Cerevel Therapeutics Holdings Inc (CERE) 2023 Q2 法說會逐字稿

Good morning, and welcome to the Cerevel Therapeutics Second Quarter Financial Results Conference Call. At this time, all participants are in listen-only mode. Later, you will have the opportunity to ask questions during the Q&A portion of the call. Please note that this call may be recorded. I will now hand the call over to Matthew Calistri, Vice President of Investor Relations.

Thank you. Good morning, everyone. We appreciate you joining us for our second quarter 2023 earnings call. On today's call, you'll be hearing from Ronald Renaud, our President and Chief Executive Officer; Dr. Ray Sanchez, our Chief Medical Officer; Dr. John Renger, our Chief Scientific Officer; and Dr. Susan Altschuller, our Chief Financial Officer. During our call today, please refer to our Press Release from this morning detailing our second quarter 2023 financial performance as well as our updated Corporate Presentation, both of which are available on our website.

I would like to remind you that we will be making forward-looking statements that reflect our current views related to, among other things, the potential attributes and benefits of our product candidates and the format and timing of our product development activities and clinical trials. We strongly encourage you to review the information that we file with the SEC regarding specific risks and uncertainties. I will now hand the call over to Rob Renaud, President and CEO of Cerevel to provide an overview of our achievements and outlook.

Good morning, everyone, and thank you for joining us for our second quarter 2023 business results call. I'm pleased to be here with all of you today as the new President and CEO of this exceptional company. In my time at Cerevel so far, I have seen immense passion and dedication from the team, and I'm incredibly enthusiastic about our science and innovation as we aim to build a world-class neuroscience company. Before getting into the specifics, let me share some of my initial observations of this organization. Cerevel's comprised of smart, energized with deep experience in neuroscience drug energized people with deep experience in neuroscience drug development and notable track records of success. We have an unparalleled pipeline with the potential to bring new treatments to some of the most challenging neuroscience diseases.

We're also focused on disciplined execution, aware that patients and loved ones are waiting for these important new treatment options. Before I joined the company, I was impressed with this enviable portfolio. Now that I've had an opportunity to work with this team and dive deep into the details of the science and the programs, I'm even more excited about all we have ahead of us.

Turning to our lead programs. Let me start with Emraclidine - our M4-selective positive allosteric modulator, or PAM. At Cerevel, we're exploring all aspects of the M4 muscarinic pathway, as we seek to build a franchise that can address a broad range of diseases via this mechanism. Emraclidine is a highly selective for M4 and we believe it has the potential to change the way we do and treat schizophrenia, Alzheimer's disease psychosis and other serious mental illnesses. We announced this morning that our Emraclidine Phase 2 EMPOWER program is now expected to read out in the second half of 2024, a change resulting from recent slower-than-expected enrolment. We are deploying measures to restore our pace of enrolment, and I am personally working closely with Ray and the team on mitigation strategies. Ray will provide more details, including our go-forward approach and our reasons for confidence in our updated timing. As always, we're focused on ensuring the quality of Emraclidine data, and we'll be thoughtful in our plans to add new sites or countries to ensure we maintain our rigorous standards.

Moving now to Tavapadon, the first D1/D5 partial agonist in the development for treatment of Parkinson's disease. We believe our registrational Phase 3 TEMPO program has the potential to establish Tavapadon in the backbone treatment across the spectrum of Parkinson's disease therapy. Tavapadon has the opportunity to serve as both the preferred monotherapy for newly diagnosed patients and the ideal adjunctive therapy to levodopa as the disease progresses. We expect TEMPO-3 to be our first data readout of 2024, while data from TEMPO-1 and TEMPO-2, will read out in the second half of 2024.

Turning now to Darigabat, our selective a2/3/5-selective GABAA a PAM. Currently in development for both epilepsy and panic disorder. Our Phase 2 REALIZE trial in focal epilepsy is designed to address an area of tremendous unmet medical need for patients who need better control of their seizures. We expect this program to be our second data readout next year coming mid-year 2024. We've also recently initiated the ADAPT trial of Darigabat, a Phase 2 proof-of-concept trial in panic disorder. We have confidence in the potential of Darigabat to treat anxiety related disorders, given its selective receptor subtype profile and its avoidance of alpha-1. The receptor subunit, we believe is the main driver of side effects for benzodiazepines.

On the financial front, we have a strong balance sheet that is expected to support all of our anticipated late-stage data readouts next year. Before I hand it over to Ray, I want to take a moment to welcome the newest members to the Cerevel's executive team. Dr. Susan Altschuller, Chief Financial Officer; and Paul Burgess, Chief Business Development and Strategic Operations Officer. Susan brings financial management, Investor Relations and business planning experience from leading biopharma companies. Paul brings deep experience in corporate development, business development and operations, key skills during this important juncture for Cerevel. All 3 of us have been warmly welcomed by serves senior leaders seasoned leadership team. I'm proud of how in just 7 weeks, we've come together as a new invigorated executive team. I'm energized by all that we will do together along with all of our Cerevel colleagues to build a world-class neuroscience company with multiple commercial products.

With that, I'll now turn the call over to Dr. Ray Sanchez, our Chief Medical Officer, to provide some added color about our lead programs. Ray?

Thank you, Ron, and good morning, everyone. Let me start with Emraclidine, our highly selective M4 positive allosteric modulator, or PAM, which we are currently developing in both schizophrenia and Alzheimer's disease psychosis, or ADP. In ADP, our Phase 1 healthy elderly volunteer trial is ongoing, and the results of this trial will guide our clinical development plan as we advance in this important indication.

Turning to schizophrenia in our Phase 2 EMPOWER program. As a reminder, EMPOWER-1 and EMPOWER-2 are two adequately powered 3-arm trial that each include 372 adults living with schizophrenia and experiencing an acute exacerbation of psychotic symptoms. The first trial is studying in rapidly 10 milligrams and 30 milligrams once daily versus placebo and the second trial 15 milligrams and 30 milligrams once daily versus placebo. We designed these trials to potentially meet the criteria necessary to service pivotal trials based on what we expect the FDA will evaluate in a registrational package. We're also enrolling EMPOWER-3, our 52-week open-label safety extension trial and prioritizing the completion of nonclinical and clinical pharmacology studies to accelerate a potential registrational package for Emraclidine schizophrenia.

As Ron discussed, we have seen a recent slowdown in enrollment. Enrollment in this program had strong momentum at the outset, but we've observed a slowing of that initial pace in recent months, with some ex-U.S. sites taking longer to stand up than planned and several U.S. sites yielding slower enrolment. We are responding accordingly with mitigation measures, including increased site and investigator outreach and plans to enhance enrolment in existing sites. We will also look to add additional high-quality sites in the U.S. in 1 to 2 more countries without going beyond a total of 30 sites per trial to preserve data quality and mitigate the placebo response risk. We will continue to stay laser-focused on executing these trials while maintaining the quality of the data. We recognize the central importance of Emraclidine to Cerevel, our investors and the patients we seek to serve, and we are acting with deliberate speed to address these potential headwinds and restore our prior pace of enrolment. With the strong efforts of the team, I am highly confident in our ability to deliver within these revised time lines.

Turning now to Tavapadon, our D1/D5 partial agonist. Our Phase 3 trials known collectively as the TEMPO trials are ongoing, along with the corresponding open-label extension in which we are encouraged by a high rollover rate of 90% or more. We expect data for TEMPO-3 to be our first data readout in 2024 with data for TEMPO-1 and TEMPO-2 coming in the second half of 2024.

I'll now discuss Darigabat, our selective GABAA or PAM, which is currently in development for epilepsy and panic disorder. We believe Darigabat has the potential for both antiepileptic and anxiolytic activity comparable to currently available benzodiazepines or with reduced side effects. Darigabat's novel mechanism of action and expected tolerability profile provides the potential for a new treatment option that may be used chronically. Our Phase-2 REALIZE in focal epilepsy is progressing, and we expect results in mid-year 2024. Here, we also are encouraged by a continued high rollover rate into the realized open-label extension.

Beyond epilepsy, we're excited about expanding the potential applications of Darigabat through the initiation of the ADAPT trial, a Phase 2 trial in panic disorder. The ADAPT trial will evaluate Darigabat 25 milligrams twice daily versus placebo and enrolled 228 patients with panic disorder. The primary endpoint will be the proportion of subjects who are free of panic attacks during the last 2 weeks of the maintenance period, and key secondary endpoints will be the change from baseline in the panic disorder symptom scale, or PDSS total score at week 14 and the change from baseline in panic attack frequency during the last 2 weeks of the maintenance period. A new drug has not been approved in panic disorder in nearly 20 years. So we are excited about the potential of providing Darigabat to patients in need of new therapies.

With that, let me turn it over to Dr. John Renger, our Chief Scientific Officer, to provide an update on our early stage portfolio. John?

Thank you, Ray, and good morning, everyone. I'm very pleased with the progress that we've made in Discovery Research and early clinical development. Let's begin with our capital selective kappa opioid receptor antagonist or KORA program, also known as CVL-354. We recently completed both our single and multiple ascending dose trials in which a broad range of doses were administered and considered well tolerated. These trials will enable us to interrogate a wide range of receptor occupancies at both the kappa neurocircuitry receptors.

This dose range will provide us with the potential for the selection of doses that can either preferentially target the capital receptor or provide a dual inhibitory activity at both kappa and new receptors simply by increasing exposures. We anticipate that this dose flexibility will enable us to explore efficacy and better understand tolerability across a number of populations of interest, which include major depressive disorder, post-traumatic stress disorder and substance use disorder. Our results to date demonstrate pharmacokinetics support once-a-day administration and the ability to dose without regard for meals. In addition, we demonstrated a predictive dose-related change in serum biomarkers that are consistent with opioid antagonist.

We are also pleased to announce that we received National Institute on Drug Abuse or NIDA grant funding of up to $8.1 million over 3 years to support the ongoing clinical development of CVL-354, including our recently initiated Phase 1 80% receptor occupancy trial that will include the termination of both kappa and mu-receptor pet tracer displacement to further characterize selectivity across compound exposures. We anticipate providing updates on our internal Phase I data and plans for next steps in the future.

Moving to other exciting news in our early-stage pipeline. We recently received a grant from the Michael J. Fox Foundation for Parkinson's research to advance our internally initiated TMEM175 program, which is aimed at slowing androstopping the progression of Parkinson's disease. As context, TMEM175 or transmembrane protein 175 is a recently identified in structurally unique protein, which is believed to be an endolysosomal potassium and proton channel. This target has been a particular interest to our team because of a strong genetic relationship to idiopathic Parkinson's disease.

Our TMEM175 program consists solely of internally identified compounds that have been discovered by our Cerevel chemists and scientists. It represents one of our initial efforts to develop potentially disease-modifying therapies intended to stop the progression of debilitating neurodegenerative disease. We look forward to working closely with the Michael J. Fox Foundation. This grant will support our program's research efforts and enable progress to be made in finding promising new chemical matter. I look forward to sharing more details on the compelling science behind this effort as we continue to advance this program. With that, I'm now going to turn it over to Cerevel's Chief Financial Officer, Dr. Susan Altschuller, who's going to review our financial performance for the second quarter. Susan?

Thank you, John. For the second quarter of 2023, operating expenses were approximately $97 million, comprised of $74 million of research and development expenses and $23 million of general and administrative expenses. We ended the second quarter with roughly $825 million in cash and marketable securities on the balance sheet, which provides us runway comfortably into 2025. Opportunistically bolstering the balance sheet remains a priority for the company to ensure we maintain the financial strength to maximize the value of our broad pipeline. As our track record shows, we will be thoughtful about how we access capital, and we'll consider a variety of options, including evaluating partnerships and regional collaborations in service of meaningful value creation for our patients and our shareholders.

With that, I will hand the call back over to Ron for his concluding remarks.

Thanks, Susan. At Cerevel, we believe we have an unparalleled pipeline in neuroscience. We're thinking big. And as I start my tenure as CEO, I can tell you that the potential of this company is inspiring. We are committed to bringing important new treatment options to patients facing some of the most devastating neuroscience conditions, including schizophrenia, Alzheimer's disease psychosis, Parkinson's disease, Parkinson's disease, epilepsy and panic disorder.

I am pleased and honored to be at the helm of this company and to be part of the incredible work we're doing together here. I've gotten under the hood and have taken a close look at our operations, and I can assure you we are focused on execution. Our entire executive team is working together to deliver on promises to bring new medicines to patients as quickly as possible. With our Tavapadon TEMPO-3 data expected in the first half of 24, followed by Darigabat realized data midyear and the busy second half of '24 with the EMPOER and remaining TEMPO readouts. I look forward to updating you as we advance this robust portfolio.

I'd like to conclude with my sincere thanks to our employees and to the patients and investigators in our clinical trials who graciously make everything we do possible. With that, let's open the call for questions.

I would now like to turn the conference back over to Ron Renaud for closing remarks.

Operator, I think there should be some folks in the queue. I see them in here. So could you double check, please?

One moment. Yes. Our first question -- one moment for our first question. Our first question comes from the line of Umer Raffat from Evercore ISI.

[Mike Cory]. This is Mike Cory on for Umer. Welcome, Rob, looking very forward to working with you. A few for me. I just want to better understand the drivers of the schizophrenia trial delays. Second, what -- if you can, what is the CRO that you're using? And Ron, just as an outsider coming in and with the wealth of experience, there's something seems to be that different in the conduct of psychosis or schizophrenia studies. What do you think it is that, in general, is causing them to be more delayed, maybe reasons outside of COVID. Thank you.

Yes. So thanks for the questions. I'll let Ray provides some color on some of the logistical issues. But basically, we said this in our prepared remarks, we'll say it again. We know the importance of Emraclidine. We sow the potential for this to be a truly transformative therapy for patients. And I think you can hear in our comments that we're moving to bring this ahead as quickly as possible. But while we do this, we're going to continue to be incredibly rigorous in our site selection with an eye towards minimizing variability and some of the other factors that Ray can talk about in terms of things that play a role in placebo effect. But we're not going to compromise on this at all.

To your point, yes, undeniably, we've reported delays in the past with some of our other programs, Tavapadon, Darigabat and now Emraclidine. And I think what I would tell you here, as I'm new, Susan is new here, Paul is new here. We're taking a fresh look at everything. We're putting a fresh set of eyes on how we do everything. And how can we do a better job at forecasting these enrolment time lines?

We know that this is critical given the importance of Emraclidine, Tavapadon and Darigabat in their respective indications. And what I can tell you is we do need to do a better job at this, and we're committed to getting this right. And these are some of the things that we're looking at right now. With regard to some of the specific issues around, the factors driving delay in the CRO, I'll let Ray take that.

Yes. Thank you, Ron. And good morning, [Mike.] So [Mike,] what I can tell you is that all the principal investigators, I continue to talk to in the Emraclidine program are extremely excited about this new class, specifically in Emraclidine because of its one daily and dosing and no need for titration. So there's a lot of excitement there. We are continuing to understand the root cause of some of these delays at the site level. Importantly, because we strive to use the best sites, we're not going to compromise on data quality, data integrity trying to manage and mitigate placebo response -- but you have to understand that each of the sites also -- they rely on referrals to ensure that we get the right patients, and that's the key thing, getting the right patients.

And so, in doing so, some months are better than others. But collectively, that -- those are some of the bottlenecks that really hold getting the right patients into the trial. But again, because we are so focused -- so laser-focused, as I said in the call earlier, on getting this right, making sure that we just don't exacerbate the placebo response, and we work closely, which we are with the investigators, we're heightening our communication plan with them to ensure the greatest likelihood of success for these trials. So that's really our main focus. And those are some of the challenges that we're up against in terms of the sites and what they're experiencing.

Thank you. One moment for our next question. Our next question comes from the line of Mohit Bansal from Wells Fargo.

Thank you very much for taking my questions and welcome, Ron, Susan and Paul, looking forward to working with you.

Thanks.

So my question is also on the same line because [Vestaron] in the limited time you have spent with the company so far. When you look at the time line, I mean, there could be one or two reasons. Like one is obviously, was this a case of a little bit providing aggressive time lines to investors and now realizing that's probably not fair or it is the other way around, where there is something fundamentally changing in the marketplace, where it is hard to enroll these patients. I'm asking this because -- I mean these -- especially the schizophrenia trials, this looks -- I mean, look, it is a short trial.

So it is still -- we are still ways away from the point where we can say that the trial is fully enrolled. So just trying to understand if it is -- like what exactly is the underlying cause is? And then the second part of my question is like, so you mentioned that you are doing some more work in terms of figuring out the right data package for the filing for schizophrenia trial. So just -- ask that. So how should we think about the time line for schizophrenia in terms of filing time lines and how much data you need to generate there? Thank you.

Yes. So thanks for the good words. First of all, again, I'll keep coming back to this, and you'll hear us say this over and over again. Our focus remains on ensuring the quality of data, and we're going to be rigorous in our site selection. We're going to be rigorous in the investigators that we work with and our focus on placebo variability reduction strategies. You've seen in the industry what happens as the number of sites increase as the number of patients increase, that variability increases, and that is something that we are really focused on, on minimizing. And so we're just not going to compromise in any way, shape or form on the quality of the sites that we work with.

I know there's, there's going to be a natural -- there's always a natural inclination as a sponsor to want to speed things up, to want to hurry up and meet the time line. And it's unfortunate that we push this out. On the other hand, again, we're not going to compromise the quality of the sites that we're using here. And so we're going to continue to stay focused on that. And so with that data reading out in the second half, I don't want to point towards exactly when we would file anything with the agency. That being said, we're putting all of the pieces in place, and we've been putting all of the pieces in place to be prepared to file an NDA for Emraclidine here. And so we're working down that pathway at the same time that we're focused on execution of this program. And that's all happening in conjunction with each other.

Thank you.

Thank you. One moment for our next question. Our next question comes from the line of Graig Suvannavejh from Mizuho Securities.

Hi, thanks. Thank you for taking my questions. And Ron, Susan and Paul, congrats on the new positions, and I look forward to working with and partnering with you. I have two questions, if I may. First, Ron, just bigger picture as you step in as new CEO, maybe just a broad question on whether you're coming in with a view that you need to do a review of the business and you need six months before making any changes? Any kind of thoughts on like overall strategy? Just bigger picture thoughts.

And then my second question maybe is the best for Ray with regards to this Emraclidine trials. And I just wanted to ask, in light of the Phase 3 negative readout for the Sunovion and Otsuka TAAR1 program where it was described to a very large placebo response. Could you just remind us the measures that you're putting in place in order to best minimize the chance that you'll potentially see a high placebo response in order to ensure that we minimize the risk of a negative trial outcome? Thanks.

Yes. So thanks for the question. And I'll take the first part of that, and then I'll -- as you ask, let Ray take the second part. So absolutely coming in where 7 weeks or 8 weeks into this, obviously, I want to turn over as many stones and make sure from an operational perspective, we're working as efficiently and as effectively as we possibly can. There's a lot going on here. We have more than 2,000 patients on Cerevel's studies right now, where a double-digit number of studies, not to mention the number of those studies that are part of registrational pathways. And so, I will tell you my initial views on everything here at Cerevel, is that our company -- our fundamentals are very strong. I believe we have an unparalleled pipeline of neuroscience assets.

I think you'd be -- I think you'd struggle to find another portfolio of neuroscience assets in the industry that looks as broad and as robust as what we have here in Cerevel. But we've got to continue to focus on the progress of these clinical trials, the execution of these clinical trials and making sure that we can forecast these enrolment time lines much more effectively. Obviously, we know that, that helps all of the folks in the investment community as they try to figure out what we're doing, but it's also helpful for us. It's important for us and our planning as we think about how we roll these programs out. And so we're looking at that. We continue to prioritize the progress of these trials, and we're preparing for multiple pivotal trial readouts next year. And I want to make sure we execute very well on all of those.

Great, thanks and...

For the question. And as you know, we've underscored how we're trying to mitigate the placebo response, and no doubt that the data that you outlined just a few moments ago was quite so bring a thing to the field. So what we're doing and what we've mentioned before, as you know, it's ensuring that we get the right patients. So -- and how you do that is really critical. And so we have a process in place to do that, that really looks at the patient qualification because as you know and others know that the patient profile really drives the outcome of these trials, as does the quality of the raiders at the site when we say quality sites, we're talking not just about the ability to access the right patients, but their ability actually to have competent really robust raters. And so we have a plan in place to address that.

Other things that we're doing is we have a placebo mitigation protocol at each of the sites that allows for certain interventions to be made or not be made to ensure that the placebo response is kept at bay as much as possible, but also limiting the number of sites and limiting the number of countries. And when you do that invariably, you're going to see waxing and weighing of the enrolment However, at no point do you dilute the data and you position your trough with the greatest life success. So collectively, that's the confidence that we have that these trials are positioned for the greatest lets of success and outcomes.

Thank you. One moment for our next question. Our next question comes from the line of Tazeen Ahmad from Bank of America.

Hi, good morning. And also Ron and team, congrats on the new roles, and we look forward to working with you. I just wanted to clarify, you've mentioned now on the call several times that you need to find the right patients for the schizophrenia program. Can you maybe give us a little bit of color on what the right patient looks like? And how that might translate into what you ultimately think the market opportunity would be in schizophrenia, would it be toward the broader population? Or are you thinking that there is a subset of the population, which could still be quite large that might be best suited for your drug? And then secondly, can you just remind us what your cash runway is?

So I'll turn the first part of your question over to Ray and Susan on the second part.

Tazeen, hi, good morning. Thanks for that question. So the trials are meant for the generalized schizophrenia population. When we talk about the right patient, remember, we're conducting clinical trials. So we're trying to detect the signals this therapy has. And so in order to do that, you need to refine the patient population in terms of the severity of disease. So as you know, we have a PAM score of at least 85 up to 120. And those -- and then a variety of other criteria. It's really to define the patient population that's going to really give you the best opportunity to detect the signal of the miracle to be a robust therapeutic in the population. However, it doesn't mean that you're restricting the population in any way to suggest that it only works in certain patients and not others. It's really for the general schizophrenia population. But because you are conducting a clinical experiment, you have to have certain controls in place to ensure the greatest likelihood of success.

Great. Thank you. As noted, we are well capitalized and ended the second quarter with $825 million on the balance sheet. So that funds us through all our key data readouts next year and comfortably into 2025. So we'll continue to be thoughtful about resource allocation and opportunistic in bolstering the balance sheet, but we feel very good about our cash position.

Thank you. One moment for our next question. Our next question comes from the line of Paul Matteis from Stifel.

Hi, thanks for taking my questions. On Emraclidine, we noticed that a drug-drug interaction study was put on clinicaltrials.gov. Is that just a typical study check the box for an NDA? Or are you actually expecting to elucidate an interaction that could be significant as it relates to how people prescribe the drug? And then separately, I had a couple of pipeline questions on the kappa program. I was curious in your perspective now that it seems like we have a couple of external studies suggesting this target has an antidepressant effect. I guess do you agree with that? And do you plan on moving more quickly now in depression? And then John, to your point on a dose range as it relates to kappa and --, do we want to be targeting new as well? I was under the impression that, that produced more side effects. So maybe you could just kind of speak to the scientific hypothesis behind your compound and how you're thinking about it. Thank you so much.

It sounds like John can take all of these.

Thanks, Paul. Appreciate the plethora of questions there. So yes, the DDI pro-filing is a standard for a registrational package. And so as you know, you have to inform the label and potential for DDI and any kind of dose adjustments so the physician can make the right decision for each patient based on their background therapies. And so these are pretty much standard. For KORA, yes, so we're really excited. So now, as you mentioned, the second company is shown. So as you know, the first colleague company, I'll say, showed a nice potential for looking at the core mechanism of action as an adjunct on the standard of care in MDD, the major depressive disorder.

And now recently, we've seen another colleague company showing that monotherapy also showed a nice effect, positive benefit in the MDD as a monotherapy. So we think this is very consistent with the mechanism of action, what's been published quite extensively in preclinical models. As you know, there's a lot of potential for this mechanism to actually go beyond MDD. And so that's going to lead into the answer to the next one, which is -- as you know, we've been working closely with it NIDA. And we received, like I mentioned this morning in additional funding to go for even more studies there in the clinic, pet receptor occupancy being one of them.

And so when you think about what it is that you want to achieve, so both -- if you look at the both competitor molecules, the first one is a very kind of non-selective approach that we've seen as the adjunct and what you've seen with the more recent data is one that we consider to be highly selective to kappa. And so you have -- in both cases, you have a nice demonstration that either mixed activity or highly selective activity is effective.

However, as you think across what the different potential indications could be -- some of those may actually benefit from having some new activity. And so what we want to do is be able to think about how we take this particular molecule and actually look at dose ranges that are appropriate for different indications. And so as an example, if you went into a substance use order study in opioid patients, you definitely do not want to have new activity because you could induce withdrawal. It's extremely unpleasant for the patient.

And so in that, it would be a different dose range and potentially another indication where you would actually benefit from having some new activities. So I think with this molecule, knowing that we can cover a very broad range in a well-tolerated fashion. It gives us a potential to actually look at those ranges that are appropriate for different indications based on what we know about the etiology of the disease and what would benefit each group. And so it's a really exciting molecule, really exciting science. And so stay tuned, and we'll share more as we can.

Thanks, John.

Thank you, Paul.

Thank you. One moment for our next question. Our next question comes from the line of Joseph Thome from TD Cowen.

Hi, good morning and thank you for taking my questions. Maybe the first one, as we think about Emraclidine in ADP, I guess, what would you be looking for in that healthy volunteer study to advance the next level? And I guess, how tied are the EMPOWER results to advancement in ADP. Do you want to wait for the EMPOWER studies to read out before committing to the next step? And then maybe just a quick one on the Darigabat panic disorder study. Can you comment a little bit on how severe patient symptoms are at baseline in terms of pre-treatment or I guess just baseline severity? And then when we think about through the titration and maintenance period, can patients use any rescue medication, if they do have an attack. Thank you.

I'll turn that over to John Renger.

Sure. So I'll speak to the ADP questions first and then Ray can address the second. So -- as you know, the population for ADP is differentiated from the schizophrenia population, primarily by age. And so what we have to do is a healthy elderly PK study. And then what you want to do is then go into the patient population. So what will we be looking for? What we want to demonstrate is that we can achieve the exposures of drug that we have related previously to pet receptor occupancy data so that we're confident that we're able to achieve CNS receptor occupancies that will test the mechanism of the M4 in ADP patients.

And so what we're looking for is safety and tolerability at the exposures that we want to achieve to take forward in the ultimate patient population. And so -- as you know, what we are in the middle of is at a multiple ascending dose study to do that. And so that data will help us then demonstrate that we have a path forward. And so what we're looking for is really just to see that we have the same kind of well-tolerated profile that we've demonstrated previously. As you know, it's a very different population than the schizophrenia population. So it's difficult, I think, to make any conclusions about whether one would inform any other at this point. Obviously, there's a rationale to believe it will be effective in both. And so that's the question that we need to answer, but we are going as quickly as we can, and we're not waiting for anything else to gate our decision to progress in this indication or potentially others. And so I think it's not a wait-and-see type of approach is go as fast as we can as safely as we can.

Thank you, John. Joseph, so listen, we're really excited about the potential to come up with a new therapy, which is much needed in the landscape or panic disorder nearly 20 years ago, that was the last medication approved for that. So the population that we're using is a moderate population. And so we're looking at the panic disorder symptom scale severity of 12% or greater 12 being the threshold of moderate disease. They also have to have at least 8 panic attacks with no free week of panic attacks in the month prior to the screening visit and in the 2 weeks leading to the baseline visit have at least 4 panic attacks.

And so that's something that, as you know, that severity does drive. And so I appreciate that question, severs drive the outcome of a lot of these studies. So we're using the right population to ensure that greatly positive success. No rescue medication is allowed in the trial, as you know, that potentially confound the outcome. So rescue medication is not allowed. And we're also at every visit doing screens to make sure that they're not using other therapies as rescue. So those patients would be censored or discontinued appropriately. So all in terms of how do you design the trial with the right methodology to ensure the greatest leaf success and that's what we're trying to achieve.

Great. Thank you very much.

Thank you. One moment for our next question. Our next question comes from the line of Jeff Hung from Morgan Stanley.

Thanks for taking my questions. And also my congrats to Ron, Susan and Paul on the new roles. Two questions for me. First, can you talk about the challenges for identifying the appropriate patient population for dementia-related apathy? And in the context of challenges identifying appropriate patients, what is your latest thinking on the size of the market opportunity for this indication? And then second, for the ADAPT study in panic disorder, how is emraclidine going? And can you remind us of what you need to see to consider the proof of concept of success? Thanks.

Again, John or Ray?

Yes. So I'll start with -- thank you, Jeff, with the dementia-related apathy. As you know that this is a new path that we're carving forward. We received fast track designation from the FDA in order to do so. So we'll be working very closely with them. But it is an experiment that the trial that we're conducting is truly experimental. We're looking at various primary endpoints and so forth in terms of scale, but not that there's no formal hypothesis testing per se. One of the challenges is, of course, the landscape recognizing who these patients are.

So the families, the caregivers, the practitioners really understanding what apathy is. So we've been working very closely with the ISCTM group, which FDA has been involved with in order to understand the criteria to identify these patients. So that's the biggest challenge is really to identify the patients that are out there because we know that half of the patients with dementia suffer from apathy. It's a leading neuropsychiatric syndrome and a predictor of disease progression. So we're continuing to stay laser-focused on that trial and also helping the sites identify the right patients.

In terms of the panic disorder trial. So as you know, it's a 14-week trial really with a 12-week maintenance phase. It's 80% powered to detect a difference of 20% and in the proportion of patients, meaning between active and placebo in the proportion of patients who are free of panic attacks during the last 2 weeks of the maintenance phase and why that endpoint because that's the endpoint that it's been -- that the precedent has been said that the FDA has historically wanted to understand. And as you know, it takes time for patients to respond to therapy. So that seems like an appropriate endpoint. So those are the parameters. And so we are excited about continuing that trial. As you know, we've just initiated within the last few weeks. So we have not provided any time line at this point, but we're excited about the progression of the program moving forward. And so stay tuned as the program continues.

Thank you.

Thank you.

Thank you. One moment for our next question. Our next question comes from the line of Michael Yee from Jefferies. Pardon me, Michael Yee from Jefferies, your line is now open.

Hello, can you hear me?

We can.

Yes.

Great. Following up on the questions around the enrolment for schizophrenia. We wanted to ask around clarification and color. You go up to the ct.gov, you've got a lot of sites listed up there. I think some of them overlap at the major centres as some of the competitor enrolment centre. And so I just wanted to understand, is it sites getting up? Is it, hey, we've got the sites, but we don't really like the criteria or the patients that are coming in, and we're not really happy with some of that. Maybe just shed a little bit of light on that because what we see is a lot of centres, and we're just trying to think about what the actual latistical issues are.

And then related to that, I know that you are running nonclinical studies and other studies that are related to the NDA. I know that the competitor is taking many months, but typically it's standard to file an NDA around 6 months after a completion of the data set. So do you feel comfortable based on the time line that if your data comes out in second half of '24, that the timing involved the non-clinical studies and all that should have a filing in first half of '25. Thank you.

So, yes. Ray?

Yes. So Michael, Good morning. so as you know, we are some -- we're always seeking the best sites. And of course, everyone else, it potentially or what they are as well. So there are going to be some overlapping sites with other sponsors. To that end, it's really around, to your point, really looking at getting the right patients. And so we have a method by which we help the site achieve that. That's independent of the actual site, proposing the patients exclusively. So we have another independent committee that looks at the criteria to make sure we have the right patients in the trial. And that waxes and wanes over time. And it's really patient accessibility that sometimes can be a bit of the bottleneck.

We're working with the sites closely to measure that and continue to understand the root causes of what's holding them up in certain cases. But just to remind you that we started with a bolus of patients, really an exciting, very ahead of schedule type of enrolment initially. In the last few months, we've seen this slowing down in the U.S. Secondly, for ex U.S. sites and of course, we choose countries where historically, we've had good data that we know the sites well, there's been also a slowing down of getting those protocols approved. Really, in the bottleneck there is really at the country level, at the IRB level in those countries.

And I do think it's just a volume issue that they're grappling with. But we are -- we have all the sites that we need currently up and running, and we're looking at new countries and new sites potentially in the future. And again, always focused on data quality, not diluting the data in any way, not exacerbating placebo response. So we want to get this therapy out to the patients sooner than later, but we also know in order to do that. We need very robust data, and that's what we're trying to achieve as well.

And [Mike,] I'll speak to the second question. So in rerepreparedness for submission. So obviously, we are all over the time lines to make sure that we have all of the preclinical data, the CMC data for the CMC module and the NDA and also all of the required clean pharm studies to inform undoing and those types of things. And so we will definitely -- I'm not going to commit to how much time it is, but we will definitely position to have the data in hand when we get the readout. And so we are very focused on minimizing that time line from data readout to submission, and we're doing all the work necessary to make sure that we get the NDA completed as quickly as possible.

I think that can't be underemphasized -- it's a pretty important part of the package besides the Phase 3 data. Thank you.

Thank you. One moment for our next question. Our next question comes from the line of Charles Duncan from Cantor Fitzgerald.

Good morning, Ron and team, thanks for taking our questions. Congrats to the new joiners on the call on the opportunity I had a question on Emraclidine, and then actually one on Darigabat. With regard to Emraclidine, in the over -- in the sites where you see overlap with a direct agonist, I guess I'm wondering if you have any feedback to share with regard to investigator interest? And then in addition to enrolment rate, can you provide any color on dropouts from that study? And then also in EMPOWER-3, do you have any patients that have rolled over to that open label?

Thanks for the question, Charles. I'll let Ray take those.

So Charles, yes, we've seen -- yes, we have patients rolling over. That's the way the program is set up that patients have the opportunity when they complete the 6-week trials to roll over into the 52-week open-label extension. And of course, that is for us to continue to gather the exposure data, the long-term exposure data that we need when we do file that NDA. In terms of Emraclidine and the investigators, as I mentioned earlier in the call that one of the things that I've been really comforted by and excited is really the level of enthusiasm that the investigator community has for Emraclidine, but specifically for this new class, really giving patients a better alternative to treating psychotic symptoms. So again, we're working closely with them to ensure we get the right patients as we've been mentioning through the morning. And so I hope that answers your question. Is there anything else you'd want to know about that?

Yes. I think that's clear, and I appreciate all the color that you've provided on your efforts for enrolment. Just moving on quickly to Darigabat, I guess I'm wondering about the high rollover rate that you mentioned in the open label extension. I'm quite intrigued with that, to me, in an epilepsy patient that perhaps reflects enthusiasm above the therapeutic profile. So I guess I'm wondering if you could provide any further color on that.

Yes. So it's always difficult to predict the rollover rate in terms of patients rolling over. So when you see robust rollovers as we're seeing, we get excited about the potential of the therapy in that patient population. And they're quite eager as you know, to try to come up with a therapy that really suppressed or seizure activity. So we continue to be excited about the rollover rate, and we're monitoring it closely. We're getting the exposures ultimately over time that we'll need when we do file after our Phase 3 program. So it speaks to all of that.

Might the rollover rate as well as persistence within open label speak to the tolerability as well, differentiated tolerability?

It may. At this point, it will be conjecture because we obviously have to look at the data. But obviously, if somebody rolls over and stays on your therapy for a long period of time, then it puts tolerability in a good light. But in terms of what the -- what that would look like, I think we should just wait for the data to read out.

Okay. Thanks for taking my questions.

Thank you, Charles.

Thank you. One moment for our next question. Our next question comes from the line of Douglas Tsao from H.C. Wainwright.

Hi, good morning. Thanks for taking my questions. And congrats to everybody for joining the team. Maybe to start with Emraclidine, not to beat a dead horse, but Ray, I'm just curious in terms of finding the right patients. Are you taking any sort of logistical or any additional screening issues? I mean, obviously, we have the patient inclusion and exclusion criteria to get the right patients. But are there any logistical things that are perhaps slowing down the process a little bit? And what benefits might those provide?

So Douglas, there's nothing that's slowing down the process. Remember that we started with great momentum and the process hasn't changed from that to what we've seen in the last few months. We have a very robust kind of safety net to make sure that, as I mentioned earlier, that the investigators stay true to form to make sure that we get the right patients ultimately to drive the success of the trial. So that's not slowing the trial down. I think it's really around that. It's really around finding the right patients and that waxes and wanes over time. But we have to stay steadfast, and we've got to stay very committed and focused to ensuring that at no time we get the wrong patients. And again, that's what we're doing and positioning these trials with the greatest likelihood of success based on the parameters and that quest.

Okay. Great. And then just as a follow-up, just given some of the moving parts with the pipeline and obviously, some studies are now reading out later than was originally planned. Does that affect how you think about moving some of the earlier stage assets into later-stage development just as you think about sort of managing your cash runway? Thank you.

Yes. I'll take that one. Look, we're very conscious of the balance sheet. We pay close attention to that. And as Susan mentioned, we're going to do what we need to do to be opportunistic to make sure that, that balance sheet can continue to support not only the late-stage programs that we spent most of our time talking about today. But many of these really interesting and important early-stage programs. and so the early stage program, we won't shortchange that as well. And so this is something that is equally as important as making sure we get the latest program, right?

Okay, great. Thank you so much.

Yes, you bet.

Thank you. At this time, I would now like to turn the conference back over to Ron Renaud for closing remarks.

So I want to first of all, thank everybody for the questions this morning, but also for the warm welcome. I know that Susan and Paul and I are super excited to be here, to be part of one of the most exciting pipelines in neuroscience and to really be part of building this world-class neuroscience company, it's something that I'm incredibly excited about. We're well funded with the resources to maintain all the work we're doing well in 2025.

We're looking at things with a fresh set of eyes, and we'll have lots of discussions with all of you and many more over the coming months as to the things we're learning along the way. But I think on balance, what you're going to find is there's a lot of incredibly important work going on here at Cerevel 2 late-stage programs, 2 NDA registrational programs underway here and then a significant number of programs right behind that, that's going to keep us busy not only with these NDAs for the next 12 months to 24 months, but for the foreseeable future after that, and that's incredibly exciting. So I look forward to having more discussions with all of you on all of these programs as we move ahead. Thanks a lot, and I hope everyone has a great day.

This concludes today's conference call. Thank you for participating. You may now disconnect.