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I would now like to hand the.
Conference over to your speaker today, Liz Hicken, VP of Investor Relations. Please go ahead.
Good morning everyone and thank you for joining us. Yesterday we issued a press release announcing organizational changes at Zentalis. This morning we issued a second press release discussing the clinical data that will be presented today. Those press releases can be found on the investors section of our website at www.zentalis.com and the accompanying slides will be available after the call. Before we begin, let me review our safe harbor statement. During today's presentation we will be making forward looking statements. These statements are subject to risks and uncertainties that may cause actual results to materially differ from those forecasted. A description of these risks can be found on our most recent Form 10-Q and 10-K on file with the SEC. On today's call, Julie Eastland, Mark Lackner and Ingmar Bruns will review the azenosertib clinical data, regulatory updates and organizational changes.
We are pleased to be joined by lead investigator Dr. David M. O'Malley of the Ohio State Comprehensive Cancer Center who will be presenting the clinical data from Part 1B of our Denali study. At the conclusion of the prepared remarks, we will open it up to Q and A. Now I'll turn it over to Julie Eastland, CEO of Zentalis. Julie?
Yep, good morning. Thank you, Liz. And good morning to everyone on the call. Thank you for joining. We're excited to be here today to bring you an important update on our latest clinical data from our trials of azenosertib, along with our clinical development and regulatory plans which are focused on patients with platinum-resistant ovarian cancer, commonly referred to as PROC.
It's been a busy two months since I joined Zentalis in November of last year and I was very excited to take this role because I believe azenosertib has the high potential to be a very important treatment option for physicians and patients who continue to be in dire need of new choices. The Zentalis team has a clear view of how to bring azenosertib to patients quickly and efficiently. And so this morning we're pleased to share with you both our vision and strategy, which includes our regulatory strategy and importantly the clinical data that supports those future plans. With regards to the PROC setting, let me make just a couple points. First, there's clear unmet need in this patient population. Monotherapy chemo has a low response rate and a limited durability and cyclin E1 positive patients tend to have poorer outcomes.
Second, cyclin E1 positive patients comprise a large portion of the PROC population. This represents a meaningful market opportunity. Ovarian cancer is a $3 billion market and is expected to double over the next three years. The successful launch of mirvetuximab in patients with high folate receptor alpha expression underscores the demand for biomarker directed therapies. This limited overlap between patients of those that have cyclin E1 expression is about 20% and this creates then a large opportunity for Azeno and cyclin E1 positive patients. Third, we will present a large amount of data today that demonstrates that patients with cyclin E1 positive PROC overwhelmingly respond better to Azeno with objective response rates over 30% seen consistently across our studies in this patient population. Importantly, we are prepared to continue development in this patient population via a companion diagnostic. Next, the path forward for this strategy is clear.
We have FDA alignment on a seamless trial design where a dose confirmation cohort will lead directly into further expansion following additional FDA feedback post the dose confirmation. We anticipate kicking off this dose confirmation portion of the study, which we call part 2A in the Denali study in the first half of this year. Finally, Zentalis is prepared to execute against this strategy. As Liz just mentioned, we announced the refocusing and streamlining of the organization to extend our cash runway beyond the top line readout in Denali Part 2, which has the potential to be a registration enabling study that may allow us to seek accelerated approval if successful for Azeno. Turning to the next slide, you're going to be seeing a lot of data today over three different studies, so let me just hit the punchline here for you so you don't have to wait.
Across these studies we present today, you'll see that cyclin E1 positive patients have a consistent response rate above 30% at or above total doses of 300 mg. This is on an intermittent schedule of five days on and two days off. We saw durable responses over five months and in some cases this data continues to mature. Our safety profile we will share with you in detail today also demonstrates that Azeno is well tolerated at active doses and now I'd like to turn it over to Mark Lackner, our Chief Scientific Officer, who will walk through some highlights of the azenosertib mechanism of action and a rationale for the E1 approach.
Mark,
Great. Thanks, Julie. I'll now take a few minutes to focus on the biology of WEE1 and the central role it plays in regulating the cell cycle, which is a tightly controlled and highly regulated process that ensures fidelity of DNA replication and cell proliferation. Let's start with the panel on the left which shows that WEE1 is a master regulator of the cell cycle that normally acts as a brake to allow cells to repair damaged DNA before replication and mitosis in the so-called S and M phases. Importantly, unlike other cell cycle regulators such as CDK2 that act at just one checkpoint, WEE1 acts at multiple points in the cell cycle, including both the G1-S and G2-M checkpoints, and thus may offer an opportunity for more robust inhibition of the cell cycle.
Let's turn now to the role of WEE1 inhibition and the rationale for cyclin E1 as a predictive biomarker shown in the panel on the right. One of the hallmarks of cancer, of course, is enhanced cell proliferation through acceleration of the cell cycle and dysregulation of cell cycle checkpoints. For instance, activation or overexpression of the cyclin E1 protein results in dysregulation of the G1-S transition and acceleration of cells into DNA synthesis phase before they can repair damaged DNA. Cells with cyclin E1 activation are exquisitely sensitive to WEE1 inhibition by azenosertib as this further removes the brake on cell cycling and results in massive accumulation of DNA damage and ultimately cell death by a process called mitotic catastrophe.
We have previously described the medicinal chemistry efforts that led to the discovery of Azeno and we believe that its superior selectivity and overall profile, as well as optimized dosing suggest that it has potential to be a first-in-class, best-in-class WEE1 inhibitor for patients with PROC. Next slide please. All right, so based on the mechanistic rationale just discussed, we have established cyclin E1 as a highly sensitive and specific predictive biomarker that can be used to identify patients who might benefit from Azeno. This is important for several interrelated reasons. First, let's start with the prevalence of this biomarker. As you can see from the pie chart, about 50% of PROC patients overexpress cyclin E1 protein based on analysis with the immunohistochemistry assay we have developed.
Importantly, cyclin E protein levels are regulated at the DNA, RNA, and protein level, with about 20% of PROC patients having DNA amplification that leads to protein overexpression, the smaller circle within the pie chart. We think that the benefit of the IHC assay is that it captures these disparate mechanisms of cyclin E1 regulation in one assay that can be used to identify patients with rapid turnaround time. The second important point, as Julie alluded to earlier, is that multiple published retrospective analyses have suggested that cyclin E1 overexpression is a biomarker of poor prognosis and lack of benefit from chemotherapy. Patients with cyclin E1 activation tend to have poorer outcomes on current chemotherapy standard of care regimens used in PROC, highlighting the significant unmet medical need in this subset of patients.
Together with the strong mechanistic connection between cyclin E1 and the Azeno sensitivity, the prognostic significance of cyclin E1 dysregulation underscores why patient selection with this diagnostic test is tremendously important for our go forward strategy. We're very excited to be working with a diagnostic partner to develop a CCNE1 diagnostic test that we believe substantially enhances the risk benefit profile of Azeno in PROC. I'll now turn things over to our Chief Medical Officer Ingmar Bruns for an update on clinical development of Azeno.
Yeah, thanks, Mark, and good morning, everyone. We're sharing a really large amount of data across the three trials today, including an integrated efficacy and safety analysis, and I'm really confident this will contextualize the totality of the data, its support of our registrational plans. You're going to hear a similar conclusion across each of these three studies, and that is meaningful efficacy and robust safety data supported by our go forward plans. Also, we will not cover the O16 study in detail, but a summary slide and conclusions from that trial will be available in the slide deck that will be posted to our website following this presentation. Just in brief, the results in BRAF inhibitor naïve patients are encouraging. However, given the evolving landscape and our prioritized current focus on monotherapy and gynecological malignancies, we're not pursuing the phase two.
Expansion at this time.
With that context in mind, we'll now review our clinical data. So let's start with the 01 study, the first-in-human dose escalation study of azenosertib. This study enrolled 274 patients with solid tumors across both continuous and intermittent schedules. The 5-on/2-off intermittent schedule allowed for maximized efficacious exposures while improving tolerability. Total daily doses at 300 mg and above demonstrate a really meaningful clinical activity. So in the next few slides we'll walk through the data for patients who receive 300 milligram or more. Again a total of 193 so really large group of patients fell within this group and the clinical characteristics were broken out by PROC and USC.
We're focusing on PROC here and the PROC patients were heavily pre-treated with a median of five prior lines of therapy and going all the way up to 19 and the safety profile at active dose levels was generally benign and better than historical data from standard of care. Single agent chemotherapy, hematologic toxicities, GI toxicities and fatigue were the most common adverse events. Most GI adverse events were low grade with no grade 4 events observed and the rate of high grade hematologic adverse events were relatively low with the majority being grade three events. There was also one treatment related grade five event. While we have presented this event previously, we're going to provide you with some greater visibility today.
And just briefly, the event occurred in a patient in her late 70s with USC who was treated at 175 milligram twice daily at the intermittent schedule, and she had a potential covered perforation and an abscess of the tumor masses in the cecum and the pelvic area, and lab results showed pancytopenia, and the patient then opted for comfort care and passed with sepsis, unfortunately, shortly thereafter. While the role of Azeno cannot be excluded here, of course the potential perforation and abscesses provide, in our opinion, a more plausible explanation for the sepsis and also provide an alternative explanation for the pancytopenia.
Now turning to efficacy, we saw encouraging response rates and durability across the active dose levels, and as you can see, tissue samples were collected retrospectively to assess cyclin E1 expression. And as expected, cyclin E1 positive patients had better response rate than the overall population. We'll share more on this in a later slide, and patients on the intermittent schedule also had greater antitumor activity than.
Those on continuous dosing.
Based on these findings, and that's really important, we focused on the 300- and 400-milligram doses and the five days on two days off schedule for future studies with 400 milligrams of five on two off as our primary dose and schedule of interest. To summarize, a meaningful therapeutic window was identified, providing a favorable risk-benefit profile. Now I'd like to move on to the Mammoth study, which completed enrollment last spring, and Mammoth evaluates Azeno as both a monotherapy and in combination with the PARP inhibitor niraparib in patients with PARP-resistant ovarian cancer, and in the combination arms, Azeno and niraparib were tested in the dose escalation portion. We did not observe a meaningful response rate given the subtherapeutic dose of Azeno and therefore decided not to move forward with this combination.
However, the monotherapy arm in this study was able to provide really important additional data for the 300 milligram and 400 milligram intermittent doses, confirming those as our doses of interest and 25 patients were treated at 300 milligram and 36 patients were treated 400 milligram with a now established five days on two days off schedule. Patients were heavily pretreated again with a median of 3 prior lines of treatment and all of whom were treated with a PARP inhibitor and almost all with bevacizumab, right, representing a really important subpopulation of PROC patients with poor prognosis, so confirming previously observed data in this highly important subpopulation. Here the safety profiles observed across the two monotherapy cohorts were consistent with the phase 1 dose escalation study. You know we've just shown you and Azeno was generally benign as well and well tolerated.
Similar rates of treatment-related serious adverse events were observed across the two dose levels. There was only a low rate of treatment-related high-grade hematologic AEs including really just one treatment-related grade 4 event of febrile neutropenia and then another treatment-related grade four event with sepsis, and also the rate of treatment-related adverse events leading to discontinuations were low. There was one previously reported treatment-related grade 5 event. Again, I want to provide some more visibility here. Briefly, a patient in her 70s with multiple severe comorbidities who was hospitalized for pneumonia while on Azeno treatment but the pneumonia was attributed to prior radiotherapy and long-term use of steroids for asthma.
However, because of the tumor response seen, Azeno was restarted, and when the patient was then unfortunately found with neutropenia, she decided against anti-infective treatment and eventually passed away without any intensive care. And while this decline does appear multifactorial, we chose again not to exclude relatedness to Azeno. Switching gears a little bit. Encouraging response rates were seen overall, and the 400 milligram dose showed a higher response rate in line with exposure-response correlation. This efficacy was also consistent, as mentioned before, with the 001 study, increasing the size of the data set. And in a retrospective analysis of cyclin E-positive patients, we observed a 31% response rate for the 400 milligram dose and numerically higher than the response rate observed for the 300 milligram dose. To conclude here, what we saw in the Mammoth study really reiterates what we saw in the 001 study.
In particular, we observed an encouraging monotherapy efficacy signal in PARP inhibitor resistant patients, obviously a very relevant subgroup here. Insights from this study and the 001 study have helped shape the Denali study and continue as we speak to.
Support the further development of the Azeno.
With that, I'd like to turn to Part 1B of the Denali study. It's our great pleasure to have Dr. David O'Malley, one of our clinical investigators, on the line to present this, to present these data. Dr. O'Malley is a leader in the treatment of gynecologic cancers. He is the director and professor of the division of Gynecologic Oncology at the Ohio State University Comprehensive Cancer Center and the James. We truly appreciate his expertise and success in drug development for ovarian cancer and are grateful he's able to be here with us today.
So.
So now I'll turn it over to Dave to talk a little bit about his work on the clinical trials for ovarian cancer and also the interim results from Denali Part 1B.
Dave, good morning. Thank you. I'm really excited to see this data and be a part of the program. Part of my role as gynecologist at Ohio State and division director of GYNONC, I still have about 60% effort in clinical practice, 40% research and administration. All of that research is really committed to developmental therapeutics where I run the phase 1 program in GYNONC, as well as a robust portfolio of clinical trials to the point of being our institution's number one enroller in GOG Foundation trials in the country. Go to slide 23, please. We're here to really talk about ovarian cancer and the opportunity for azenosertib, which I'll refer to as Azeno throughout the presentation. Unfortunately, still, most patients recur. If you recur, you ultimately become platinum resistant.
The first line therapy really is chemotherapy plus or minus BEV and then plus or minus PARP with BEV or alone and then subsequent therapies for platinum-sensitive, and I said 100% of patients who recur essentially will become platinum-resistant, so when we look at the response rates we'll talk more about in the next slide, they're really quite dismal, about 8% plus or minus. Obviously MIRV was very exciting with regards to response rates approaching 40% in the high folate receptor alpha, which is about a third of the patients. As many of you on the call will know, I was actively involved and continue to be actively involved in the development of MIRV. What's really interesting is cyclin E1 positive patients seem to have a worse prognosis, so some of the challenges is that these objective response rates actually may be lower compared to historical controls.
Slide 24. This is a slide that I put together and modified with other gyne oncologists around the country. The bottom ORR is really still the regulatory hurdle, which is about 13% overall response rate for accelerated approval, median progression free survivals throughout the entire program. Excuse me, entire trials are really about three and a half months or the OS, right? About 12 months plus minus. But as you look up in the more recent trials, the real response rate in the contemporary way we treat platinum resistant ovarian cancer really falls to single digits. That's why I said in an earlier slide, about 8% plus or minus 5. Really what we're looking at is really dismal outcomes beyond recent approval with Mirv. Next slide, please. Denali was really a straightforward trial design.
mg five days on, two days off, which is one of the keys that we discovered over time and has led to the confirmation that cyclin E1 is a biomarker, which I'm probably the most excited about. You notice here it's one to five prior lines of therapy, so pretty heavily pretreated. We'll talk about demographics and we had to have tumor tissue available for testing, enrolled 102 patients, 102 again, overall response rates and duration, progression free as well as safety. Slide 26, please.
When you look down here in.
The lower left, I want to call your attention to about two-thirds of patients, two-thirds of patients at three or more prior lines of therapy, heavily pretreated, meeting a regulatory benchmark of, well meaning it with over 90% pretreated BEV and about half the patients pretreated PARP, which you would somewhat expect, and that's in the patient population with HRD-positive patients really doesn't apply anymore in platinum-resistant patients. It's more in that platinum-sensitive sense in the first line but obviously more heavily pretreated populations. As you see, representative of the patients which we see in clinical practice and about one-half were positive for cyclin E1. The 8% were unknown. Which was mostly tissue unavailable or not sufficient tissue left to perform the testing. Next slide please. Let's get into some of the data. This is really what we've been talking a lot about with the.
With.
Everything going on with regards to the FDA hold. So this is the safety and we really didn't see anything out of the ordinary which we've seen in the other trials with Azeno. So let's start in the upper left. GI continues to be something we have to deal with on our oral agents and really all of our oral agents. Interestingly, we early on instituted aggressive mitigation strategies and really saw a significant drop off in our grade three. So grade three is really rare as you see here in the upper left. Hematologic with this class of agents has been a challenge in the past. The five days on, two days off seems to be making a great difference to allow for mitigation. And we'll talk more about some of the mitigation strategies which we'll institute moving forward.
What's really interesting is identifying these patients again from the early on experience versus our latter experience in the toxicity and being able to mitigate improve significantly. In the upper right you do see that we have about a 40% dose reduction in eruption, about 59%. Discontinuations are a little bit higher than we've seen in previous and it was about 22% of patients, and we did have two deaths which we'll talk about more in a second. The discontinuation rate is really interesting. Again we look back here, it was often early on the experience of the sites. With the 100 patient trial we opened many more sites than just the phase one sites that were on some of the other trials.
For example, we had one site who had several patients discontinued therapy that we did some additional education and made sure that they were following the mitigation strategies. So when we look at the safety profile, it's very consistent with the other trials with a discontinuation rate that a little bit higher than expected. Again, much larger trials moving beyond phase one sites. And this has I think been overcome in most of the latter aspect of enrollment of the trial. Obviously lots of patients have asked about the grade five toxicities. I can't talk about the two on this trial.
One of them was a young woman in her 40s actually who had a tumor infiltration into her bowel and unfortunately she had a bowel perforation at that same time, was found to be pancytopenic and unfortunately succumbed to her sepsis after the bowel perforation, which is the outcome in more than 40% of patients. The second patient was a lady in her 70s, she actually had urosepsis and unfortunately we went back and look at she had a urinary tract infection. Then ultimately found to have infection which had some delay in therapy and then became uroseptic and was admitted to hospital. What we see in these patients who are heavily pretreated, if they do have a big setback like urosepsis or admission to hospital, they sometimes elect just for palliative care.
This patient did not want any aggressive interventions and actually went on comfort care, then obviously died without intervention for her urosepsis. Two different, very different scenarios and two again opportunities in the future. Slide 28 please. Obviously this is what has gotten me excited is that we have an oral agent which with mitigation we're confident we're going to be able to have tolerable because this drug works. In this world with all these new ADCs coming, we need alternatives to antibody drug conjugates. There's two populations which are presented in this slide, one of which is the intent to treat population which is anybody who received any doses and then the response evaluable which was defined in the protocol, which is a patient who made it to their first CAT scan.
So in these, as many of you know, in these platinum-resistant patients, especially with one to five prior, a fair amount of patients will have rapid disease progression. And though we tried to avoid bringing those types of patients onto trial, sometimes it's not avoidable. So the response evaluation intent to treat, the overall population is interesting 19% and about 17.5% but really the cyclin E1 positive patient population, 32%-35%. So again heavily pretreated, 2/3 of patients, the three or more prior therapies, again this in a different population, the antibody-drug conjugates. And you see in the negative cyclin E1 biomarker, the response rates are in that single digit range, again consistent with what we see in chemotherapy, but nothing that we would actually write home about. And then let's look a little bit more closely. Slide 29 please.
So when this is presenting these evaluable patients and this is the Waterfall and you see that the majority of patients had disease progression. And to me that's as important. You know, the stable disease, if it's growing and stable, that's not as impressive to me. It's a disease regression that really shows me the effectiveness of this agent. You know, again approaching that 35% response for any evaluable. Then we have four hashtags there which a patient's had 0% change. We have one patient on the right who had a marked 60% reduction but had a new lesion. And so that's why she is marked as a progressive disease even though she has a marked and the other stable. The other four that are labeled stable similar due to the.
Even though the RECIST responses were met the criteria for overall response rate due to their non-target lesions, they were labeled as stable disease. You can debate that, but that's what we have here. So again, very impressive. More than half the patients having disease regression and of those approaching 35% response rate as we move forward as well as five patients, five patients who had met that 30% response rate but due to non-target lesions were not able to be called a PR.
30.
Swimmer's plot. You see that the duration of response right now is modest at 5.5 months. You have to remember that very early on we have multiple patients, six actually, that are still on therapy. So we think this is going to go up. This is at the lowest it will be. You see that we did include.
We.
Did include the patients who removed early at the bottom here of the swimmer plot. But many patients were, as I said, six were still ongoing treatment. And we expect this duration response to increase next slide. So, you know, azenosertib, it works. And as I talk to people around the country as I've treated patients, we're seeing responses and we're seeing deep and durable responses. And in this race with antibody-drug conjugates, having an alternative outside of antibody-drug conjugates actually very exciting. And the biomarker in cyclin E1 is real. We see that with again in the mid-30s with our response rates. To me, the key here was the establishment of the cyclin E1 biomarker. And obviously from a toxicity standpoint, we have opportunities here for mitigation strategies. We have continued to institute those throughout the Denali trial.
Moving forward dose optimization, we're going to institute even more aggressive, I guess maybe that's not the right word, additional mitigation strategies making sure that patients are followed to the point of intervening well before some of these events will occur. For me, I wouldn't be here today discussing this unless I thought this was an agent which can benefit our patients with platinum-resistant ovarian cancer, some of the most difficult to treat, cyclin E1 positives. People ask me all the time, how does this compare to what you've had in your oral agents? Remember PARPs, right. You know, we brought PARPs forward and told everybody how, you know, it's an oral pill and how great. Yeah. So you're really having GI side effects and hematologic. We learn with PARP inhibitors.
Lenvatinib pembro is probably, you know, I've, you know, tried to educate the world on how to use lenvatinib pembro in endometrial cancer in a very hard-to-treat population. It is necessary to understand what the toxicities are. And this to me is definitely better tolerated than when PARP. So it is absolutely doable and I'm excited to have this option for our patients in the future. Thank you.
Yeah, thank you, Dave. I think that's really, really valuable perspective. Not, you know, just as a leader in drug development and gynecological malignancies, but also from the perspective of a trial investigator and a physician taking care of patients. So you've now already heard a consistent theme across these three studies and we will provide you now with an integrated analysis of the safety and efficacy across these studies. So here we illustrate the integrated safety profile of the 300 milligram dose as compared to the 400 milligram dose in PROC patients. And this is regardless of the cyclin E1 status. As you can see, the safety profiles were broadly comparable. Febrile neutropenia and sepsis were observed at the 400 milligram doses at low frequency, although far fewer patients were treated with 300 milligram in Azeno.
So there's of course a chance that low frequency events could have been missed. But overall we see a very manageable hemat GI tox profile which seems better than that of other WEE1 molecules that have published clinical data. For example, the Ignite study. Across studies, we have treated about 70 and 20 cyclin E1 positive proc patients at 400 and 300 milligrams, again five on two off schedule, respectively. And in the 400 milligram group, Azeno had a confirmed response rate of over 30%, which we consider clinically very meaningful. And although 400 milligrams showed a higher response rate, the confidence intervals of the 400 milligram and 300 milligram doses overlap. As you can see in the lower response by 300 milligram could have been confounded of course by a more heavily.
Pretreated population in that group.
Therefore, confirming the dose is a goal for Denali Part 2, which we will cover momentarily. I would also like to mention that the median duration of response, a response in the Denali study which Dave has shown that stabilized currently at 5.5 months, is actually trending upwards to over six months. But it will require ongoing responders to continue on trial in order to stabilize as well, although not fall below five.
Points at this point.
Nonetheless, of course the increase or the trend, the upward trend is another, in my opinion, very promising outlook here. And so Azeno has demonstrated significant antitumor activity in heavily pretreated patients with cyclin E1 positive PROC and particularly at our primary dose of interest of 400 mg at the 5 on 2 off schedule with really meaningful improvement over current standard of care. And we will be able to identify patients importantly with a precise patient selection biomarker. And we've seen consistent results from three clinical trials with a really large data set that validate the safety and tolerability of Azeno in a heavily pretreated patient population.
And we've now also the opportunity to further optimize, and Dave already alluded to this patient outcomes in future study through proactive measures being implemented, including early monitoring, dose adjustments as well as the use of supportive care. Azeno could offer a first-in-class convenient oral option and improving the quality of life for patients who usually have a rather toxic single-agent chemotherapy option with very limited efficacy. Now turn to Denali Part 2. We're really pleased to share that we have achieved alignment with the FDA on a seamless design for Denali Part 2 which can potentially support an accelerated approval pathway. And of course this is provided that data continues to be supportive and subject to additional FDA feedback on the data then and Denali Part 2 is designed to enroll patients in earlier lines of therapy compared to Denali Part 1B.
Patients will also need to meet our proprietary immunohistochemistry cutoff assay cutoff for cyclin E1 overexpression. We will be leveraging and are leveraging our existing network of sites from Denali Part 1B and further supporting really efficient enrollment. Part 2A will then focus on dose confirmation comparing the 300 milligram and 400 milligram doses. This will kick off enrollment in the first half of this year and then leading seamlessly into the registration intent.
Part 2B's outlined.
And as we confirm those in part 2a, we will seek alignment with the FDA and dose selection endpoints for part 2b and also on the phase 3 confirmatory study in the same patient population. And we plan to enroll. That's important. The phase 3 study concurrently with part 2B of Denali and the phase 3 study then will be of course intended for full appropriate approval, subject to positive.
Data and regulatory review, of course.
And we're really tremendously pleased with the body of clinical data that we've seen and excited about the focused path forward. And we do think we now have a very clear line of sight to getting Azeno to patients. And with that I will turn it back to Julie.
Thank you. Thank you Ingmar, Mark and especially Dr. O'Malley. Thank you for walking us through a real wealth of data and sharing our regulatory and development plans. I just want to wrap up quickly by acknowledging the tremendous amount of work that has gone into producing this data. Importantly, patients and their caregivers, as well as the clinical study sites, our investigators, and of course our current and previous and past staff at Zentalis. Looking ahead, as mentioned earlier, we plan to initiate Denali Part 2 in the first half of this year. As the study progresses, when appropriate and to the extent we are able, we'll update the market. Zentalis is intensely focused on getting azenosertib and PROC as our first approval. This is an execution story now and we're launching Denali Part 2 as a priority.
This way we can really draw towards top line data by the end of 2026. We'll continue to advance the balance of the pipeline as our resources allow. We feel that there's a real opportunity for this franchise to continue and as data matures, we'll share at appropriate forums these other data sets from these other studies. So you know, I appreciate certainly your time here today. I know there was significant data and forward looking strategy presented and we want you to really take away the key points that our strategy is focused in a large market of a severe unmet need. The data generated to date is supportive of moving this agent to patients as quickly as possible.
And we have organized and aligned our internal skill sets and our capital resources with this future mission in order to quickly and efficiently execute on these registration studies and doing that necessary work. We're excited about the path ahead and I again want to thank you all for your time today. I know you're busy and now we'd like to open it up to questions. Operator.
As a reminder to ask a question, please press star 11 on your telephone.
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Again, in the interest of time, we.
Ask that you please limit yourself to one question and you may rejoin the queue if you have any additional follow-ups. Please stand by while we compile the Q&A roster.
And our first question comes from Matthew Biegler with OpCo.
Your line is open.
Hey guys, thanks for the update and for the transparency here. I know there's been a lot of work that's gone into this, so appreciate it. Can you give us a sense, Julie, maybe from your initial interactions with the FDA on how receptive you think they'll be to a single-arm trial? Or I guess in worst case, if you had to run a randomized trial like MIRASOL, how much longer do you estimate that it would be? Assuming a PFS endpoint and then if I could just quickly squeeze in one for Dr. O'Malley, if you saw the line on the neutropenia, does it look materially different from your experience with Elahere, or do you think it's probably more an indication of the patient population treated here, you know, five prior lines, et cetera? Thanks a lot.
Yeah, thanks so much for the question. You know, let's let it go. Dr. O'Malley, why don't you go ahead and respond to the question on neutropenia and then we'll address the agency question.
Yeah, I mean, Elahere is a completely different. An ADC, tubulin is the payload. So from that standpoint, it's kind of apples to oranges. Hematologic toxicity of Elahere is actually pretty low. So much different from a standpoint of that regards. And with the oral dosing versus every three-week dosing, mitigation strategies are separate. So I don't think that it's Azeno is going to be a higher hematologic toxicity than Elahere, but it's kind of apples to oranges in those regards.
Thanks, Dave. Regarding sort of the question on the FDA support of an accelerated approval trial, I'm going to turn it over to Ingmar and he can tell you a little bit about his thoughts there.
Yeah.
Part 2A, as you've seen, is aligned with the FDA. There is clear alignment around the dose confirmation portion. The FDA is also supportive of a seamless design. There's no need for us to go back to before we start the study. Of course, when data comes in, there will be another touch point on the fit of the actual data set for accelerated approval, which is very normal. We also have a synopsis and a design for the phase three confirmatory trial already in place, but this is going to be reviewed by the FDA this year and alongside the dose confirmation there as well.
Thanks again.
Thank you.
Thank you. Our next question comes from Tyler Van Buren.
Buren with TD Cowen.
Your line is open.
Hey, guys, good morning. Thanks very much for the presentation. Great to see the newfound focus and refined development strategy. My question is related to just the efficacy. It clearly appears better than standard of care chemo, but many of your patients are fifth line plus and quite severe. So can you elaborate on the difference.
In the health of the patients that.
You believe you will be able to enroll in Denali Part 2, and how one might expect that efficacy to improve or if there's any precedent out there?
That you would point to in terms of what we might be able to see?
Yeah, thanks for the question. Ingmar, do you want to talk about patient health and prior studies?
Yeah.
The first part of this is that these patients will have fewer lines of pre-treatment and are generally healthier.
Right.
There's exclusion of comorbidities. Right. And the other important piece is also that we've really tightened the guidance on those modifications and the use of supportive care.
It's been a bit of a week.
Point in the past, and you know, I think the sites are obviously very willing to employ these measures. And I think, you know, there's clarification now on timing and, you know, and more extensive use of, you know, supportive.
Care measures, which we really think will.
Make a significant difference here both on, you know, reducing dose interruptions, dose reductions, but also ensuring that patients are staying alone longer on trial and therefore increasing.
The chances of longer duration of response.
Then the second part of this is how we think the efficacy will increase with an earlier patient population. While there's no actual evidence here for Azeno, of course, but there's an analogy out there. I think if you look at Elahere.
Here, if you look, look how the.
Response and duration of response has evolved from the SORAYA to the MIRASOL trials. Right. Then that's kind of the ballpark we're.
Expecting here as well, with less pretreated and healthier patient population.
Thank you. Our next question comes from Brad Canino with Stifel. Your line is open.
Hi.
Thank you for the update today. I just want to ask how comfortable?
You are with durability based on these.
Data, and how do you view the?
Importance of improved side effect management to potentially keep patients on drug longer.
See those numbers increase.
And I'm asking this both for duration.
ORR for accelerated approval and PFS for the likely conversion to full approval.
Thank you.
Yeah, I think similar to the previous answer. Right. I think we think in the past there's some room for improvement on maybe also trial oversight and interactions. And I think we had a large. Already alluded to as well. We had a relatively large number of patients with low grade AES that then decided to discontinue. And I think management of these AES.
Interactions with the sites and these.
Patients will improve that. So we're really kind of confident that this will increase and improve, and there's, I think, very effective measures that can.
Be put in place.
Yeah. And I think Dr. O'Malley said earlier, you know, learnings from the development of other agents and other small molecule agents, you know, are learnings that will apply here in terms of being close to sites, being close to patients and really helping them with options in supportive care to improve that. And of course, an earlier line of therapy will be very helpful, as we talked about before. And hopefully seeing patients who are in better shape, being able to stay on the study longer should provide better PFS, should provide an opportunity for more patients to see a first and second scan. So that certainly is our goal and we're confident in having how we're thinking about running Denali Part 2 in that.
Yeah.
And I think there's also an important piece that's really learning on these trials. Right. I think they've alluded to this as well. I think everybody learned. Right. We learned as a company. I think the investigators learned as they gained more experience and this will help to manage and also avoid early discontinuations.
Right.
Which here clearly, despite the still very strong duration of response. But that certainly impacted this with early discontinuations. And as we are more confident how to manage this drug and have more experience with the drug, we're really confident we will be able to reduce these.
Thanks for the question.
Yeah, let me add on there, I.
This, you know, this is David O'Malley. I think as we looked here, a drug can't work if you're not getting a drug. So these mitigation strategies, we are very confident that we'll see improved responses and duration response. The other is, you know, there were four patients on the trial that actually stopped therapy when the FDA hold was put on, even though they had a partial response and also impacting the duration response and there's a number of patients who dropped off of trial early on. Some of that's from disease, but some of that is going to be from toxicity assessments. And being able to educate is really key. And one of my goals throughout this program development is to continue to refine our mitigation strategies. And so we've made great strides throughout this process in the next steps.
Very confident that it's going to help your question duration, but also, I believe will impact our overall response, particularly in less heavily pretreated population.
Thanks, Dave. And we appreciate your partnership and that of the GOG and the other sites on those efforts. Do we have another question? I know, I just want to do a time check. We have about five minutes, maybe six minutes left.
Our next question comes from Mike Ulz with Morgan Stanley.
Your line is open.
Good morning and thanks for taking the question. Maybe just a follow up on one.
Of the earlier questions regarding just regulatory.
Feedback, particularly on Part 2B of Denali.
If you could just clarify what points you need to get feedback on from the FDA and roughly when you might expect that to happen?
Thanks. Yeah, so it's really just the need to show them the actual data. Right. That we'll generate in 2A.
Right.
Because this data, of course, doesn't exist at this point and needs to be.
Shared with the FDA for feedback.
And then they will define the bar. Right. As you know, there's endpoints and efficacy bar and eligibility criteria, these points.
Right.
That's a normal process and we're on.
Track to get there.
Maybe I'll just add, just for real clarity, you know, while the dose confirmation portion of 2A is enrolling and while we collect that data and prepare to have conversations with the agency, the agreement on Part 2A of a seamless design means that we get to continue to enroll patients in either our preferred or selected dose or potentially in both doses until we have that conversation with the agency around the data between 400 and 300. So we won't lose time from an enrollment perspective. We do expect to have the enrollment mostly complete in the part A by the end of this year with an opportunity to have a conversation with the FDA hopefully in the first half of next year and all of that stuff, subject to enrollment timelines, et cetera, but that's the broad outline.
Thank you.
Thanks, Mike.
Thank you.
Our next question comes from Andrew Berens with Leerink Partners.
Your line is open.
Thanks. Thanks for hosting this. A couple for me. I noticed in the cyclin E1 Venn.
There were some patients that were.
amplified that were not overexpressed? What percentage of patients is that? How are they diagnosed and do they respond to E1? And then can you give us some more details about partial clinical hold? Any details on how it was resolved with the FDA? And I think you're still doing some.
Dose finding it seems.
Then lastly there was someone on.
The advisory board from Pfizer. Now that you guys are not pursuing the BRAF combination strategy with that person still on the board, are there any changes to the Pfizer collaboration? Thanks.
Yeah, I think so. In response to the question on the advisory board, mayb
e I'll just note that that advisory board obviously was in support of the study and continues on, but obviously we have completed that part of the trial and so that advisory board will continue to support Liz as he turns that person's no longer on our advisory board and he. Pfizer. Oh, okay. These people move fast. Sorry, Andy, can you remind me of your first question? Apologize.
It was on cyclin E1, the Venn.
Diagram the patients that were amplified and not overexpressed.
Thank you. I think this is a really important point and I'd like to have Mark kind of talk about the difference between CCNE1 and amplification and cyclin E1 protein overexpression. Mark, can you take that question?
Yes, of course.
Yeah, it's a good question. There is a very small subset of patients that have amplification but don't have overexpression using the cutoff that we've defined. And I think that's the key point. So it's maybe about 10% or less of the patients that have amplification that don't have overexpression using that cutoff. It's such a small number that I think it's really hard to say whether those patients also respond. But I'll note that there was a separate study, an IST that was done by Funda Meric-Bernstam with ADAVO where they selected based on cyclin E amplification as the enrollment assay and saw a high response rate. So we do think it's an independent predictor. And I think the differences just have to do with that cutoff. And we really have tried to define the IHC cutoff to maximize the response.
So you do potentially lose a few patients, you know, if you're trying to really enrich for the response.
Okay,
thanks.
There was a question on the clinical hold, any color? I know you probably not going to.
Tell us everything, but any color would.
Be appreciated on how that was resolved.
I think it's pretty straightforward. You know, remember, Andy, the company had been enrolling patients in really this phase one dose and schedule studies. You know, the agency certainly hasn't seen the totality of the data. That was provided to them obviously, as a response to that and earlier data cuts certainly than the December 2 cut that we've shared with you today. You know, all of that data and discussions with the FDA certainly provided the context around the safety and the efficacy of the data sets at that time. I think, as is clear, the FDA obviously saw that there was no need to make dose modifications to the 400 milligrams, importantly, because that is our preferred dose going forward. In the totality of the data, they didn't see safety signals that concerned them to continue on with the clinical hold.
So I think it's really as simple and straightforward that the data really speaks for itself. And the agency agreed that there was merit and greater benefit versus risk in the profile of this asset and that it should be continued to be pursued in this patient population. Obviously that just really has no directed therapies. So they're very supportive of that. And certainly in those dialogues then the discussion about moving forward and agreeing on moving quickly into Part 2 and Part 2A in particular with that seamless design, they certainly are very supportive of. And that is, you know, conversations that were had. So I hope that helps you to understand and clarify. Obviously, I was not at the company, neither was Ingmar. We did not participate in the dialogue, but certainly we can follow along with the discussions in the minutes.
And we have a great regulatory team who did a fantastic job with prior management pulling really all these data sets together to quickly get off of clinical hold on the merits of the data we share with you today. So it is now.
Thanks for letting me ask the question.
Yeah, no, Andy, thank you for that. It is the top of the hour, so unfortunately, if we do not get to your question, please follow up with us and we will make sure to get your questions answered. Thank you so much for joining us. Thanks, everybody. Have a great day.
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