Welcome and good morning. My name is Michael Schmidt. I'd like to welcome you to the first session at this year's Guggenheim Oncology Conference. The first presenting company is Zentalis. It's my great pleasure to welcome Kimberly Blackwell, CEO. Kim, welcome, and thanks for joining us this morning.
Yeah, sure. Thanks for having me.
All right. Why don't we jump right into Q&A, kicking off with ZN-c3, which is a WEE1 inhibitor. I think most of us are familiar with the drug, but just to set the stage, could you just remind us of where you are with the program and how it has evolved since you joined the company as CEO last year?
Yeah, sure. Well, the most exciting news is we now have a drug name. It's Azenosertib. That's always kind of a pivotal moment for a company to rally around what we think is an amazing name for an amazing drug. I joined the company in May of last year. At that point, the company really was focused on best-in-class chemistry against a number of targets. We continue to develop assets around targets, but WEE1, Azenosertib, is our lead asset. We've announced programs not only in dose optimization but in combination with chemo. Ovarian is really one of our lead indications along with uterine serous, so a GYN onc play. We've announced a partnership with Pfizer, layering the drug on top of BRAF regimen known as BEACON and BRAF-mutated CRC.
A lot of work, a lot of announcements, and a lot of excitement about the various opportunities for the drug. You know, where I'm at from a just a broad development standpoint is this is a drug that works when tumors cannot repair their own DNA because it drives the cell cycle forward in the absence of adequate DNA repair. It also works in tumors that have high amounts of DNA synthesis or is driven by something known as replication stress. Our development plan is not only robust but laser-focused on getting those types of cancers onto the drug.
Great. Thanks. Then I think some of us may remember, adavosertib, the AstraZeneca drug, going after the same target. Maybe remind us how differentiated, ZN-c3 is from the AstraZeneca drug and what we've learned from their experience so far?
Yeah, sure. Well, you know, WEE1's a really validated target in the cancer space. Adavo is a drug that I studied in triple-negative breast cancer when I was a practicing oncologist not terribly long ago, although my kids remind me that I'm no longer a real doctor, so. You know, when AZ made a formal announcement that they were discontinuing the drug, they said it's an amazing target, but we just couldn't get the dose. I can tell you when I talk to my peers, my old peers and practicing oncologists who have worked with that drug, that that is a drug that helped a lot of patients but was plagued by the fact that it hit 13 kinases. We hit five kinases.
The eight that they hit created a lot of hem-tox , which is a tox that not only is not tolerable by patients but is not tolerated by physicians 'cause you measure it, and you understand the risk of continuing a drug when a patient has a CBC abnormality. The eight kinases that they hit that we do not hit at any significant level are ones that make sense as far as hematologic toxicity. If you at least look at the last safety data that we presented of our drug with a monotherapy, hematologic toxicity is not a problem. I feel like that in itself has clearly differentiated and made this a much easier drug. Nothing's easy, but compared to Adavo, it's a much easier drug to develop because of its clean kinesiogram. There was something else I was gonna say.
Oh, we've also demonstrated that we're different from them just in the very simplest principle that we can give the drug continuous. I'm a firm believer that if a patient's not taking the pill, it's not gonna help them. One of the things that I've done since assuming this role is we've really thought deep and hard about dose optimization. We will be declaring a recommended phase II dose for monotherapy in the first half of 2023. This was not a go back to the beginning and start over.
This was, let's take the dataset we have as a new member of the management team and look and say, "What are the things that we think we could tweak to make the drug better?" It's really for small molecules, it's about driving up exposure and minimizing any tolerability concerns, and I think we've been able to do that. We're just really waiting for longer follow-up, and then we'll have a final recommendation in the first half of 2023.
I think, you know, you did decide to look at some intermittent dosing schedules as well. Could you just maybe highlight, you know, how much more exposure you think you could achieve, you know, looking at some of those alternative dosing schemes?
Oh, I'll highlight without telling you anything. How about that? Just to be clear, we had, past tense, when I assumed this role, been looking at intermittent dosing schedules. We had multiple phase I studies. Intermittent was always part of it. I think part of the first datasets around Azenosertib was really about, look, we can give this drug continuous. Here's the data. Clearly a differentiator from Adavo, which is the AZ WEE1, what I'll call the first generation WEE1 inhibitor. All along that, and again, when you step into a new role and you look at the totality of the data, there had been absolute plans to look at intermittent dosing schedule. It just probably wasn't appreciated as much that in all these phase I studies, we weren't just looking at continuous, we were looking at intermittent driving up exposure.
This is not gonna be the same dose that we can give continuous given at an intermittent schedule. There is a clear ability to drive up exposures that's tightly linked and consistent with all small molecules I've ever been involved in where exposure drives efficacy. I think we are very pleased with what we've been able to do in a very short period of time because we were doing this work before I took this role. The question really is with Adavo no longer being at play, we have an opportunity to be first in class, we have an opportunity to be first in class in multiple indications, and we have an opportunity to not only be first in class, but fast in getting to first in class by developing this drug as a monotherapy.
This is a drug, it's rare in the cancer space right now. It's one of the many drivers that took me to assuming this responsibility as CEO. We have monotherapy activity. It's very unusual outside of the cell therapy space to see drugs with monotherapy activity, and we have it. A monotherapy play is the fastest path to getting a regulatory decision, in my mind, where you do not have to randomize and isolate effect. It was really important that we had the penultimate, I think that's the right word, dose, because we're gonna make a monotherapy play not just in one disease, but in multiple diseases.
Yeah. Let me talk about some of those. USC is one of the monotherapy opportunities for your drug. Perhaps just remind us of where you are in your USC study and how investors should think about the path to registration there.
Yeah. Uterine serous carcinoma, I think most people, even I, you don't see it very often. It's 10% of all endometrial cancer. It's p53 driven, and the study is ongoing. There are sites that are open for enrollment and accruing, and in Q3 of 2022, because it is a monotherapy play, we announced that those timelines would be affected by this dose optimization work. I think, you know, we are committed to understanding if our drug works in that space. Compared to many of our other opportunities, and I'm still excited about what we've seen with the drug, both in the phase I. I'm excited that Adavo generated an efficacy signal. We're still waiting the results of their phase II run USC study.
I think it's a fast path, but we're also thinking very deeply about other opportunities that are much larger that we're going to be running in parallel. We have a cyclin E-driven ovarian cancer that is also open for enrollment. That's was previously known as a study known as biomarkers of interest. The signal across our portfolio led us to make a decision that we were gonna go laser-focused on cyclin E ovarian. That was something that I announced very early on in my leadership because of the signals, not only what we were able to generate at Zentalis with our own drug, but there were two datasets that are in the public domain in 2022 in that same cyclin E-driven ovarian cancer.
One was cyclin E protein overexpressing with adavo, a drug that's given 10 out of 21 days, and it was a 57% response rate if you throw in the CA-125, and a PFS that's gonna be over 6 months. My logic triangle, which is quite simple, is we got a drug that we perceive as better than adavo, never been studied head-to-head. You see a signal with adavo that's 53% in a very hard to treat patient population, also in the regulatory landscape where Mirve was approved with a 37% response rate. We have a way of identifying those patients. The most important, that's why it's the bottom of the triangle, is the cyclin E science is very strong as it relates to WEE1 inhibition.
The second external dataset, and I'll wrap this answer up, is in December, we saw this was after we made a decision to be laser-focused on cyclin E ovarian cancer. We saw another dataset from 6 centers here in the U.S. led by Funda Meric-Bernstam, you know, 37% response rate, again, over 6-month PFS in cyclin E amplified ovarian cancer. You got two clinical datasets that say the drug works in this population of ovarian. You got a drug that you believe, I believe is a better drug than adavosertib because it's more highly specific, and we can drive up exposures without hemetox. You got this foundation, which is we can identify the cyclin E patients that are driven, and the science. You know, you've got to follow the science as well as the money.
To me, that is the other monotherapy play here, which is really about a much larger opportunity. We believe cyclin E-driven ovarian cancer could be as high as 50% of all ovarian cancer. Layer that on another foundational, which is there's at least a regulatory precedence in that exact same patient population. That's exactly the ovarian cancers we're putting on our cyclin E from the SORAYA mirve approval. We know that in particular, cyclin E-driven ovarian cancers are not very sensitive to chemotherapy. I can get into as much detail or as little detail as you want, but cyclin E and HRD are mutually exclusive. If your HRD pathway's intact, across the board for 25 years and we know that it makes you resistant to platinums.
We've got a population of patients that don't respond well to chemo and have a high likelihood of responding to our drug, and it sets a path towards what you would wanna see as a confirmatory study that has a higher likelihood of success than perhaps any other drug with just chemo in an unselected population.
Great.
Sorry. ovarian's important to us. USC is important to us.
Gotcha. Yeah. Maybe just a couple quick follow-ups. In USC, have you had regulatory interactions as to the, you know, what the efficacy hurdle is in that setting, and when will we get updates from that study this year? I had a second one.
Okay. Regulatory interactions are highly confidential, so I won't answer that question. We know that the hurdle, the chemotherapy alone in either second or third line USC is less than 10%. We've partnered with GOG. We've gotten the input about, you know, a reasonable person would say that if you saw something around 25%, 22%-25%, that's a tripling in what you would expect from chemo. Again, given the regulatory environment, it's about generating the signal and the safety data and the dose data, but also understanding what your confirmatory study would look like from day one. There was a second... Oh.
The data this year.
As part of the update on the recommended phase II, we've committed to giving an update around the timelines for the USC study.
Okay. In ovarian cancer, you obviously, you mentioned the CCNE1 focus. you know, just remind us, where you are with that, monotherapy study as well, and what investors should learn this year?
It's open and accruing. We've not committed to putting any data out. You know, one of the hallmarks for me as the leader is I wanna make certain we're putting out the most meaningful data sets possible.
Right. I guess why have you chosen a tumor-selective histology approach as opposed to the sort of a basket approach including other tumor types that overexpress or, you know, have CCNE1 amplification?
Cyclin E is a driver for many kinds of cancers. The second largest cyclin E-driven data set is actually non-small cell lung cancer. Crowded landscape. Third is triple-negative. Bladder is in that group. Ovarian is an unmet need, and cyclin E plays a role in chemoresistance. It really lays the groundwork for not only a population of patients where the drug has been shown, at least with Adavo to work, should work better with our drug, but is a, to me, a clearer, faster, I don't know if you can say clearer, faster, and regulatory all in one sentence, but to me, that's a much more high likelihood of success than trying to go after multiple tumor types.
We're still, you know, a small, publicly traded pharmaceutical company, and, you know, we have really a robust portfolio of what I think are the lower, I don't wanna say lower lying fruit opportunities, but the fastest path to generating meaningful data.
Yeah. Obviously, there is a lot of opportunity as well in combination with chemotherapy for your drug. We've seen some data last year already in ovarian cancer as well in combination. Just remind us where you are with that, with the combination study and what expectations should be for investors, how that is progressing at the moment?
Yeah. Well, we remain incredibly excited about the chemotherapy opportunity. Again, just we no longer have to necessarily chase adavosertib. We've stopped that a long time ago. They were unable to really give that drug. When they gave it with chemo, they were doing dosing schedules of six, eight, or 10 days out of 21. We've demonstrated we can give the drug continuous. We've also. The chemo data that was presented at AACR was a subset of continuous dose patients, but we've been looking at intermittent dosing in that trial from day one, which makes sense, right? You're doing a dose escalation. We're very excited about that. We've committed to providing an update of the results of that phase I for chemotherapy backbone. More importantly, you know, we've brought in a chief translational officer, where we're really trying to understand which of the patients.
Ovarian cancer patients benefit from chemo. The dilemma in ovarian cancer is which patients don't benefit from chemo, where does your drug play a role in those patients that don't derive a lot of benefit? Not any, but, not a lot. I think we've done some pretty interesting work there that will define the path forward, and we're committed to disclosing that in 2023.
Okay. There's obviously a number of different chemotherapies that are being used in ovarian cancer. Are you know, looking at combining with all the available options or perhaps, focusing on one particular option?
We haven't disclosed the exact plan. I do believe a focused approach in drug development always works better than perhaps, especially in ovarian, where there's just not clarity as to who responds to platinum anymore, who responds to paclitaxel, who responds to gemcitabine. The decision will really be based on the highest likelihood of success in a confirmatory study.
Okay, great. You're also planning a combination study with PARP inhibitors, which, you know, have sometimes some of them have a more challenging tolerability profile, I think especially the Glaxo compound. Perhaps talk about your confidence in being able to combine the WEE1 with the PARP, and where are you with that study as well?
Yeah. I just have to make a side comment, which is, although the PARPs are hard to tolerate, chemotherapy's a heck of a lot more harder to tolerate. You know, the reality is that PARPs are here to stay independent of the discussions around which patient populations, you know, will get the drug and the labels in the maintenance setting. Our study is looking at niraparib, and again, it was started at a time where the olaparib was owned by a company... I mean, it's just very practical stuff. Was owned by a company that also had a WEE1 in development. That's been discontinued, so that opens a pathway to think about other PARP combinations for our drug. We've not disclosed that at this point. That study amazingly has accrued...
Not amazingly, but in the U.S. in particular, is accruing like gangbusters, which really to me tells you how much the need is for non-chemotherapy options post-PARP. That is a trial that's enrolling patients post-progression on PARP. It's very similar to what we're doing with our BRAF study where we're enrolling patients post-BEACON. In the setting of a dose escalation for both our niraparib study where we're giving our drug concurrent or alternating like they did in the STAR study, which was olaparib-adavo, we're doing Azenosertib alternating with niraparib. That's all embedded in the ongoing accruing study. We're enrolling patients that have progressed on maintenance PARP, and we're looking long and deep about HRD status and, you know, HRD mutations to help us identify the signals that we're seeing in that study. We have not committed to an update on that study this year.
Just while I'm thinking about it's a very similar play for our BRAF partnered study with Pfizer, which is BEACON. You see less than a 20% response rate and 4 months PFS. Those patients do not respond to chemotherapy. It's a really 30,000 patients in the United States a year. High unmet need. We're working. Pfizer was a perfect partner because they've already built out a robust network of people working in that disease in the US and globally, and we're enrolling patients that could have received BEACON. In fact, they could have had BEACON as their last regimen. Very quickly in a study that's up and accruing, any signal that's seen there to me will drive tremendous value.
Okay, great. Maybe just one last question on ZN-d5, which is your BCL-2 inhibitor.
Yeah.
Just maybe talk about, where you see opportunity to differentiate from, Venclexta and, where your drug is in the development path at this point.
Right now, we're most excited about the amyloidosis study that's ongoing, and we've committed to declaring, I think that's the right word, declaring a recommended phase II dose by the end of this year. Even though most people aren't super familiar with light chain amyloidosis, it's a disease that has a median survival of 40 months and has a multitude of really pretty horrible symptomatology that affects patients' lives. By being able to declare a dose, which again, the plan has always been to expand once you get to a dose to phase II as a single arm, potentially registrational, collect registration quality data, that is a very exciting opportunity, and we'll be disclosing the clinical data and the dose by the end of the year.
venetoclax is already in the NCCN guidelines. If in fact we're as good as venetoclax, to have that in your label will really be a first approach to filling in some of the white space around venetoclax, which again, the white space is not insignificant. It represents an opportunity. I'm just being very practical about this. It would take a much, much, much larger study to really be able to say we have a better profile than venetoclax, but that doesn't bother me because there's so much other white space that venetoclax has not filled in, and that includes things, opportunities with BTK combinations, opportunities with hypomethylating agents. We do and have started enrollment and have dosed patients on our WEE1, ZN-d5 BCL-2 combination in AML. We presented that preclinical data at AACR last year.
This isn't just, "Gosh, we have two drugs, we're gonna throw them together." There's a very strong scientific underpinning behind why driving cells no similar than anything else that drives cells faster through the cell cycle. This is kinda how I think about it, is if you're driving cells through apoptosis and then you're also taking the brakes off your cell cycle, it's a highly synergistic combination. Again, those are our two currently disclosed plans around our BCL-2 asset.
Great. Thank you. Well, with that, I think it's time to wrap up, Kim.
Well, it does. Thank you.
We thank you for being here and appreciate the time.
Okay, thanks.