Everyone, thanks for joining the OpCo Conference. Pleased to be with our next presenting company, which is Zentalis, and Dr. Kim Blackwell. Kim, welcome.
Thanks for having me.
We're going to do a fireside chat. Yeah, maybe just start with kind of an elevator pitch. I know a lot of people are familiar with azenosertib, the WEE1 inhibitor, that you're devoting a lot of your assets to, but, you know, Zentalis is a much bigger company than just that. So kind of what is, you know, what is the elevator pitch here?
Yeah, sure. Well, I'll kick it off. We have a very exciting 2024 in front of us. Our lead clinical asset, azenosertib, is a first-in-class, best-in-class WEE1 inhibitor. We're laser-focused around generating clinical data as to where the drug works, in particular in gynecologic malignancies, ovarian cancer, and a subset of endometrial cancer known as uterine serous carcinoma. And we're on track to really having several data sets that look at how the drug performs as a monotherapy in those patient populations where there are very few, if no treatment options. So, we're excited about azenosertib. It works as a monotherapy. We've done a lot of work to optimize the dose in order to drive up the activity and maintain the safety of azenosertib.
Later this year, you'll see monotherapy data sets around a zenosertib in ovarian cancer, uterine serous carcinoma, and then the results of our phase I dose escalation study that's been ongoing here for a couple of years. So, we're excited about the data disclosures and the data readouts later this year.
And then maybe also just about your core capabilities as a drug.
Yeah, sure. So, besides our lead clinical asset, we kicked off the year with a very exciting announcement that we had entered into a partnership with Immunome around an ADC platform and with a lead target of ROR1 asset. And I think people were like, "Wow, Zentalis is working on ADCs." Our fundamental underpinnings are applying best-in-class medicinal chemistry against known cancer targets. And we've had great luck with ZN-c3 getting it to where it is, demonstrating the clinical benefit to patients in the ovarian cancer space. But we still have the fundamental, as you described them, scientific underpinnings and capabilities around a number of modalities. We've announced capabilities and degraders as well. But it all really boils down to the fundamental underpinnings and the very beginnings of Zentalis, which is applying best-in-class medicinal chemistry against known cancer targets.
So, we are laser-focused and prepared to deliver on ZN-c3 data sets this year, including monotherapy and combination data sets. But we still have the fundamental underpinnings of the company, which is our chemistry capabilities. And now, as we've become a more clinically focused company, our clinical, operational, and executional capabilities as well.
So, as ZN-c3 works mechanistically, you know, WEE1 as a target, effectively by inhibiting it, you're forcing cells to divide prematurely. Cancer cells, obviously, accumulate DNA damage. They can't repair it. Therefore, they go under this mitotic catastrophe and they die. It's probably going to work in a lot of different cancers. And I think with the early phase I data, you've showed that. As you mentioned, we should get more phase I data later this year. But why kind of the concerted focus on gynecological cancers, uterine, ovarian, as you mentioned? It was this a lot of this just driven by the early phase I data that you saw. Is it as a lot of it maybe theoretical? Does, like, the biology there's just a strong biological rationale there, or, you know, maybe are there also other opportunities outside of gynecological cancers that you're also thinking of?
Sure. Well, let's start with WEE1 being a validated cancer target. It's a critical protein to slow down cell cycling in order for these kinds of already messed-up cancer cells to repair to the best of their ability, DNA damage. When we inhibit WEE1, we remove those cell cycle checkpoints. In the case of the G1/S checkpoint, it's removed because we dephosphorylate indirectly CDK2, and that removes it and allows the cell to go through that checkpoint. And then we dephosphorylate CDK1, which removes the checkpoint between G2 and mitosis. That's that was a lot of words to say. We're basically accelerating the cells to the point that they can't stop and repair their own DNA. WEE1 as a target was actually this is a fun fact discovered 50 years ago. So, this isn't something that was discovered 20 years ago.
When we have more time, I'll get into some of the funnier details about how it was discovered 50 years ago. But with that said, we know it plays a critical role in the regulation of DNA repair by putting these checkpoints in. By removing them, we basically are driving a three-wheeled Toyota at 100 miles down the freeway. At least that's my simplistic analogy of what ZN-c3 does in terms of modulating cell cycle and causing cancer cell death. You asked a question about why gyn malignancies and why Wee1 is a critical target. It's a whole host of things that went into our focus on ovarian cancer and uterine serous carcinoma. The preclinical model suggested high amounts of activity of Wee1 inhibitors as a monotherapy.
The fastest path to getting a drug approved, whether it be accelerated or requiring a randomized phase III, is really to have a drug that works as a monotherapy. What we saw early on was monotherapy activity in several tumor types, but a very robust activity as a monotherapy in ovarian and uterine serous carcinoma. The focus on gynecologic cancers is because that is where the monotherapy activity has been the most impressive, intriguing, validated to date, not just in the preclinical models, but also in the clinical space and the work that we've done with azenosertib.
Is it fair to say that, yeah, I actually didn't know that it was discovered over 50 years ago. So that, I mean, that.
50 years ago.
Yeah. I mean, that does showcase, you know, I mean, I'm sure, like, p53 and RAS were also discovered around then too. So, there's a lot that we know about these targets. Is it fair to say that we have not seen successful development of a WEE1 inhibitor because it's been too toxic?
Yeah, I wouldn't say it's too toxic. I mean, you know, with all drugs, you can get to a dosing schedule. The question is, with a small molecule inhibitor, are you getting the continuous exposures? Are you getting the exposures you need to see to completely inhibit WEE1 and really accelerate the cell cycle? And it gets again, I'm glad you started with what are the fundamental underpinnings of Zentalis. It gets back to chemistry and really having the best WEE1 that's inhibiting the most focused amounts of kinases. There have been some historical WEE1 inhibitors that had high amounts of kinase inhibition on 13 kinases. We hit five. That is a major differentiator. You might say, well, 13 to five doesn't seem like that big a difference, but in the world of small molecule inhibitors, that's a game changer.
We still believe we have the most focused WEE1 inhibitor available. We've been able to give the drug continuously. We've switched to a 5:2 schedule to drive up exposures, which the preclinical models pointed to us as being augmenting or even further increasing the responses that we were seeing. We demonstrated that and showed the data that supported the new dosing schedule in June of last year. So, we think that we are on the right track. We have the right dose. We have monotherapy activity. But the fundamental, I love the word, underpinnings. The fundamental underpinnings of our success to date has been we have a highly specific WEE1 inhibitor.
Yeah.
That we believe has the most monotherapy activity across many drugs that are working in the cell cycle modulation space.
You came on board. I don't even think it was two years ago, but you have big chops in big pharma developing drugs and getting them across the finish line. I think that that's exactly what this company needs. What did you see in the data that was there with continuing dosing that you said, "There's a drug here. We just kind of need to tinker around with the schedule a little bit"?
Yeah. Well, with most small molecules, exposure drives efficacy. These tumors are smart, I think, very simplistically. I treated patients for 20 years. And if the patient's not getting the drug, the drug doesn't work. And so the two things you got to have is the right dose and a very favorable safety profile. And what I saw early on, I was a board member before I assumed the role of CEO, was the drug was working as a monotherapy, in particular in gynecologic malignancies. And it was really well tolerated with grade three or four events on a continuous schedule at less than 10%, which in a phase I study is really remarkable for any drug.
So what I saw was an opportunity to develop this drug as a monotherapy and get it to ovarian cancer patients by not having to layer it on top of other drugs. And that's exactly what our clinical development plan is, is examining, demonstrating, enrolling patients in the platinum resistance space to demonstrate that the drug works as a monotherapy and is incredibly safe.
The street, speaking of safety, I mean, the street kind of seems fixated on safety, and kind of there's this conspiracy theory that you went from continuous to intermittent because the drug was too toxic. But if you look at the data, it actually I think the switch was actually driven by efficacy because it seems like you're getting better exposures now. Like, can you explain that? Kind of seems like a paradox.
I don't know if it's a paradox, but again, it's the complete opposite as to why we were motivated to drive up exposures and give the drug on an intermittent schedule. It actually wasn't the safety. The drug could be given safely, continuously, safer than many already widely used, approved drugs in a similar patient population such as ovarian cancer, like the PARP inhibitors, for instance. It was really about could you optimize efficacy by driving up exposures, which is super critical to be successful when developing a drug as a monotherapy. It's, that's a very different play when you're developing a drug as a monotherapy compared to when you're layering it on top of another drug.
Yeah.
Your exposures are not as important, especially if you're layering it on top of a synergistic agent. So, the data that supported doing more dose optimization work, which we read out last year, was really an incredible safety signal, monotherapy activity, and an opportunity to drive up exposures by allowing for a very short break. The intent of the intermittent schedule was never to give the drug five days and give it, take it off five days. It was really just to have a short break window to see if we could drive up both Cmax and exposures, which were critical drivers of efficacy in all of the preclinical models that we had examined.
But it also improved safety too. I mean, you had less dose reductions. You had less dose interruptions, which also contributed to the higher exposures, right?
And, you know, we had predecessor WEE1s that had higher low-high levels of febrile neutropenia. We've seen none. You know, it's those kind of what are the important safety signals that we're tracking very closely, you know, discontinuation, sepsis, febrile neutropenia. We've just not seen any of them in the data we've disclosed, you know, to date. And those were important drivers behind our belief we could get the drug successfully developed as a monotherapy in ovarian cancer.
Yeah. Let's talk about the market opportunity in ovarian. ELAHERE, obviously, recently approved in platinum-resistant ovarian, sales pointing to blockbuster opportunity. That company was acquired for a lot of money. So how do you view the opportunity? Is there a lot of other room for other players here in the space?
Yeah. I think there's tremendous room for improvement. I think you and I had a discussion about this. You know, when we were developing the PARP inhibitors in the same patient population, platinum-resistant ovarian cancer was considered an orphan disease. In fact, it was deemed an orphan disease by the FDA in 2012, as it relates to the PARP inhibitors and platinum-resistant ovarian cancer. Now, looking in 2023, 2024, this patient population of patients who have progressed after receiving platinum-based chemotherapy, also known as platinum-resistant ovarian cancer, is no longer an orphan disease. It's nearly doubled with estimated prevalence of about 340,000 to 350,000 patients in the US, treatable patients. So, it's, and that's, I think that's, there's a little bit of good news for the ovarian patients out there.
It's probably earlier detection, more awareness of BRCA screening if you get diagnosed with ovarian, the impact of PARP and better maintenance therapies. But what that's actually done is created a huge need for patients to have therapies in the platinum-resistant ovarian cancer setting. In the case of the ImmunoGen now AbbVie drug, ELAHERE, they were limited to about 1/3, maybe 35% of the platinum-resistant ovarian cancer patients because they needed the presence of a certain antigen, folate receptor alpha, in order for the ADC to have the efficacy that's in the label. We have studies that are designed to look at an all population, meaning all PROC patients. We also have studies that are looking at ovarian cancer patients post PARP. That's the MAMMOTH data set that will be reported out later this year.
Yep.
In the case of DENALI, which is our registration intent phase II study, we're enrolling all-comers, but we're looking at the Cyclin E-defined populations of platinum-resistant ovarian cancer. We believe that the drug is going to work in a broad population of platinum-resistant ovarian cancer. We believe that there are better, newer, more therapies needed for this pretty large population of women facing platinum-resistant ovarian cancer.
Yeah. I'm going to hone in on something that you just said, registration intent DENALI, because this is a question that we get a lot, right? Like, what is the regulatory strategy here? Do you think that DENALI can be registrational?
Well, when I say registration intent, we're certainly collecting the data, having the discussions that are necessary to think about filing on the data in an accelerated approval fashion, I guess, is what I'll say.
Yeah. Do you think?
The ELAHERE development strategy, which was an accelerated approval off of a phase II pivotal study in platinum-resistant ovarian, and then a fast-follower confirmatory phase III study was successful in getting accelerated and almost any day now, I would assume, a full approval, but that's not been determined yet. And so we believe that that sets a regulatory precedent that if the drug is active, the durability of benefit to patients is, you know, let's say roughly six months. There's not any significant safety, even in a small population of patients, and that we've successfully committed to and enrolled to a phase III study. That seems like a sound regulatory strategy, and that's exactly what we're hoping to accomplish by the DENALI study with a data readout in the H1 of 2025.
Yeah. Let's kind of talk about that readout. So, you've got you're enrolling three different cohorts, right? Two of them are kind of CCNE high. One is amplified. The other is the other expression. And then you're also enrolling CCNE low, kind of as maybe proof of concept. But, like, how should we, you know, think of that data as, you know, as it starts to come in front of us?
Yeah. And just to clarify, DENALI's enrolling all-comers. So, if you meet all the other eligibility criteria, independent of the Cyclin E status of your tumor, you're allowed to enroll and be treated on the study. What happens after the patient's enrolled, after they're actually swallowing the drug because tissue is mandatory, then there are cohorts of patients defined by Cyclin E status, either amplification or IHC protein overexpression. That gives us the ability to look at Cyclin E-defined platinum-resistant ovarian cancer in very specific ways. But the study is enrolling all-comers.
Gotcha. And so, I mean, some of the impetus behind using CCNE status, do you think, you know, what we saw from adavosertib, which was a prior WEE1 developed by AstraZeneca for years, they just never got it across the finish line, but they recently published, or it might have been an investigator-sponsored trial. It was called IGNITE. And I thought that it showed some compelling, you know, proof of concept for why CCNE status is a good marker for response to this kind of ATR-CHK1-WEE1 axis. Do you agree with that? Was that some of the rationale behind using CCNE status in DENALI?
Well, it kind of came after our development strategy to understand the role that Cyclin E plays in predicting larger benefit to patients treated with the azeno. It really started back way before the IGNITE, although the IGNITE data was a very strong data set that supports our belief that ZN-c3 will be successful and maybe even more successful in Cyclin E-defined tumors. The science of ZN-c3 and WEE1 inhibition is you dephosphorylate CDK2, and that is the preferred binding partner to Cyclin E. So, I love it when the science kind of adds up and it makes sense that Cyclin E might predict for a larger benefit to WEE1 inhibition.
Second, we had a number of ovarian models in particular but also triple-negative breast cancer defined by Cyclin E status, where, and this is, you know, in our corporate deck, where Cyclin E-driven tumors had largerZN-c3 had larger efficacy in preclinical models for Cyclin E-driven tumors. And then I'll call it the icing on the cake for a lack of better analogy, as we saw the IGNITE data in June of 2022 with adavo. And just to remind everyone, adavo is a drug that could not be given at a consistent schedule. It was five days on, five days off. The half-life of the drug was eight hours. So, there was a period of five days where there was really very not five days, but two to three days, just if you look at the pharmacokinetics. That's not the case with azeno.
So, we got to see that kind of activity in Cyclin E-defined tumors in the IGNITE study was very motivating, very reassuring. I don't know what the exact word is for us, but and that was with a drug that couldn't be given at the same consistent exposures that we are giving ZN-c3. So that was the third kind of piece that really made us feel very secure that the drug not only was going to be active in ovarian because IGNITE was only ovarian cancer, but that we had designed the right study. It just kind of coincided with the initiation of the DENALI study.
Yeah.
So lots of arrows pointing to DENALI is an important data set for proving that ZN-c3 works in ovarian and in particular defining a Cyclin E something that even defines a larger benefit from the drug.
Yeah. Let's talk again just about the opportunity. If we just look at Cyclin E status, I mean, it seems to tend to be upregulated as you progress from down the lines from platinum sensitive to platinum resistance. If we just benchmark against ELAHERE with folate receptor alpha, I think you said maybe 40%. What do you expect is the percentage that would be classified as Cyclin E high, CCNE high, or amplified?
Yeah. So, we've looked at this in a number of different ways with large data sets and then our obviously our own data that's been generated from the trials. We actually had a poster at the ovarian meeting last fall, the AACR ovarian meeting on this. Right now, we're stating that the prevalence in the PROC setting of Cyclin E positivity, either defined by Cyclin E amplification or non-amplified but protein overexpression, is somewhere between 60% to 80%. And then we've also published that we don't believe that the prevalence of Cyclin E positivity in ovarian is very different between the PSOC, which is the less heavily pretreated, and the PROC, although the numbers are numerically higher. It's not like, you know, 0% to 80%. It's somewhere between 60% to 80% when you look across the spectrum of ovarian cancer.
You know, that really represents a much larger opportunity than even what's in the label for ELAHERE at the moment.
Got it. Got it. Let's talk about the opportunity then in platinum sensitive. You know, obviously, it sounds like the kind of all the focus on getting this drug approved is initially going to be in platinum refractory, platinum resistant. But in platinum sensitive, you know, recently, you kind of updated your thinking about more of a maintenance setting versus a combination with chemotherapy. Can you just kind of talk about, you know, some of the impetus behind that?
Sure. Not only did we update our thinking, but we defined and committed to the opportunity for azeno in the first-line PSOC setting. The thinking was really driven, and the trial design, the preliminary trial design that we put out there is really meant to capitalize on the fact that we have an orally active drug in ovarian as a monotherapy. That puts us in the same bucket as the PARP inhibitors in terms of the way that doctors would use the drug, in the maintenance setting because, you know, these women, maintenance means they've just completed six cycles of doublet chemotherapy. Some of the commercial uptake and clinical uptake for the PARP inhibitors with having that flexibility, having an oral agent with the PARP inhibitors, represents a very large commercial and clinical opportunity.
So the first thing that was really driving our thinking is not only our own, but the talking, listening to the KOL community said, "Listen, you got an oral agent. It's perfect to be put in the maintenance setting. The last thing we want to do is start up, even though it's an ADC, it's still chemo-like in the maintenance setting. Patients perceive it as chemo because it's given like chemo and has some of the chemotherapy side effects." So, one of the things regarding our commitment to moving it up into earlier lines therapy is it's oral, and we have monotherapy activity.
Yeah.
Second, in the first-line setting, it's become pretty clear that the PARP inhibitors in the HRP, meaning the non-BRCA mutant ovarian cancer patients, are no longer going to become a standard of care. That leaves a maintenance therapy for the HRP or otherwise, for all practical purposes, the non-BRCA. The only thing that's available to those 40% of first-line ovarian cancer patients is Avastin bevacizumab, which really only improves progression-free survival by about two months. So we have an orally active drug as a monotherapy, well-tolerated, makes it a setup, an ideal asset to be moved into the maintenance setting, and a clear comparator of what we need to beat in the HRP population.
All of those things really led us to believe that moving the drug into the first-line PSOC setting gave us a higher probability of being successful for approval in that large, unfortunately, patient population.
Yeah. Got it. So this wasn't anything about, like, a fundamental shift in what you're doing. I mean, this is more just based on kind of an opportunistic opportunity here given the label changes that we're about to see with PARPs not being labeled for use in these patients that are homologous recombination proficient.
A clear comparator in Avastin used globally that most people, and it's not just ovarian, but many tumor types, believe it. The drug adds something, but it really doesn't add that much compared to placebo. So that also, and then global buy-in by the thought leaders.
Yeah. I agree with that. My father was on Avastin, and it doesn't do anything. And that's been well vetted out in, I think, multiple trials now. But let's just finish on some milestones. You know, you've talked before that you'd like to present more data from kind of the all-comers phase one trial. I assume, you know, like last year, heavy focus still on the gynecological cancers. But maybe we'll also get some other data from some of the other things, other patients that are treated, colorectal, pancreatic. Let me know if I'm off on that. But also then maybe.
No, no, no. We're committed to showing the full data set from the phase one study. It is a lot of patients. The study has been up and running since 2019, starting at doses of 25 continuous. But as I presented in June and November, a large referral bias of ovarian and USC at these phase I centers just because of the documented activity of the drug.
Then kind of the distribution of continuous versus intermittent that we should expect, is it kind of like an even breakdown, or?
Yeah. I haven't disclosed those exact numbers, and I don't want to misquote you, but,
But we will see more patients with the.
We will see more patients in the intermittent, as I disclosed in June and November. We've left it open because there was such a demand to have access to the drug while the other studies were being open at these large phase I academic centers.
Got it. And then MAMMOTH, that's going to be the first data that that I think we've ever seen in a post-PARP setting. I mean, there may have been some patients in the phase I that had a PARP, but this is going to be more of a concerted effort there.
Yeah. We had presented some post-PARP, previous PARP exposures in the data set from the phase I-00I study, but MAMMOTH is a population of platinum-resistant ovarian. All of the patients will have progressed to having on a PARP, having received a prior PARP, but not necessarily as the last therapy they received. And it's not defined. The enrollment is agnostic to HRP or HRD status.
Yep.
Tissue was mandatory in MAMMOTH, and so we are collecting the data that we need to understand some of the important biologic questions within MAMMOTH, especially in the post-PARP setting, including things like BRCA reversion mutations, which lead to PARP resistance.
Yep.
HRD versus HRP, does ZN-c3 work better, the same, or worse in those two populations? And then the most, at least one of the most important questions, one of the most important questions is really around the Cyclin E-defined platinum-resistant ovarian as an enrichment strategy for driving up clinical benefit.
Got it. Well, this should be really exciting to see. It sounds like it's going to be really data-rich here. So, looking forward to it. Thanks, as always, Kim.
Yeah. And I'll just one other thing real quick is we have two other important data readouts, one with ZN-c3 and a BCL-2 inhibitor in relapsed/refractory AML. Then the fourth data set is the BRAF CRC partners partnered program partnership with Pfizer in BRAF V600 CRC, layering our drug on top of the BEACON regimen, which is an approved regimen in the second line and beyond. So not just two important monotherapy data sets, but also really a peek into how we think about building the ZN-c3 franchise at this point.