All right. Good afternoon, everyone. Welcome to day one of our global healthcare conference. Thanks for joining us. Very excited today to have Zentalis's CEO, Kim Blackwell. Thank you, Kim, for joining us.
Thanks for having me.
Great. For those in the audience who may not know the company, maybe give us a brief overview of Zentalis.
Yeah, sure. So Zentalis's roots are in best-of-class medicinal chemistry going after validated cancer targets. And our lead asset currently is a novel and first-in-class WEE1 inhibitor oral that we're developing for the treatment of multiple solid tumors, but primarily platinum-resistant ovarian cancer and a less common form of endometrial cancer known as uterine serous carcinoma. So I'm sure we'll be talking a lot about all of the clinical activity and data readouts this year around the lead asset, which is also known as azenosertib.
Great. Well, yeah, why don't we start with Zeno, the monotherapy program? What have you shown us so far with Zeno, and then what can we expect over the next 12 months?
Yeah, well, the history of azenosertib has actually been in the clinic since late 2019, so we have a pretty robust data set around efficacy and safety. The most recent data demonstrated that we have a 31% response rate in platinum-resistant ovarian cancer. We reported that out in 2023. When you combine its activity in platinum-resistant ovarian cancer and uterine serous carcinoma, which are similar diseases, they have similar genetic alterations. The confirmed objective response rate was 37%, with a median duration of response at 6.5 months. We're pretty excited about that data set generated off of our phase 1 dose escalation trial.
Okay. And what are we going to see this year from Zentalis?
Oh, you're going to see a lot this year. We have 2 monotherapy data readouts in the second half of this year, both, one solely focused on platinum-resistant ovarian cancer, a study known as MAMMOTH, that has 3 cohorts. The third cohort is a monotherapy cohort of platinum-resistant ovarian cancer. We've committed to showing the final report on our Phase 1 001 trial. This is multiple tumor types, but a heavy enrollment bias to ovarian and USC given the activity that we demonstrated last year with monotherapy as ZN-c3. We're really tracking not only on time, but these we view these 2 data sets as very important, data sets that will demonstrate both the safety and efficacy of the drug when used as a monotherapy in platinum-resistant ovarian cancer.
Okay. And I guess the questions that people have are the CCNE1 biomarker. I think there, you know, it's that you've had some data there, but I think people want more, you know, to make sure that that biomarker is the right one. When will we see more data in terms of the biomarker?
Yeah, so the two monotherapy data sets that I just outlined very briefly, one is our phase 1 study. It involved all tumor types, but again, heavily enrollment bias, just referral bias to these phase 1 centers with ovarian and USC. Tissue is not mandatory, but we've made a pretty significant effort to get either point-of-care testing results, whether that be next-generation sequencing or retrospectively collect the tissue. So we're hoping to have, given the number of patients that have been enrolled since the last update in 2023, a robust data set around that, but it won't be everyone because tissue wasn't required in order to enter in the study. That's a little different than our dedicated phase 1/2 study known as MAMMOTH, where tissue's been proactively prospectively collected since the study opened.
MAMMOTH, just to take a minute to describe that a little further, it's platinum-resistant ovarian cancer, up to 138 patients, readout later this year. All patients were required to have had a prior PARP inhibitor at some point in their course of treatment for their ovarian cancer prior to enrollment. BRCA mutation was not required. HRD was not required. The thing that was required is that your doctor thought you would benefit from the use of a PARP inhibitor. And really, that mirrored the practice style in ovarian cancer at the time the study was started in 2021. Everyone got a PARP inhibitor in the maintenance setting, and those are exactly the patients we were going after to enroll in this study.
tissues are prospectively collected, and we have a third of the three cohorts monotherapy where we feel pretty confident we'll be able to have adequate numbers of patients whose tumors are fully interrogated for cyclin E amplification status, cyclin E IHC status. Because NextGen sequencing's being centrally done, we'll have data on HRR mutations as well as HRD status. And we've, you know, announced prior relationships with the usual suspects diagnostic companies that are capable of doing those kinds of testing like Foundation Medicine. So we feel pretty confident that that monotherapy set, and this is all happening this year, will enable us to hopefully show adequate numbers of patients fully characterized for the biomarker strategy that then takes us to DENALI with its readout in the first half of 2025.
Okay. So just to clarify, so you said part two is not requiring CCNE1 enrichment, or it's not going to have enrichment, but it requires PARP. You've been treated with a PARP. And then there's a part three that is?
Yeah. The second study I've described is Mammoth.
Yep.
Everyone had to have a PARP inhibitor. But there's actually three treatment cohorts on that trial. The first cohort was layering azenosertib, our drug, on top of niraparib, which is an FDA-approved PARP inhibitor in patients who have progressed on PARP. Cohort two is alternating our drug, azenosertib one week, niraparib one week, azenosertib one week, niraparib one week, à la Temyap-STAR study that was done with the predecessor WEE1 known as adavosertib. And then the third sequential cohort, well, it's a cohort of the monotherapy treated patients. And if you say to me, "Kim, what are we going to see this year that has a similar patient population that will help us answer some of the biomarker interrogation? I'll call it interrogation for some reason.
When I think about biomarkers, I like that word. That third cohort, that monotherapy cohort, is highly similar to the patients that we're currently enrolling on DENALI. So that is a monotherapy data set in the second half of this year where tissue is collected and Cyclin E status, just to get back to your original question, will be available.
Okay. And just the reason I ask is because, well, I guess PARP inhibitors have had broad labels, but they've been recently narrowed. Is there reason to believe that most of the patients that you will get, in that part three, the monotherapy arm, will be patients that are HRD, positive?
It's a difficult question to answer only because we're, you know, still analyzing the data, and I wouldn't tell you if we knew. But the practice style was everyone got a PARP.
Yep.
So if you got diagnosed with ovarian cancer in, let's just make this up, 2022, you got six cycles of carbotaxol in the sensitive setting, you then got a PARP inhibitor. Then you went on to get maybe more carbotaxol and then maybe some single-agent gemcitabine or topotecan. Those are the patients that would be eligible for this study. So it's probably going to be a in terms of HRD status, it's going to be a pretty heterogeneous. I'm trying to manage expectations. It's not going to be 100% of the patients have a BRCA mutation because that's not how PARPs were being used in the ovarian. So we'll have to wait for the results. But the good news is we'll have the ability to, to answer that question and, more importantly, how it relates HRD status, BRCA mutations to the patients that benefit the most from the drug.
Okay. The reason I ask is just because my understanding is that CCNE1 doesn't exist with most of the HRD mutations. Is that correct?
Yes. So what we know is that cyclin E amplification and BRCA mutations do not exist in nature for all practical purposes, at least functional BRCA mutations. And the reason for that is when you have a cyclin E amplification, your tumor is very highly proliferative. In the context of a BRCA or an HR, even an HRR mutation, but mostly BRCA because that's where most of the data comes from, if you have a highly proliferative tumor that's driven by cyclin E and it can't repair its own DNA, it's synthetically lethal.
Okay.
But I think I'd be a little cautious about that fact and the patient population that we enrolled in MAMMOTH because people were using PARPs like candy. They weren't paying much attention to BRCA or HRD. But yes, we will be able to further, in a well-designed prospective study, like, kind of look at those relationships because we'll have all the data from and what we've disclosed is up to 138 patients from the MAMMOTH study.
Right. Okay.
Just in terms of baseline biology and demographics.
Right. Okay. And then the other outstanding question, I think, you know, is just this drug holiday, the alternate dosing regimen. I think institutional investors were somewhat mixed on whether, you know, there was a benefit in all the parameters. So how much extra safety data will we get with the, you know, the alternate dosing regimen?
Yeah. So, we call it intermittent, but that's fine just because I like to use the same terminology. For those of you who haven't followed this story closely, up until 2022, the dose the drug was given continuously. Then we made a switch to give it Monday through Friday for all practical purposes and have two days off. For those of you who followed the WEE1 story for a long time, adavosertib, which was the predecessor AZ drug, was being given five days on, five days off. And what we saw in a data set, one of the last data sets we'll see from adavosertib in November of last year, they had an over 35% response rate in cyclin E driven cancers, even giving a drug five days on, five days off.
We give the drug five days on, two days off, and we believe that that's allowed us to do two things. One, drive up exposures in CMAX, and two, maintain the tolerability that we saw when it was given at a lower dose continuously. So we feel very confident that we did the right thing. The two days off is still less than six half-lives, which, as a, I'm not a clinical pharmacologist, but at least in my mind, that's not an adequate what's the right word? It's not a worrisome period off. And I think that's allowed us to broaden the therapeutic index of the drug. And as we demonstrated in May, when we compared continuous to intermittent, we saw in smaller data sets an increase in the response rate, which was exactly what we intended to do, which is exposure drives efficacy.
At least that's been my experience as 25 years as a drug developer. If you're going to develop a drug as a monotherapy, you have to optimize exposures, CMAX, and maintain safety.
Okay. Well, I think some of the concerns that I heard from investors was, you know, as the exposure goes up, the safety's going to look worse in terms of, you know, getting some of the myelosuppression that we saw with the with the daily dosing versus the intermittent dosing. So I did I guess, do you think we'll see enough exposure data this year to get people comfortable that it's, it's manageable and that that was the right route to go with the dosing regimen?
Yeah. I think not only will you see additional exposure, but you're going to see additional patients treated at our go-forward dose, both in the final report from 001 and the monotherapy cohort from MAMMOTH. I will say that, as we've tracked developing this drug as a monotherapy, the things that we've tracked even more closely than the line item listings, you know, of 12% anemia and 13% neutropenia, I do believe this drug is going to perform very similar to other cell cycle modulating drugs like the CDK4/6, where you see neutropenia, but you don't see a lot of febrile neutropenia. So we've really tried to emphasize that what we're tracking is also not just the safety line items, but the tolerability of the drug. Are patients staying on? How many adverse event discontinuations? And as of November, in the data set that we updated, zero.
How much febrile neutropenia? Zero. Those are those two things clearly, and I said this, clearly differentiate this drug from the predecessor WEE1 inhibitor, adavosertib, where you saw a lot of even the last data set of adavosertib, this IGNITE data that was presented in November, they had a 13% AE discontinuation rate. We've seen nothing. Now, granted, they had more patients, and we'll continue to track it. And we will have the data sets to confirm what we've seen early on. But I'm particularly keen on are patients staying on the drug? Have we seen febrile neutropenia? Have we seen the things that really, you know, would make it a difficult drug? And we've just not seen that.
I feel pretty confident that we'll continue to track those things closely, and we'll have these data sets in patients all treated on the same dose in the second half of this year.
Okay. And then just maybe on the CCNE1 biomarker, you gave us some, you know, you described why it's important and, you know, in rapidly dividing cells. I know some of the data sets, the amplified CCNE1 versus the overexpressed CCNE1, has had different response to the WEE1. Is there any rationale why it should be different, or do you think it's just different data sets? I mean, I think there was even an update from Intrigue, you know, that showed some different responses with CCNE1.
You mean the IGNITE data set in November?
Yeah.
You know, right now, the science would point us to we don't necessarily care how the tumor becomes cyclin E positive. It can either be born with eight or more gene copies or in the process of becoming treatment resistant, it drives up cyclin E because tumors are smart, and if they drive proliferation, they can overcome chemotherapy. Simple-minded way that I describe it. I think it's going to end up, again, just from a broad view, hypothetical, I think we're going to end up having similar patient populations defined by protein and gene like we did with HER2. You've been doing this a long time. So if I we don't necessarily care how the tumor becomes cyclin E addicted or cyclin E driven. It's just a matter of can we define it uniformly, consistently enough to get the drug registered at the FDA?
That's what we are spending a lot of time working on.
Right. Okay. Maybe just one more on the monotherapy before we talk about some of the combination data we're going to see this year.
Sure.
What in terms of the registration path, I mean, you gave 2025, 2026 maybe. What does the registration path look like for USC and PROC?
So what we've committed to is the data of the first data set, the top-level data out of Denali in the first half of next year, which is less than 18 months from now, if anybody who's counting. And this is our up to 180 patients 180 patients, sorry, not a race up to 180 patients, all-comers, as long as you have tissue and you've had no more than 4 lines of therapy, you're eligible for Denali. Global study. But then the patients are going to be, as part of the statistical plan, binned based on their cyclin E status. So Part 2A of Denali is cyclin E amplified. Part 2B of Denali is cyclin E protein overexpression in the absence of gene amplification, so less than 8 gene copies. And cohort 2C is what we call our double negative, so not cyclin E driven.
You're not amplified and you don't have high levels of the protein. This enables us to have a registration intent study that would enable us to file on all-comers or a Cyclin E defined population. And we're committed to showing that data in the first half of next year.
Okay. For PROC, the regulatory pathway, is this still a single-arm trial on response rates?
Well, we've committed also as a company, both internally and externally, to file on an NDA in 2026 off of the DENALI and/or the TETON data sets. In my mind, the accelerated pathway looks like a single-arm study very similar to what ImmunoGen was able to accomplish with SORAYA, which is, you know, a response rate like they saw, 30, a little over 30%, and a durability of response of at least six months. So that's kind of the parameter that's been set that they then also successfully executed by having a randomized Phase III of their drug compared to single-agent chemo. And so I think that's a very similar approach to the way we're going about it.
Okay. And USC?
So we have an ongoing phase 2 single-arm study for uterine serous carcinoma, which is USC, isn't it? University of South Carolina or University of Southern California. Although someone got confused the other day. It stands for uterine serous carcinoma. It is one out of 10 endometrial cancer diagnoses, but it constitutes 40% of all endometrial cancer deaths, meaning it tends to be late presenting, completely non-responsive to chemotherapy. And the predecessor WEE1 [inhibitor], adavosertib, that's no longer being developed had a roughly slightly over, I think, 27%-28% objective response rate at SGO just about a year ago in uterine serous carcinoma. It's a smaller way smaller patient population and opportunity than PROC, but we do have an ongoing study in collecting regulatory quality data to define the activity of the drug known as in uterine serous carcinoma known as TETON.
We've committed to reporting that out in the second half of 2025.
Okay. And then before we go into some of the combination, I guess just briefly, you articulated a frontline trial in ovarian cancer. Obviously earlier, a lot larger opportunity. When I think you're going to have the guidance was to speak to the FDA this year and confirm plans. What have you learned anything so far? And what's the strategy for the frontline at this point?
Yeah. Our guidance was to provide additional details around the trial design and the timelines, you know, the projected timelines by the end of this year. What we've disclosed is that we are taking the drug into the patient population after six cycles of carbotaxol that for all practical purposes are no longer eligible for the benefits of maintenance PARP, also known as HRD negative, also known as HRP. That's about 40% of all stage three, four diagnosis, serous ovarian cancer. What we've also disclosed is that we're going to layer the drug on top of BEV and compare it to BEV alone in that first line maintenance setting. And that's kind of what's on the schematic and what's publicly been disclosed. There was something else I was going to say too, but I can't remember. Let me think about it. Oh.
We think this offers the highest likelihood of getting the drug into an earlier line of setting. We have a PFS and PROC heavily pretreated of at least 6 months. We have a response rate of 30%. We've got the only orally available drug besides the PARP inhibitor class that has monotherapy activity in ovarian. So we're pretty excited about that opportunity to take that 40% of first-line PSOC that used to be getting a PARP that's no longer getting a PARP because there's a survival detriment for giving those women PARP. And BEV compared to placebo increases PFS of about 2 months. And we've got a drug that's got durable objective responses in later line and it's orally available. And what we've heard across the board is the last thing we want to do it's, you know, the maintenance setting is kind of like the adjuvant setting for ovarian.
You've given all your chemo, now you're going to let the patient go. But physicians, unfortunately, wait till the cancer comes back. Physicians want to do something above and beyond BEV. That's why PARPs have been so widely used and in the BRCA mutant population in particular have made a huge advancement in the way that these women are cared for. So we're going to go after this kind of what we consider an unmet need first-line population with an orally available monotherapy active drug. We're pretty excited about the opportunity.
Okay. We talked a little bit about this before, but selecting HRD negative, you should get more CCNE1?
Yeah. So I see where you're going with all of this. So HRP, because we can't call it HRD negative, my scientists are all over me about this. I will call it HRD negative till the day I die too, Andy. So just to be clear, it's we have to call it HRP now, which thoroughly confuses the heck out of me. But in HRP patients, they have less response to carbotaxol. They have more burden of disease. They actually, their PFS for single-agent Avastin is much shorter than the HRD, probably because they're starting with a lot more cancer because their tumors don't melt away to carboplatin. We believe that part of that phenomenon could be driven, you know, more disease could be driven by those cyclin E positive patients.
So all of the science is kind of pointing us to moving the drug into the HRP population, also known as HRD-negative population, because we think that's an unmet need. We have not disclosed whether or not we're going to focus on Cyclin E positive or not. That will be part of the update later this year.
Focus on it meaning exclude patients that are not CCNE1 positive?
Defined by, yes.
But would you would be checking it, I would assume, when you have tissue?
Yeah. And in fact, we have not disclosed anything, but you could imagine a trial where you're really, you know, cyclin E positive ovarian cancer is very common. And we estimate it to be at least 60%-80% of all diagnosed ovarian cancer. So it's not like you're cutting your population from 40% of all ovarian down to a smaller. It's really going to be a good chunk of all ovarians. So if that's where the science takes us, that's where we'll let the science. We want to design a trial for the fastest regulatory approval pathway in that earlier line, setting.
Okay. This is a good segue with the last few minutes. You mentioned it'll be on top of Avastin, BEV.
Yeah.
What? So it's a good segue to talk about some of the combination strategies. What is the rationale for combining with BEV? Is there any preclinical data that you have that a WEE1 plus a VEGF inhibitor or?
Yeah. There is some data that WEE1 in preclinical because you think about it WEE1 as a target when BEV was in its heyday and people were doing BEV resistance versus BEV. There wasn't a lot of attention paid to it. But in colorectal in particular, without spending another 20 minutes on this topic, it does appear that WEE1 and Cyclin E might drive some BEV, but very, very small. And again, that's in the literature. There is no overlapping tox, which makes it, you know, a good, good, partner for our drug. But more importantly, we've got this monotherapy activity. And whether you like it or not, BEV is here to stay as a standard of care. So it's hard to imagine a first-line maintenance where BEV isn't given. So there's some practical considerations to why we think it's a good combination.
Right. And if I recall, and it's been a while since I looked at the data, I thought the VEGF makes HRP patients appear more like HRD positive patients. Isn't there some data suggesting that?
There's a little bit of data, but I think you have to kind of stand back a little bit and kind of imagine it. But yeah. I mean, not imagine the data, but I think it, you would need much more patients to really understand that phenomenon.
I mean, I think that was the rationale behind the PALS study that AZ did or the consortium did for AZ.
Correct. But at the end of the day, it's really HRR mutations that I think drive that phenotype that benefits from PARP inhibitors.
Okay. Other than a VEGF inhibitor, you're going to have several other combination data sets this year. So which one are you the most excited about?
Well, I'm excited about both of our combination data readouts. The first, they're both going to happen the second half of this year. So we have a trial combining our drug on top of the proapoptotic BCL2 inhibitor that we've developed internally. It's an internally owned BCL2 inhibitor and relapsed refractory AML. The preclinical data was very strong and we presented that at AACR in 2022, but very simplistically, if you're driving apoptosis, the whole process starts with DNA fragmentation. That's what the first step in apoptosis and it's highly synergistic with WEE1 that just finishes the job by driving these cells that we're already thinking about becoming apoptotic into mitotic catastrophe. And it's a mutation unselected population of AML with an all-oral regimen. So we'd be pretty excited about clinical activity in that setting.
Then we have a Pfizer-partnered clinical study going after the BRAF V600E CRC patients where BEACON is currently approved in the second-line setting. That's encorafenib and cetuximab. What we know about BRAF V600E CRC is that FOLFOX, FOLFIRI has a 3% response rate and basically the majority of the patients progress at the first set of scans, like less than 2 months. Therefore, BEACON, which is the approved therapy, has a very low response rate, I would say 19% in a 4-month PFS. So we're layering azeno, our WEE1 inhibitor, on top of the BEACON regimen. The data for BEACON and azeno, there's no overlapping tox. And we're enrolling both BEACON naive and BEACON refractory patients. So we have a clear parameter, which we think good looks like, which is BEACON's about a 19% response rate in 4 months. So we'll see that data later this year.
Then any activity in BEACON refractory because chemotherapy doesn't work in these V600E CRC, we would be pretty excited about. Again, that's kind of what I would be tracking with that data readout later this year.
Just remind us, Pfizer's invested in Zentalis already?
They made an equity investment where no rights or anything else was exchanged. Adam Schay, which is on our SAB, who runs the clinical oncology franchise for I don't know what his official new role is, but he's been part of our SAB and they're supplying the encorafenib as well as thought partnerships for that study.
Okay. So they're excited about this data set too?
I can't speak for Pfizer, Andy, but we're excited to be able to show the data later this year.
Okay.
Because it's a completely unmet need. They've, you know, BEACON's being moved up into the first line in combination with chemo. That's an ongoing study known as Breakwater. So we've designed our phase 1, 2 study to really look at the activity in both BEACON naive and BEACON refractory. And it then takes it from two oral agents and cetuximab if we're successful in developing it. And I probably should put this plug in that the BRAF models, when we showed it to, you know, investigators who had been working in V600E CRC like Scott Kopetz, and we showed them what adding a Zeno on top of BEACON, we saw tumor regressions. And they basically said, "We haven't seen tumor regressions in these models." So we were pretty excited, which then led to the, you know, sense of urgency in the clinical trial.
But I'll end on this note because I think Zentalis, having such a great drug, it's hard to like, there's so many things that we can do with WEE1 inhibitor given that it's a cell cycle modulator with a completely unique mechanism of action. We're going to be presenting at AACR the preclinical data in combination with a KRAS G12C, both the Amgen and the Mirati compounds. And so BRAF is just the tip of the iceberg. If WEE1 shows additive or synergistic activity on top of encorafenib, you could imagine, and you'll see the preclinical data at AACR, you could imagine that it will be synergistic with many mutationally oriented drugs to make them work better.
And we can. I know we're out of time, but when you cut off that mutational driver, it causes high amounts of replication stress, which means the machinery of proliferation and DNA synthesis is shut down. And that's what happens when you inhibit BRAF and KRAS. That's exactly where our drug works best because it just drives a cell into mitotic catastrophe because you've pulled the plug out of the Tesla. I don't know if that works. You pulled the plug out of something by inhibiting KRAS. But as we're seeing, the durability of some of these single mutations, single drug combinations, leaves a lot of room for improvement.
And so that's why I'm particularly interested and excited about presenting the data set around BRAF because I think it's really a proof of concept with a clear clinical development plan that would probably spill over, carry through to other molecularly targeted agents.
You're going to have some KRAS data too for sure.
Preclinical KRAS at AACR.
Okay. Well, thank you, Kim. That's all the progress. Looking forward to the.
Thanks for having me.
A lot of data you have this year.
Okay. Thank you.
Thank you, everyone.