Okay, good morning, everyone. Day two of the Jefferies Healthcare Conference. My name's Akash Tewari. I am a Pharma and Biotech Analyst here at Jefferies, and I have the pleasure of hosting Kim Blackwell, CEO of Zentalis. Now, Zentalis, you know, it's one of the rare names in oncology that we've liked with us. We like a drug that's very efficacious and then has a role in the treatment of a lot various GU cancers. I know there was a big announcement last week in terms of what the clinical development plan is for your WEE1, and I think we've gotten a ton of investor questions and this is stuff that, you know, we're still trying to figure out on our end as well.
So, Kim, why don't I give it to you for some brief intro remarks about some of the thought process behind the decision, and then we can go into one-on-ones.
Yeah, great. Well, thanks for having me. Good morning to everyone who is here. As Akash said, we're really excited about our novel, unique, first-in-class WEE1 inhibitor, and in particular, it's a drug that's highly active in gynecologic cancers, including ovarian cancer and a form of endometrial cancer called USC. Last week's update was more of a clarification update than a big update, but it was kind of the second update we've had since an announcement around June, in June at the ASCO meeting that not only had we done some dose work and found an optimal dose of our drug known as azenosertib at 400 mg 5:2, but the drug was both safe and highly active with a 37% confirmed objective response rate in ovarian.
So this announcement now, nine days ago, was really a follow-up to update people as to the work we're doing, the plan, and whether we were on track with the plan. So the headline was supposed to be, "We are moving forward. We are on track, and we have a plan to get this drug as a monotherapy in a form of ovarian cancer called platinum-resistant ovarian cancer that constitutes about 42,000 treatable patients in the U.S. and the EU5 each year." And for those patients facing what is, for all practical purposes, chemotherapy-resistant ovarian cancer, there have been very limited options up until the past year when a drug known as mirvetuximab, an ADC targeting FRα, became available in the same setting, but only for about one out of three, 35%—35%-40% of the patients facing this disease.
So with that, we have a monotherapy response rate. This week's announcement was or last week's announcement was really to highlight that we have a trial ongoing that we believe will represent a pivotal study known as the DENALI study, enrolling these patients. It's enrolling all-comers, ovarian cancer patients. And although we hadn't put out any guidance, we set clear guidance that we expect a dataset on this in the first half of 2025 with anticipated NDA sometime in 2026. We updated some other guidance around datasets, and this includes an updated dataset in the second half of 2024 with another monotherapy platinum-resistant ovarian cancer population known as MAMMOTH. And then we updated some additional datasets, including a dataset in a form of endometrial cancer known as USC that we'll report out sometime in 2025.
More importantly, we updated the monotherapy data that we had released at around the time of ASCO in June. We committed to having a final data presentation in the second half of next year around this very large all-comer, all-tumor-type trial. But it's really been the workhorse for us, understanding azenosertib. The first patient was dosed in the trial. We've now dosed over 180 patients at multiple dose levels, and we continue to keep the study enrolling and open mainly because of the demand from our investigators to make the drug available for both ovarian and uterine serous carcinoma patients. So headline was, "We have a plan to get this drug registered, approved, and two monotherapy datasets in the ovarian and one dataset in the USC or endometrial population." We also updated the safety data from our phase I study.
We've enrolled 46 patients at this point. We've had no drug discontinuations. For those of you who aren't familiar with WEE1 as a target, it's an incredible target. There have been drugs that have targeted before, but they were not as highly specific kinases as the kinase were develop, kinase inhibitor we're developing known as azenosertib. And to date, we've had no febrile neutropenia, which has been associated with the targeting of WEE1 with what I'll call predecessor inhibitors. We've had no sepsis, and we've had no drug discontinuations now with over nine months of follow-up. We also updated the longer follow-up since ASCO with a median follow-up of 6.5 months.
This is the foundational dataset that gives us a reason to believe that not only will we generate an additional dataset, but there's a high probability I think those are the words I'm supposed to use that this will be a dataset that represents availability, getting the drug to patients through some type of regulatory approval, most likely an accelerated approval with a fast-follower confirmatory study against single-agent chemo. So we're excited because the drug has activity. We've proven now with what I think is more than adequate follow-up that it's safe. We have a plan. We're on track to meet that plan, and more importantly, it's, it's going into a space that's completely an unmet need. Our drug has the ability or the potential to address a large proportion of these platinum-resistant ovarian cancer patients, and there's just not a lot of options for them.
So, I think I'll finish with that. That was the headline.
Yeah.
Do you want me to move on really quick to the other?
Yeah, sure. Sure.
Yeah. So the second sub-bullet or sub-heading was in June. W e had announced that we had a high amount of conviction around this drug given the monotherapy activity and the safety we were seeing, that we were moving the drug into an earlier line of therapy known as platinum-sensitive ovarian cancer. Now, this is a large population of ovarian cancer patients, unfortunately, because it represents almost over 75% of all women diagnosed with ovarian cancer worldwide. The standard of care in these women is to give them six cycles of platinum and paclitaxel. Sometimes they're debulked, which means that the tumors are removed at some point in the chemotherapy course. And then at this point, there really is a treatment paradigm split. If you have a what's known as a BRCA mutation or also known as HRD, they're not the same, but they tend to track together.
That's 60% of all ovarian diagnosed at stage three or four. You go on to receive a PARP inhibitor. The other 40% of the patients and sometimes bev, and that's a global standard. If you do not have a BRCA mutation or you're something known as HRP, or in the old days, we called it HRD negative, but it's the same thing. It basically means you're not eligible for the benefits of a PARP. And in that scenario, the standard of care is bev. We have a drug that is active as a monotherapy, and we announced a plan to do a randomized study in the first-line platinum-sensitive space, layering azeno on top of bev compared to bev. And we can talk about, you know, expectations of what we would need to see, what we want to see. This is a very large population of ovarian cancer patients.
We had previously announced, with the guidance of some of our U.S. Investigators, in particular, a second-line trial. A second-line means after the patients have progressed on bev, they go on to get more chemo, and then they go on to some sort of maintenance therapy. The global standards for second-line are very varied. We've always set out to have an intention to have a global registration for azenosertib in the earlier lines of therapy known as platinum-sensitive ovarian cancer. There's been a lot of changes in the landscape in the past couple of months. In particular, the indications for PARP inhibitors have become more narrowed such that a lot of the patients that are known as HRP do not receive PARP inhibitors in this setting.
This allowed us an opportunity to really understand and study azeno on top of what has been over a decade, some would call it a bit of an older standard of care, bevacizumab. So what we've announced is that instead of moving to utilizing the drug in the second line, we saw a much, much larger opportunity to layer the drug on top of single-agent bev in what's known as the first-line maintenance setting. I'm sure you'll have some questions about this. But it was driven by opportunity and the practice standard changing, the changes in the way these women are managed. It had very little to do with we didn't think our second-line trial was a good design. It didn't mean that we don't believe in our drug being active in combination with chemo. We had demonstrated that in June of this year.
It was really larger numbers of patients, a clear global standard of care in the first-line maintenance setting. Besides the PARP inhibitors, we're actually the only oral agent demonstrated to have monotherapy activity in ovarian cancer right now.
Understood.
So those were all the arrows along with global consensus that this is where we needed to move the drug. And that was really the second announcement earlier last week.
Understood. So, one thing that I wanted to kind of address because this is the question that I think I've gotten a lot from investors is, you know, I was certainly, you know, we were at ASCO. I remember we spoke a lot at that meeting, and there was a lot of excitement on the chemo combo. And I think the thought process was, okay, you had 25% refractory patients, and then you also had a bunch of PD-L patients where we know WEE1 doesn't work particularly well. So of those 119 patients, you still had probably a cohort of 80. And my suspicion was your chemo combo response rate in that PROC setting was probably in the 60s, right? Like, that's really impressive without a biomarker.
The question that I think I've gotten the most from investors is, okay, how has the safety data for the chemo combo evolved over time, right? Like, has the heme tox worsened over time? Is that what led to maybe looking at monotherapy? And to me, I, I can see how we think that at the first glance you read the press release. B ut at the same time, you do have actually in PROC a chemo combo study that you are pursuing. A nd that's going to read out, I think, in 2024, 2025 where you're it's actually, you know, with paclitaxel, carbo, and gemcitabine. So let's start off with that, right? So what is the therapeutic window that you've seen from the dataset that you presented, the 119 patients you had at ASCO? How has that evolved over time in the chemo combo setting?
Yeah, so I think that's great. So, as you said in June, we announced a very phase I-B. So I think a lot of people—it was by far one of the phase I studies I've ever, you know, phase I you usually are studying one combination getting to dose and calling it a day. This was four different chemotherapy backbones. The data in at least three of the arms was actually relatively mature. The only—and we were very successful in getting a recommended phase II dose on the backbone of pegylated doxorubicin, on the backbone of paclitaxel, and on the backbone of carboplatin. That differentiated our drug from historical WEE1, where they were really having to limit the drug to like six out of a 21-day cycle.
Right.
We were very excited. Even in the platinum refractory population, we were seeing like this over 30% response rate and an enduring duration of that of over six months. So we have not lost confidence or excitement around the ability to combine this drug with chemotherapy. In fact, I think without sounding terribly unfocused, I think the data that we demonstrated at ASCO shows that WEE1 as a target and inhibition of WEE1 as a target has high amounts of synergy with chemo. The reality is, if you get metastatic cancer in the developed world, you're going to get one of those chemotherapies.
Right.
We've announced that kind of was under the radar. B ut in the announcement, not under the radar, but last Monday, we proceeded with a study in triple-negative breast cancer in combination with carboplatin and pembrolizumab. Whoa. Pembro. It's an early my time. In triple-negative breast cancer, we have a gemcitabine combination ongoing in pancreatic cancer. We're committed to demonstrating the gemcitabine combination in osteosarcoma, the results in the first half of next year. We are very excited about the activity and the safety, which in my mind. A and I took care of these patients for over 20 years, really doesn't necessarily represent much, if any, additional toxicity on top of the chemotherapy alone. But what we saw is moving the needle in terms of efficacy.
The complexities of moving the chemo combination into the platinum-sensitive setting and what is the global standard of care, especially in the second line, it is very complex. In the U.S., they give Doxil platinum as the standard. Like, that's what you got to beat. In the rest of the world, Doxil may or may not be available. And you could say, well, you as a company could supply that, but there would not be global uptake even if we did demonstrate superiority to that. Whereas moving it to the first line, where carboplatin is the standard and bev, especially in this 40% of HRP patients, is a clear this is what you've got to beat. This is what our investigators are saying.
This is what there is no question that if you design a trial with chemo comparator or layered on a what we call a single chemo, the global practices are all over the place. And that, besides the size of the opportunity, drove this decision. It has little to nothing to do with our chemo combinations and the dosing that we were able to obtain. The one remaining question, and I said this at ASCO, and I'll continue to say it, is I'm still keen on the gemcitabine as a combination. Every preclinical model we've looked at shows that the drug is highly synergistic with gemcitabine, which is a standard of care for many solid tumors, has very little activity in platinum-resistant ovarian cancer.
We've not declared exactly what our plan is in studying the chemo combinations moving forward outside of the very large phase I-B study at this point.
Understood. So, okay, so two points on that. So A, do you think we will get an update on the chemo combo ASCO dataset sometime maybe next year, just so we can see kind of the therapeutic window? I think that would be helpful. And then number two. T o me, it almost sounds and this I feel like is, you know, you look at the PICCOLO trial for ImmunoGen, they kind of have this issue too. I feel like what you're telling me is part of the reason you go into second line plus is you think you're going to have an underperforming placebo arm because these patients are going to be prior treated with PARP. They're then going to get rechallenged with platinum-sensitive chemo. If you look at the PALOMA-[six] study, these patients underperformed.
So, right, so chemo doublet normally would show maybe 11 months PFS, 10 months PFS. Then you would have maybe 40% of your patients who were prior PARP experience, they would have dragged the mean down, right, to maybe something six to seven months. And so then you would have maybe nine months or eight months for your comparator arm, and then maybe you thought you would have been able to show 12-13 months. Your concern is that maybe patients wouldn't be rechallenged with platinum, you know, platinum-sensitive chemo in a second-line setting, depending on what geographies, you know, you're in. Is that the concern here?
Yeah, it's actually not a concern. It's a reality, which is that the platinum plus something is very heterogeneous globally. And, you know, you have patients that get six cycles of carbo Doxil in the first-line setting. They have it just they have to have six months before they progress. Yeah, so they could have three years. You treat them with carbo Doxil, they're going to be exquisitely sensitive. You treat them with Doxil platinum or something else, they might not be as sensitive to it. So you were really looking at a couple of variables, not concerns, in a design of a second-line trial that becomes much, much, much, much... I'll say much one more time because it's early in the morning, less an issue because you're really just saying you got a drug that's oral and is monotherapy, and you're layering it on top of bev.
You've removed the variable of the chemo component that you have to beat in the second-line setting. It's a real practical trial design issue. Again, I keep going back to we want to help as many patients as possible. The first-line setting enables us to help as many patients as possible. It's twice as many patients as what we would have addressed in the second-line setting.
Understood. Then just on the follow-up, are we going to get an update with that ASCO dataset on?
What I said in June this year is, and I just said it, is I'm pretty keen on declaring a dose with gemcitabine. And it would make it an ideal time to update. We've already updated the safety and efficacy data. I was going to say we're not enrolling and did not enroll in the pegylated liposomal. So I just want to set an expectation that it would be a carboplatin, paclitaxel, and then the gem. We've not committed to a date. I want to be specific on that because the gemcitabine, as I mentioned at ASCO, the limiting step with combining any drug with gemcitabine is thrombocytopenia.
We will move forward once we have a robust safety and efficacy data, not just in that disease, but that's where I think also the safety and efficacy in osteosarcoma as well as pancreatic cancer will allow for three datasets to help us, you know, look at the totality of dosing and activity.
Understood. Now, maybe just on the trial you're going forward with in platinum-sensitive, you know, I think the issue we had internally, I think a lot of investors said is I could have bridged your PROC chemo combo data to your platinum-sensitive with the first trial design. It's hard, I think, to bridge on the first-line maintenance setting because there's no like direct, okay, you know, A plus B equals whatever. Yeah, but then, you know, I was talking to an investor this week, and her point was kind of, well, if you looked at PARPs, you know, they had, you know, these were HRDs. They struggled maybe in a late-line setting. They worked in maintenance, right? So like there's the sense that maybe that is the low-hanging fruit in the treatment paradigm. You know, if you were to because I think admittedly, it's hard to bridge that data.
What gives you confidence on that strategy and why WEE1 would show success in that HRP population?
A 37% monotherapy response rate in ovarian and USC, a safety signal. I think most people who, you know, appreciated the thoughtfulness of even the design around the second line, it wasn't just, hey, azeno combines really well with chemo. It was a maintenance versus no maintenance. And that, I think, you know, people ask me what gives us confidence in the second line we can win. It was we're safe and effective with chemo, but we're also including a maintenance versus nothing. The performance of bev and HRP is somewhere between 11 and14 months. And we have a monotherapy activity with a PFS of 6.5 months and no overlapping tox. So it's not even the lessons we learned with the PARP inhibitor, although I just said we're the only other drug to my knowledge that has that amount of oral monotherapy activity.
It's that with the monotherapy activity and the safety and what we know what we need to beat with bev, it gives us a higher likelihood, at least of conviction, that not only do we know what we need to beat, but because the drug is active, because it's oral, what we've heard over and over again is practitioners do not want to give it ADC immediately after six cycles of carbo Doxil. So I'll just switch to competitive landscape. There are no ADCs in this space right now. And so we're uniquely equipped, I think that's the right word, to move into this space because we are oral and we have the monotherapy activity. That's very different than some of the ADC where you're basically giving an additional chemo in women.
You know, the practice of ovarian cancer is you give six cycles of doublet chemo and patients need a break. So it's not just our efficacy as a monotherapy. It's our safety. It's its oral availability. And it's also a clear standard that I think women deserve better in the first-line setting.
Understood. Then lastly just on PROC, you were talking about ADCs. I mean, I think the most intriguing dataset came out of Daiichi and Merck with this CDH6 where, you know, 44% response rate without a biomarker. But I think it was more, you know, like if you looked at some of the higher doses where they had maybe 17 patients, the response rate was in the 60s. And you know, like and that seems like kind of a breakthrough, right? It was similar to what we were thinking in terms of your chemo combo, no biomarker, a response rate over 50% in that type of setting. How do you think looking at the Merck-Daiichi dataset versus the monotherapy for WEE1, those two regimens would stack up competitively in PROC?
Yeah, you know, we don't have any head-to-head comparisons. It's early data. I'd argue our data is coming out of a phase I study too. So, just to be fair to both datasets. T he drug has activity, but it's also got a chemotherapy liability, which is the topo I inhibitor as the toxin. I still keep going back to there's 42,000 women in the U.S. and EU5 that need. They got really one non-chemotherapy option right now, and that's only available to 35%-40% of women. There's more than enough opportunity. We've seen that with the success of ImmunoGen over the past two quarters. I'm not worried. I actually think it's an okay thing to bring as many drugs to these women facing ovarian cancer as possible. It also really highlights why I feel very confident we have a plan in PROC.
But also you want to move these drugs when you see what you need to believe into earlier lines. And we have a comprehensive plan, both in PROC and the platinum-sensitive space. But I don't know why anyone would struggle with we want more than one drug in PROC given the size of the opportunity.
Makes sense. Hey, thanks so much. I know we are out of time. I really do appreciate it. Thanks so much, everyone.
Thank you very much.