AACR. One of the biggest gifts I got about two weeks after I took this job is going to ASCO and talking to the gynecologic oncology community. This is a group that had worked with Adavo for a long time, and they realized that giving a small molecule continuously could not only potentially drive up efficacy, but we demonstrated tolerability in combination with chemo, which had been, I don't know, fatal flaw is too strong a word, but Adavo was incredibly difficult to combine with chemotherapy. They tried to combine it with carboplatin and really ran into a number of dose-limiting myelosuppression side effects. That's what I heard from the investigators. That's what's put in the literature. They were all super excited about the fact that we could give our drug continuously, which is the data that we presented at AACR. When that study is completed, that was a dose escalation study. It is a phase 1b, phase II dose escalation combining our drug with chemotherapy. We presented data on Doxil, we presented data on carboplatin, we presented data, early data on paclitaxel. My interpretation of the data is not only were we able to give it continuously. Just to remind everyone, Adavo was giving it 10 out of 21 days with these similar combinations. We saw a much higher level of activity compared to what Adavo had put out into the universe with multiple other investigator-initiated studies. We were particularly keen on, you know, the paclitaxel data was very intriguing to me, given that that is a workhorse, not just an ovarian, but many solid tumor. To see a response rate greater than 50%, in patients who had previously seen carboplatin/paclitaxel was super exciting. Yeah. Maybe you can comment just on gemcitabine combo. We haven't seen that yet. Just, you know, your thoughts there. Is that an attractive combination as well? Yeah, I'm not gonna take everyone back to the thrilling cell cycle biology, but the reality is gemcitabine, whether it be inhibiting CHEK1, if we could combine gemcitabine with some of the other, PARP inhibitors in particular. Unfortunately, it's too toxic to combine those two. Gem basically dries up your DNA supply, or it alters the DNA supply. So again, G1S is taken off. The cells are trying to make a lot of DNA. Gemcitabine dries up the supply pool, and then we take off the brake. The cells didn't have time to catch up. So we're excited about the gem combination. We are accruing to that cohort in that study. We also will update our data around gemcitabine and our WEE1 in our dose escalation study for osteosarcoma. Again, I won't go back to cell cycle biology, but osteosarcoma, its hallmark is basically P53 mutation, unmet need. Gem has a less than 10% response rate and a PFS or an EFS that's just over two months, which is basically the first set of scans. That's from a registration study. We'll be able to assess that data set. It's an early data set, dose escalation in comparison to what we know gem performs like in a P53 mutation. I think that's important because then we'll have two different cohorts, two different patient populations with a chemotherapy backbone that makes sense in combination with WEE1. Is the osteosarcoma data more to give you a read on efficacy or more for the safety and the combinability, or maybe it's both? Well, I feel like we've already put out a pretty sizable data set about it's safe to give our drug. Yeah With chemotherapy. It's really now, can we see a signal in a disease that's just horrible. I mean, when you get the call from the parents and the patients, and they really have high-dose ifos. I was talking to someone last night. The options are the same options they had in the 1970s and the 1980s for this disease. Mm-hmm. The standard of care still remains ifosfamide or HMAs drugs that have been around for a long time. It's not hard to imagine that a drug that adds to chemotherapy in that setting could make a major contribution, but we need to generate the data set and make good decisions around it. Yep, makes sense. For the chemo combination, is the goal to ultimately select one chemo for combination, or could you move forward with a few, or what's your thoughts there? You know, we really haven't disclosed. You know, at the end of the study, which is going to ultimately accrue well over 100 high-grade serous chemo-refractory patients, it will be a robust data set that should enable us to make a good decision as to what the path looks like moving forward. Okay. When should we expect sort of the next update from that study? We really haven't discussed that. Yeah. Gotcha. We've discussed it, we haven't disclosed it. All right. Wrong word. Makes sense. Gotta get the words right here. Maybe we can just go to the USC real quick. You're in a phase II registrational study, and you'll sort of give us an update later this year. Maybe you can just talk about that and what the focus should be. Yeah. The update later this year is really going to be about safety and an enrollment update. It will not include efficacy data, primarily because of its registration capability or intent. We plan on disclosing that data sometime between now and the end of the year. It's a global study. You know that USC only constitutes about 5% of all endometrial cancers. It is a P53-driven cancer. We'll update everyone as to where we are with it. It's, you know, again, globally enrolling. Yeah Registration intent study. Should we expect final data sometime next year? Is that a fair- We really haven't disclosed that. Yeah. We'll update where we are with enrollment. Yeah Sometime later this year. Okay. Maybe we can shift to the BCL-2 program and maybe just to start at a high level, just maybe give us the key points on that program. Yeah. Poor BCL-2. Just eight minutes. You can tell how excited I am about the WEE1 inhibitor. Again, going back to the very roots of the company, it was, can we dial out things that could be clinical liabilities for assets? BCL-2 is an important anti-apoptotic protein. By inhibiting it, you drive cells into programmed cell death or apoptosis. Just big picture, we've also disclosed, because of the expertise we've gained, a protein degrader approach against XL. You're very quickly seeing with the disclosed focus of the company since I joined, really depth and expertise around two areas. One is this WEE1, G2/M emphasis and how do you identify cancers that have lost the first break of the two breaks necessary in messed up cells. This approach to how do you drive cells into apoptosis by inhibiting either BCL-2 or BCL-XL, which was a target of a drug known as Venetoclax. We can talk about XLs at any time. Our BCL-2 inhibitor, in my mind, has three biochemical advantages. One, it has higher amounts of efficacy against a broad panel of B-cell tumors. Two, we dialed out the XL activity. About 7% of patients that receive venetoclax have to deal with thrombocytopenia, which is thought to be directly related to targeting the off-target effects of venetoclax against XL. Three, the molecule, as we've disclosed, has activity in venetoclax-resistant mutations, including 101, which the CLL community is really learning more and more about how common those mutations are every day. Those seem like three differentiating avenues that a company sitting on a drug that has better features in each of those areas might pursue. Where we are right now is we have a monotherapy trial in NHL. It's a dose escalation study. I didn't know much about the history of venetoclax development, but when it was initially studied, especially in CLL, patients were coming in with incredibly high white counts, and so they ended up in a good and a bad way. Their blasts were so destroyed by the BCL-2 inhibitor, they developed something called tumor lysis syndrome. That kind of set the precedent for how other BCL-2s would be developed, but we are in the process of establishing monotherapy dose in the fed state. Our priority trial that we've disclosed is using our drug in the setting of light chain amyloidosis. Again, a disease that I had treated like way back 25 years ago, but have come to learn how horrible the disease is. Overall survival is 40 months from the time of diagnosis to the time of death. How devastating the disease is, but that it also has a biomarker, which is really this, how many light chains are these monoclonal plasma cells putting out into the body, so you can follow the status of the disease almost easier than you can a solid tumor or a hematologic disease. We are studying our BCL-2 inhibitor in patients facing light chain amyloidosis. We believe that that's an area where it will have monotherapy activity, and we're super excited about a lot of stuff apparently this morning. super excited about the opportunity to help those patients facing amyloidosis, where the first-line therapy is chemo with Velcade, and now they're adding Darzalex, the CD38 antibody. We're studying patients as a single agent to demonstrate activity. again, we're super excited. We are super excited. Yeah. I gotta find a better word than super to this morning. Then the final thing, which again, really came out of the preclinical work that Zentalis has done, is combining the BCL-2 with our WEE1 inhibitor, and we presented that data at AACR earlier this year. I think a lot of people at just sheer face value thought, "Oh, we have a WEE1 and we have a BCL-2." We have a incredibly smart contributory SAB who said, "You gotta combine these two drugs, in particular in AML." The data, the preclinical data we presented earlier this year, and that trial is ongoing as well. More to come around the BCL-2. For right now, that's our clinical development plan. Makes sense, and thank you. In the past, mentioned providing sort of an update second half of this year. Is that still the case? You know, what might we sort of expect there? New CEO sitting on an amazing wealth of assets. I would tell you today if I could, but I wanna make certain that we have- Yeah The plan completely together, that it's scientifically sound, and that it represents the fastest path forward to demonstrating clinical evidence we need around both the WEE1 and the BCL-2. Yep. That makes sense. Almost out of time, so looks like a lot to look forward here. Why don't we wrap it up there, and thanks, Kim, for your time today. Yeah, thanks for the great questions.