Good day, and welcome to the Zentalis Pharmaceuticals Investor Call. At this time, all participants are in listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. To ask a question, please press star one, one. As a reminder, this call may be recorded. I would now like to turn the call over to Elizabeth, Elizabeth Hicken, VP of Investor Relations. Please go ahead.
Thank you, and good morning. Thank you all for joining us. Today, we issued a press release announcing an update to our azenosertib clinical development program. That press release and accompanying slides from today's call can be found on the investor section of our website at www.zentalis.com. On today's call, Dr. Kimberly Blackwell, Zentalis' Chief Executive Officer, will walk us through the clinical development update, and then we will move to Q&A. Before we begin, let me review our safe harbor statement. During today's presentation, we will be making forward-looking statements. These statements are subject to risks and uncertainties that may cause, cause actual results to differ materially from those forecasted. A description of these risks can be found in our most recent Form 10-Q and 10-K on file with the SEC. With that, I'll turn it over to Dr. Blackwell.
Thanks, Liz, and to everyone for joining. The purpose of today's call is to provide additional details regarding an FDA partial clinical hold on our azenosertib studies, ZN-c3-001, ZN-c3-004, also known as Teton, and ZN-c3-005, also known as Denali. The clinical hold was a result of two patient deaths due to presumed sepsis that occurred in the first half of 2024. Under this partial hold, patients on these studies may continue to receive azenosertib, and enrollment of new patients is paused. I want to emphasize that patient safety has always been Zentalis' top priority, and it will continue to be. We take each of these events incredibly seriously, and I want to recognize the significant strength, commitment, and contributions of all cancer patients, their families, and their care teams when they decide to participate in a clinical trial.
We are working with the FDA to resolve the partial hold as quickly as possible so we can continue the development of azenosertib monotherapy for patients facing cancer. I want to remind everyone that azenosertib is a WEE1 inhibitor that is currently being evaluated both as a monotherapy and in several combinations for multiple solid tumor types and acute myelogenous leukemia. The partial hold does not apply to any other studies, including the combination studies. Azenosertib has been in clinical development since 2019, and we will review the status of some of the studies along with the enrollment numbers in subsequent slides during this call.
I want to emphasize that although the resolution of the partial clinical hold is necessary to continue the development of azenosertib monotherapy, we believe that based on available safety and efficacy data, azenosertib has significant potential to benefit patients facing cancer, especially those patients facing gynecologic malignancies. On today's call, we will be sharing information on all Grade 5 events that are potentially drug-related that have been observed across all studies of azenosertib. We will share an enrollment update and then end with the data that we plan to disclose the rest of this year, which we think is incredibly important to understanding the therapeutic potential of azenosertib, and that forms the basis for our current enthusiasm for advancing this program forward. It would be premature during the course of today's call to discuss any ongoing regulatory dialogues.
Besides our already planned disclosures in the second half of 2024, we plan on providing future updates regarding the clinical development plans and progress once the partial hold is lifted. Next slide. Before I get into some of the safety event details, I want to provide an update on the azenosertib development program and the status of the ongoing studies. We have treated over 500 patients with azenosertib monotherapy, and over 200 patients have been treated at a dose of 400 milligrams on a 5-2 intermittent schedule in the studies shown here. Study 001 is our original dose escalation study, which has enrolled patients across multiple tumor types since 2019. This study is fully enrolled, and we remain committed to disclosing the data from the study this year. Today's news does not impact that plan.
Study 004 or Teton, is our study in uterine serous carcinoma. Enrollment in this study is now paused. Study 005 or Denali, is our phase 2 monotherapy study in platinum-resistant ovarian cancer. Cohort 1 B of that study has over-enrolled with over 100 patients, and we have closed this cohort to further enrollment. Given the large number of patients that have been enrolled to Cohort 1 B with full biomarker characterization, we plan to disclose the data from Cohort 1 B of Denali later this year. Study 006 or Mammoth, is our study looking at a dose escalation of azenosertib in combination with niraparib, either concurrent or sequentially, and azeno as a monotherapy in PARP-resistant, platinum-resistant ovarian cancer.
This study is also fully enrolled, and today's news does not impact our intent to disclose top-line data from all three cohorts of Mammoth this year.... Next slide. I would like to now review all Grade 5 treatment-related events that have occurred across our azenosertib trials since 2019. These deaths are unfortunate, as are all deaths that occur in the setting of clinical trials. Our company prioritizes safety throughout all of our development plans, and this slide outlines the circumstances around each of the eight azenosertib-related deaths that have occurred on our sponsored trials for solid tumors. As noted in the footnote on the bottom of this slide, this chart does not include two deaths, or does not include a death that occurred on a study sponsored by our former development partner in China, or an aspergillosis-related death on our non-solid tumor acute myelogenous leukemia study.
Close to 800 patients have been treated with azenosertib since 2019, and more than 500 patients have been treated with azenosertib monotherapy to date, including more than 200 patients that have been enrolled at a dose of 400 milligrams 5-2 . We have learned a great deal about the management of patients receiving azenosertib, and as we have previously described, the drug can cause adverse events that include fatigue, GI side effects such as nausea and diarrhea, and low blood counts resulting in neutropenia, thrombocytopenia, and anemia. We believe these side effects are largely on-target effects of WEE1 inhibition, and we continue to work towards optimal management strategies to further minimize any side effects that can possibly occur from treatment with azenosertib. Next slide.
In the past year, we have seen tremendous interest in our studies and support from investigators, as evidenced by a stark increase in enrollment, most notably in our Denali and Mammoth studies. Over half of all of our monotherapy enrollment has occurred in the past 12 months. We believe that this exponential increase in enrollment demonstrates the unmet need of the heavily pretreated cancers that we are studying azenosertib in, especially as an active oral agent with a novel mechanism of action. Next slide. I want to emphasize that the purpose of today's call was to provide the context of the events and the setting in which the current partial clinical hold took place. We believe that important information and data regarding the therapeutic index and the drug's clinical efficacy will come with disclosures before the end of the year.
Just to summarize these data sets, we will present the final results from the initial dose escalation ZN-c3-001 study. As a reminder, this study was conducted in solid tumors. However, we have a high number—higher number of ovarian and USC patients due to cohort expansions within the study. Second, Mammoth. We will present top-line data from the phase 1/2 Mammoth study, which evaluates azenosertib plus a PARP inhibitor, niraparib, and azenosertib monotherapy Co hort 1B, which, as I said earlier, has enrolled over 100 patients and is a data set we believe is incredibly important due to the extensive biomarker work that has been done.
We have continued to observe clinical benefit in patients, which we believe strongly supports a successful path forward for the development of azenosertib, especially as a monotherapy in patients facing ovarian cancer. Before I turn to the question and answer, I want to close by reiterating that we will not be able to clearly guide timelines for coming off the clinical hold or how this hold will impact future development of azenosertib, but we are committed to working closely with the FDA to resolving this as quickly as possible. With that, I'm happy to take your questions, and I will turn it back over to the operator.
Thank you. As a reminder, if you'd like to ask a question, please press star one, one. If your question has been answered and you'd like to remove yourself from the queue, please press star one, one again. Our first question comes from Matthew Biegler with Oppenheimer. Your line is open.
Great. Thanks for walking us through this, Kim. Obviously, can't speculate on the part of the FDA, but, you know, what are some of the steps that you're thinking internally to resolve the hold? For example, you know, I don't know if you're using prophylactic filgrastim or maybe if there's a way to more aggressively monitor patients for drops in blood counts. What's your thoughts there?
Sure. Well, as I mentioned at the beginning of the call, I won't mention any of the specifics around the discussions with the FDA. We are learning more about the drug every day. We are allowing investigators to use supportive care as they deem necessary, and we are monitoring the patients as appropriate in each of the clinical trials. We haven't mandated any growth factor support, as you suggested. We are monitoring closely blood counts and obviously in this, the setting of any possible infections, we are encouraging physicians to take appropriate supportive care measures. As you saw from the listing, the complete listing of all Grade 5 events, each of these events has occurred as singular events. The 7 of the 8 solid tumor-related events are due to some sort of infectious component in the setting of low counts.
I wanna emphasize that neutropenia is a known side effect of the drug, and most oncologists are very familiar with how to manage both neutropenia and signs of infection in the setting of neutropenia.
Yeah, that's almost what makes it a little more strange to us because it seems like the absolute rates of neutropenia aren't much different than like a CDK 4/6 or an oral SERD that you would see in breast cancer. So what is it about, you know, the ovarian cancer patients in your trials that makes them more at risk for this kind of sepsis?
Yeah. You know, we have several data sets coming out later this year, and so I think at this point, I'll just wait till that data is available to you know, cross-agent comparisons. Although I do believe that the drug is certainly within line of many, many drugs that are used for the treatment of cancer. And I'll leave it at that, Matthew.
Great. Thanks for taking our questions, Kim.
Thank you. Our next question comes from Brad Canino with Stifel. Your line is open.
Hi, good morning, and thanks for the questions. I wanna ask, do you still have confidence that you will be able to reaffirm the dose selection of 400 milligram 5-2? You know, how much of a dose optimization might be a part of this?
Yeah. So as I mentioned on the call, thanks for the question, Brad. We've treated over 200 patients at this monotherapy dose of 400 mg 5-2. And we continue to believe that there is a very beneficial therapeutic index of the drug at this 400 5-2 doses. It would be really premature to comment on any program amendments of any kind while we are trying to resolve the partial hold. I think the enrollment that you saw today really suggests the full support we have of our investigators, as well as their perception that of the potential therapeutic index of this drug at a dose of 400 5-2.
Okay. Then maybe separately from this update, can you help us understand what led to Denali phase 1b enrollment increasing from what was a target of 30 to 102? You had the prior guidance that the Denali Cohort 2 top lines would be in first half of 2025. So I think there was an assumption that those cohorts might have been opened by now. You know, would you correct any way I'm thinking about that, you know, in terms of why patients weren't starting to be accrued to the biomarker cohorts yet? Thank you.
Yeah, sure. Thanks for the question, Brad. I think it's an excellent one. The enrollment in Denali Part 1B, and I just wanna be clear, the Denali study actually started in February of 2022 as a study that was enrolling patients that had specific mutations of interest that might convey sensitivity to WEE1 inhibition. We then further amended the study after five patients were enrolled in Cohort 1A to start enrolling in Cohort 1B, which was a cohort of non-biomarker-defined platinum-resistant ovarian cancer. The reason that we modified the study at that point was because we had some very strong biology that Cyclin E might be an enrichment or a predictive factor for the sensitivity to WEE1 inhibition, especially in ovarian cancer.
So the over 100 patients that I mentioned today on Cohort 1B are all platinum-resistant ovarian cancer patients, where tissue and sequential plasma was mandated for participation within the context of the trial. So I just wanted to set that before I answer your question about why we over-enrolled to Cohort 1B. When 1B was initiated, we knew that Cohort 2 would be a Cyclin E-defined cohort, a group of platinum-resistant ovarian cancer patients. And the bottom line is we've had overwhelming enthusiasm, not just by the sites that we've chosen to allow to participate in this study, and not just in the U.S., but globally for allowing patients to have access to single-agent azenosertib. We had very generous enrollment criteria, allowing for up to 5 prior lines of therapy.
As you saw from the enrollment curve, even within the past six months, we've had really a very high level of enthusiasm about offering the drug to patients. We have done extensive biomarker work in Cohort 1B that we think will potentially allow for a very clear patient population to be successful in getting the drug to patients. And so it was really a practical. We thought we could learn more about both the biology of WEE1 inhibitors, the patient population that benefits from the most, not just based on their tumor type, but the nature of the patient, their prior treatments. And really, the largest driving factor is the sheer amount of enthusiasm that we had around allowing patients to participate in Cohort 1B.
Thank you.
Thank you. Our next question comes from Tyler Van Buren with TD Cowen. Your line is open.
... Hey, guys. Good morning. So I presume that similar sepsis-related deaths were observed with the adavo, given the higher grade 3 heme tox observed with that agent. But I'm curious to hear any comments you might have related to that experience following this partial hold, and if what you're seeing is more similar or potentially different. And then the second question is just your latest thoughts on or comments on what you hope to see and what expectations should be for the monotherapy PROC updates by year-end.
Sure. Thanks for the questions, Tyler. You know, we, as I mentioned in the call, we believe that some of the myelosuppression, in particular neutropenia, is related to direct inhibition of WEE1. We've done a fair amount of work in the lab to understand this. We have three large monotherapy datasets that we will be showing, and as you saw, these are not small datasets. And so I'd like to really say that we will have full interrogation of not only the neutropenia rate, but really practical stuff, as I've mentioned before, in terms of discontinuations, interruptions, and dose reductions. And I think it's a little premature at this point to compare, you know, what we're seeing in the trials without having the data to be able to show you today to what was seen with adavo.
We maintain that our azenosertib is a more targeted WEE1 inhibitor. It hits less kinases at therapeutically relevant levels. It was intentionally designed to avoid human kinase activity. And so although during today's call, we won't be able to compare and contrast what we've seen with the adavosertib experience, we maintain that this is a better-tolerated drug and is able to be given more consistently than the dosing schedules that were worked out with adavosertib. And I apologize. I'm gonna have to ask you to repeat your second question. I just wanna make certain I address it appropriately.
Of course. Yeah, no worries. It was related to the Mammoth and Denali PROC updates by year-end. What expectations should be for both of those updates?
Yeah. So I think those are great questions. You know, the commitment to present the Denali data is new today. As you saw from the enrollment curve, the Denali enrollment has really driven the close to 250 patients we've treated with monotherapy in the past 12 months since ASCO 2023. And so that should be a very robust dataset of platinum-resistant. Many patients will have received multiple lines of therapy, and as you and I have discussed before, given the tissue requirements, we will be able to look, with that large enough of patients, to look at the Cyclin E components of the tumors that those patients are facing. Right now, we believe that Cyclin E is positive in at least 60% of all platinum-resistant ovarian cancer patients.
The fact that we have 100 patients should give us an ability to have adequate numbers of patients to look at the activity in each of the groups within the Denali cohort. Mammoth is slightly different than Denali in that it is patients who are required to have received a prior PARP inhibitor and progressed on such therapy. But with the exception of that prior PARP, it is a very similar patient population. We allow a number of lines of prior therapy. And the Mammoth study is intentionally designed. It was not a randomized study, but it was really to look at the activity of azenosertib as a monotherapy compared to combinations with a PARP inhibitor.
That third cohort within the Mammoth study was really based on very strong data preclinically, that azenosertib worked as well as PARP inhibitors, in particular in PARP-sensitive tumor models, and it maintains monotherapy activity in PARP-resistant preclinical models. So we're very excited to share both of those datasets later this year. And I think, in the totality of the data, when you layer that on top of the phase 1 data, should really fully define the therapeutic index of azenosertib moving forward.
Thank you. Our next question comes from Akash Tewari with Jefferies. Your line is open.
Hey, this is Amy on for Akash. Thanks so much for taking our questions. First of all, can you characterize when these sepsis cases kind of occurred during the treatment regimen? And then as you think about going forward, modulating, you know, potential drug exposure and balancing the risk of neutropenia and/or sepsis, how do you think about it in terms of the dose, continuous versus intermittent, and, you know, chemo combo? Thanks so much.
Sure. I think I got all of this down, Amy. So the first one is of the grade five events that were listed during today's call, they have occurred since the program started in 2019. The most recent ones occurred within the Denali and Mammoth studies and are reflective of the larger numbers of patients that have enrolled in that study. There's no pattern across the grade five events in terms of when they necessarily occurred. I think your question kind of implied, did they happen early in the treatment or after the patient had been on? I have to say that each of the circumstances of the deaths are very unique. And so it's really too small of numbers of patients to make any trends or comments on the trends.
As far as the intermittent and continuous dosing schedule, we stand behind our decision, which was announced, the early data was announced in June 2023, during a corporate call, that driving up exposures leads to improved efficacy, as was demonstrated on that call, and that we were able to drive up exposures, by switching to a 5 days on, 2 days off schedule. So we, we are, committed to the intermittent as opposed to the continuous dosing schedule at this point.
You know, I think in terms of exposure, necessary efficacy and safety, I think the monotherapy, as you saw, as we broke out during today's call, has to be considered, you know, as a separate consideration to the chemotherapy combinations because of the inherent side effects associated with the use of chemotherapy, even as a single agent. So again, I think it's really very, very small numbers and, you know, and it's unfortunate these deaths occurred, but in the totality of the numbers of patients treated, these are small numbers, and it's really too small numbers to make any conclusions about trends around timing, whether it be in the monotherapy or in the combination cohort.
Got it. Thanks so much.
Sure.
Thank you. Our next question comes from Derek Archila with Wells Fargo. Your line is open.
Hey, good morning, and thanks for taking the question. So I guess just a couple from us. I guess what do you think it says about the FDA's decision to only halt the trials with monotherapy versus combo? I know you just kind of said, Kim, that it might be harder to parse that out, but I'm just curious. And then, I guess you know, was adavo ever put on clinical hold? I know you're not gonna make comparisons today, but I'm just curious if they were ever put on hold or they stopped enrolling their trials for safety reasons. And then the last question is, you know, there are some you know, typical logistics and guidelines for you know, responding to the FDA on you know, clinical hold.
So I'm just curious, you know, I just wanted to confirm. It doesn't sound like you've received any written explanation from the FDA on what the hold is or what it's for. So I just want to understand if you've received that or we still need to wait 30 days to get that. Thanks.
Yeah, sure. You know, I as far as your first question, which is any comments on, you know, the hold being specific to the monotherapy. You know, the chemotherapy combinations that were presented at ASCO last year, that was a very large study, but it was still in the context of a phase 1 dose escalation study with each of the four chemotherapy combinations. In addition, the niraparib combinations within Mammoth, as well as the combination studies that we're looking at in CRC, as well as AML, are all being conducted in the context of the phase 1 studies. So that's just the difference between our monotherapy programs, the status of the monotherapy programs, which are enrolling larger numbers of patients as a monotherapy compared to the phase 1 nature of the combination studies.
That's just an observation of the full clinical development program at the current time. I'm not gonna comment on the adavo experiences, you know, I think it's inappropriate, and certainly we, you know, I don't have the details of the full history of the adavo program. And then finally, in terms of asking about written correspondence, as I mentioned at the beginning of the call, I'm not going to... We consider all of our dialogues and interactions with the FDA confidential.
Understood. Thank you.
Sure.
Thank you. Our next question comes from Eliana Merle with UBS. Your line is open.
Hi, this is Jasmine on for Ellie. Thanks so much for taking our questions today. We have two. So first, I know that it's early, have you seen anything predictive of the patients that would be most at risk for myelosuppression or sepsis? And with more time with the data, what types of analyses do you plan to do to look at this? And then our second question is, what's your latest thinking, and, has there been any impact to your plans to initiate a trial in platinum-sensitive ovarian cancer? Thanks.
Yeah. Thanks, Jasmine. Those are great questions. You know, we are taking the totality of the data at this point and looking to see if as is appropriate with any extensive clinical pharmacology analysis, as you do with any, in the context of any phase 2 study, whether or not there are any covariates that might predict that. And other than that, we're not sharing any of the details other than we are doing the work that is done in the normal conduct of identifying patients who are at most risk of developing adverse events with any drug or any therapeutic agent.
As mentioned in the call, while we're on a temporary partial clinical hold, we'll be coming back and updating any guidance around the rest of the clinical development program once that partial hold is lifted.
Great. Thank you.
Sure.
Thank you. Our next question comes from Michael Ulz with Morgan Stanley. Your line is open.
Good morning. Thanks for taking the question. Just wondering, to the extent you can, if you can just clarify the specific trigger for the partial hold. Was it just, you know, the 2 cases of sepsis deaths occurring in sort of the same study in close proximity? You know, was it just the total number? Looks like, you know, the slide you showed with the Grade 5 events, looks like there was, you know, another sepsis, so maybe a total—actually 4. Looks like there were 4 cases of, you know, death due to sepsis. So just curious if you can provide any more color on that. Thanks.
Yeah, I mean, I think you've summarized exactly what we're sharing about the reasons for the partial clinical hold. Although the Grade 5, excuse me, the Grade 5 events have occurred across, you know, each of the studies. There were two that occurred this year in the context of the Denali study due to presumed sepsis.
Okay. Thank you.
Sure.
Thank you. Our last question comes from Michael Schmidt with Guggenheim Securities. Your line is open.
Hi, guys. Thanks for taking my questions. I know that, you know, you said you can't guide obviously, or talk about specific interactions with the FDA at this point. But just curious if you could just remind us perhaps of the administrative process with the FDA, sort of any potential timelines and, you know, analysis that may have to be done before you can share publicly what next steps might be. And also wondering, you know, around this data disclosure in the second half, if that will include any kind of regulatory feedback around the clinical hold or if that will be a totally independent disclosure. Thanks so much.
Yeah, sure. So I'll start with the data disclosures that we're committed to are completely independent around any updates regarding the partial clinical hold. So completely, you can think of them as completely independent events. And as I said earlier in the call, any dialogues that we're having with the FDA, we hold highly confidential, even those included around the administrative process that we will follow in working very closely with the FDA.
All right. Thank you. Appreciate it.
Sure.
Thank you. At this time, I'd like to turn the call back over to Dr. Blackwell for any closing remarks.
Sure. I just wanna thank everyone for joining us today, and I hope you have a great day.