Q1 2023 Cerevel Therapeutics Holdings Inc. Earnings Call

Speaker 2: Good morning and welcome to the Cerebral Therapeutics first quarter financial results conference call. At this time, all participants are in a 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.

Speaker 2: I will now hand the call over to Matt Calisti, Vice President of Investor Relations.

Speaker 3: Thank you. Good morning, everyone. We appreciate you joining us for our first quarter 2023 Thanks for joining us at this month's star of theaire'sates out.

Speaker 3: On today's call, you'll be hearing from Dr. Tony Coles, our Chairperson and Chief Executive Officer, Dr. Ray Sanchez, our Chief Medical Officer, Dr. John Renger, our Chief Scientific Officer, and Mark Bode-Rader, our Interim Chief Financial Officer.

Speaker 3: During our call today, please refer to our press release from this morning detailing our first quarter 2023 performance as well as our updated corporate presentation, both of which are available on our website.

Speaker 3: 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.

Speaker 3: We strongly encourage you to review the information that we file with the SEC regarding specific risks and uncertainties.

Speaker 3: I will now hand the call over to Dr. Tony Coles, Chairperson and CEO of Ceravell to provide an overview of our achievement and outlook. Good morning, and thank you, Matt. Thank you for joining us for our first quarter of 2023 business results call. This morning, we announced the appointment of Ron Renaud as the next President and CEO of Ceravell.

Speaker 3: the organization well as it prepares for an exciting future, most notably the seven data readouts that we expect in the coming year.

Speaker 3: As I worked with the board to plan this transition and return to my role of chairperson, we knew that a smooth change in leadership required the right timing and the right successor.

Speaker 3: The fundamental strength of the company may now the right time, and we know that in Ron we get found the right successor.

Speaker 3: Ron brings deep experience in the life sciences sector and as the former CEO of both Translate Bio and Identix Forms Sutacles, he is truly the perfect fit to become the next CEO of Cerevel. I have great confidence in Ron's ability to lead Cerevel into its next phase as we work together to unravel the mysteries of the brain.

Speaker 3: Ron will join Sarevel at a time when we are steadfast and focused on executing our clinical trials and optimizing our cash runway with thoughtful fiscal discipline. Sarevel has a tremendous pipeline that is poised to transform what is possible in neuroscience and we look forward to bringing new treatment options to as many patients as possible.

Speaker 3: Phase 2 Empower Program for Adults living with schizophrenia is enrolling well and remains on track for a day to read out in the first half of 2024.

Speaker 3: At Cerebell, we're committed to advancing our amaraclutin program on an accelerated basis.

Speaker 3: And we continue to prioritize this important phase 2 program and completion of the other necessary pre-clinical and CMC registration enabling activities.

Speaker 3: in addition to an open-level extension trial in order to bring this potentially transformative medicine to the people who need it.

Speaker 3: Driven by our strong belief and conviction in the differentiated advantages of a targeted, selective, informed musculoskeletal mechanism.

Speaker 3: We are also exploring and rackling for the treatment of Alzheimer's disease psychosis. We were pleased to receive FDA fast track designation for and rackling for the treatment of hallucinations and delusions associated with Alzheimer's disease psychosis.

Speaker 3: Beyond our work with M. Rackladin and schizophrenia and ADP, we are also advancing therapies for other serious neurological conditions by targeting new pathways with novel selective approaches. Duregobat, our selective alpha-235 GABA-APAM, is another several problems with multiple potential indications. The first of these is epilepsy, the fourth most common neurological disorder, through our phase-2 realized trial. We are studying Duregobat and focal epilepsy, an area of tremendous unmet need for patients who need better control of their C.

Speaker 3: is the main driver of side effects for benzodiazepines.

Speaker 3: We will be initiating our Phase 2 trial and panic disorder this quarter as planned and look forward to providing you with future updates.

Speaker 3: our Phase 2 trial in panic disorder this quarter as planned, and look forward to providing you with future updates as that trial progresses.

Speaker 3: We believe Tabapidon could serve as both the preferred monotherapy choice for the newly diagnosed patient and the ideal adjunctive therapy choice to leave adopa as disease progresses. All three of cerebells phase three trials in Parkinson's disease, non collectively as the Tempo trials, are ongoing along with the corresponding open label extension trial. We expect data from Tempo 3 now in the first half of 2024 and data from Tempo 1 and Tempo 2 in the second half of 2024.

Speaker 3: While we remain single-mindedly focused on executing our broad range of clinical trials, we recognize the need for continued fiscal discipline.

Speaker 3: As Mark will explain in detail at a moment.

Speaker 3: We have reduced our planned 2023 operating expenses while maintaining a rigorous focus on our key priorities.

Speaker 3: Specifically, the data readout timelines for our lead assets and investing in our early pipeline where we believe there is long-term value creation potential.

Speaker 3: We will continue to monitor our expenses for additional opportunities to manage and gate spend where possible, and we will explore external business development and partnering opportunities such as risk sharing arrangements or XUS partnerships as appropriate.

Speaker 3: CERBEL's cash, cash equivalents, and marketable securities are expected to support our seven day anticipated data readouts in 2024 and fund our operations into 2025.

Speaker 3: Importantly, we have ample cash and runway to see us through the top line data readout of our mercury phase II program.

Speaker 3: The strong fundamentals of our business make this the ideal time to welcome Ron to the team as we look forward to a bright future for Cereval and the patients we seek to serve.

Speaker 4: Great. Thank you, Tony, and good morning to all of you. First, let me say how delighted I am to welcome Ron Rado to the organization. Ron's operational expertise in experience leading dynamic organization like ours is a fantastic fit for Cerevo as we seek to develop new treatment options in some of the most challenging neuroscience diseases. Let me start with a review of enraptomy. Our robust phase two trials are enrolling well. We expect this progress to continue in support to data in the first half of next year.

Speaker 4: These two adequately powered three-arm trials called Empower 1 and Empower 2 are being conducted worldwide and will each randomized 372 adults living with schizophrenia and experiencing an acute exacerbation of psychotic symptoms. The first trial will...

Speaker 4: We are also in ruling patients in Empower 3, our 52-week open-label safety extension trial, and we are prioritizing the completion of the necessary non-clinical and clinical pharmacology studies in order to accelerate a potential registration package for a Mrakovian schizophrenic. This program is clearly a top priority for Cereval, and I am very pleased with our progress today. We are also moving forward with our Phase I Healthy elderly volunteer trial to support the development of Mrakovian in Alzheimer's disease psychosis.

Speaker 4: The results of which will guide our clinical development plan. Turning now to Dr. Rigabat, our Alpha-235 Selective GABA receptor pan, currently in development for epilepsy and panic disorder. We believe Dr. Rigabat has the potential for both anti-epileptic and angiolitic activity comparable to currently available benzodiazepines, but with reduced side effects. Dr. Rigabat has the potential for both anti-epileptic and angiolitic activity.

Speaker 4: Our phase two realized trial is progressing and we now expect results mid-year 2024. We are steadfast in our commitment to advance this important therapy and we have an experienced team that is continually deploying new mitigations to address enrollment headwinds while remaining focused on data quality. We remain encouraged in our ongoing efforts by the 90% roll over rate into the realized open label extension which speaks to the potential benefit to patients of derogabat in Pocolev-Lepsy.

Speaker 4: Beyond epilepsy, we're excited about expanding the potential application of Derigabat through the initiation of our Phase II trial and panic disorder expected later this quarter. Panic episodes present with a constellation of symptoms including a rapid pounding heart rate, sense of impending doom, weakness, disinist, disorientation and chest pain.

Speaker 4: It is estimated at least a third of panic disorder patients remain untreated and a significant proportion of patients on therapy have a partial response to treatment.

Speaker 4: We believe Derigabat as a selective GABA APAM can provide angiolitic benefit while minimizing the side effects of results from the non-selective nature of benzodiazepines. Derigabat's potential, as a well-tolerated, daily option of the treatment of panic attacks, could potentially improve the experience of patients living with panic disorder. We will provide more details on our phase 2 panic disorder trial design and progress at a future time.

Speaker 4: we believe Derigabat as a selective GABA APAM can provide angiolidic benefit while minimizing the side effects that result from the non-selective nature of benzodiazepines. Derigabat's potential as a well tolerated, daily option in the treatment of panic attacks could potentially improve the experience of patients living with panic disorder. We will provide more details on our base two panic disorder withdrawal design and progress at a future time. Turning now to Tbapidon.

Speaker 4: We believe that Tavapeton could serve as a preferred model therapy early in disease, with a potentially reduced side effect burden compared with existing therapies. For the more advanced Parkinson's patient, Tavapeton could be a preferred adjunctive treatment with aldopa due to its longer half-life and potentially improved tolerability profile and reduced incidence of dyskinesis. The clinical objective for new therapies is, of course, to enable 24-hour motor symptom in control and delay the need for aldopa dose escalation.

Speaker 4: As Tony discussed, all three of our Tvapodon Phase 3 trials known collectively as the temple trials are ongoing along with the corresponding open label extension, in which we are seeing Hyrule rate of 90% or more.

Speaker 4: We now expect data for Temple 3 in the first half of 2024 and data for Temple 1 and 2 in the second half of 2024.

Speaker 4: Our other D1-D5 program, CVL 871, which we are pursuing in the novel indication of dementia-related apathy, is also expected to read out a Phase II-A trial in the second half of 2024.

Speaker 4: We have an experienced team advancing a broad and deep pipeline of neuroscience assets.

Speaker 4: We remain intensely focused on maintaining the quality of the clinical trials we conduct and importantly, not compromising the collection of data for the sake of expediency.

Speaker 4: I am looking forward to updating you on progress as we look ahead to our data from 7 to late stage clinical trials in 2024.

Speaker 4: With that, Dr. Don Renger, our T-Scientific Officer will provide an update on our early stage portfolio. John ?

Speaker 3: Thank you, Ray. Good morning, everyone. First, I'd like to underscore Tony and Ray's warm welcome to Ron. I'm personally really excited for all that we will be able to accomplish together to write Sarah Bell's next chapter.

Speaker 3: I'm extremely pleased with the progress we've made in our research and our clinical development programs.

Speaker 3: Let me start with an overview of our clinical stage, selective Kappa opioid receptor antagonist or Kora called CDL354.

Speaker 3: Capulpio receptors represent a key mediator of behavioral reinforcement, linking the four-brain limbic neural circuits with brain stem, mild emerging, mild aminergic new plant. Reward effects of both drugs of abuse and natural behaviors, including stress responses, coalesce at the key point of the capulpio receptors.

Speaker 3: and the key mediator of behavioral reinforcement, linking the four-brain limbic neural circuits with brain stem, mild emerging, mild aminergic new plant. Reward effects of both drugs of abuse and natural behaviors, including stress responses, coalesce at the key point of the caporeceptors, via the northern signaling.

Speaker 3: Therefore, we believe that core approach is one that can correct the abral dysregulation and address a range of psychopathologies including major depressive disorder and substance use disorder. Recently, the snoblemagnetism of action has shown promise across a number of preclinical models of depression, anodonia, and opioid withdrawal symptom improvement.

Speaker 3: We refer to an increase to see a demonstration of clinical proof of concept in the phase to major depressive disorder trial, completed by one of our peers.

Speaker 3: Our recent progress on our internal program has been featured in scientific presentation presentations, which revealed the receptor-ceptet selectivity where lead molecule 354 and non-human primate pet receptor occupancy studies.

Speaker 3: These studies demonstrated those dependent target engagement of 3x4, with at least a 10-fold more potent binding and caporeceptors over mu-obu-inverseceptors, providing compelling evidence with receptor selectivity of our compound.

Speaker 3: These data are being confirmed clinically currently and are recently initiated human pet receptor occupancy clinical trial examining the human capa and near receptor selectivity of this compound.

Speaker 3: Weed and leave the clinical exploration center after occupancy binding a 354 will be important to inform appropriate dose ranging across multiple potential indications.

Speaker 3: bolstering our desire to create a muskernic M4 selectivity-based therapeutic branch guides. We'll be further up feeding our progress on this program in the near future. Once sincerely thank the teams who are hard at work in earlier stage research and clinical development, as well as supporting our late stage program, NDA filing activities. As I have stated previously, we are purpose-built to unravel the mysteries of the brain to treat neuroscience diseases. Our scientists are committed, passionate, experienced, and highly skilled at what they do, and are actively expanding our earlier stage SEPPAR-PORIAL to ensure continuity in our pipeline for many years to come.

Speaker 3: our desire to create a muskernic M4 selectivity-based therapeutic branch. We'll be further up feeding our progress on this program in the near future. I want to sincerely thank the teams who are hard at work in earlier stage research and clinical development as well as supporting our late stage program, NDA filing activities. As I have stated previously, we are purpose-built to unravel the mysteries of the brain to treat neuroscience diseases. Our scientists are committed, passionate, experienced, and highly skilled at what they do, and are actively expanding our earlier stage as a portfolio to ensure continuity in our pipeline for many years to come. We will continue our updates in the space of the program.

Speaker 3: I'm not going to hand it over to Sarah Bells in-term chief financial officer Mark Bowen-Rater for your financial requirements in the first quarter. Mark?

Speaker 4: Thank you, John . Good morning, everyone. And let me also add a warm, Sarahville welcome to Ron. I'm pleased to provide an overview of Sarahville's strong financial position as we target investments in spend on the highest value of opportunities in our pipeline. As of March 31st, 2023, our cash, cash equivalents, and marketable securities totaled $863 million.

Speaker 4: In April , we received an additional $31.3 million from our Tavapodon risk sharing arrangement.

Speaker 4: Our cash resources are expected to fund our operations into 2025, which will support us through the seven mid-to-late data stage readouts. We expect in 2024 and allow us to achieve the next inflection point for each of our lead programs.

Speaker 4: For the first quarter of 2023, total operating expenses were approximately $100 million, which includes R&D expense of $78 million in GNA expense of $21 million.

Speaker 4: Relative to the first quarter last year, R&D expense increased by approximately $23 million. This increase is primarily due to investment in our Immoracledine program, including the advancement of our two ongoing Phase 2 trials and the open, labeled, Safety Extension During Invention Trials gets afrem?.

Speaker 4: and personnel related in other infrastructure costs supporting the continued growth in expansion of our pipeline.

Speaker 4: GNA expense for the first quarter increased by approximately $4 million over the first quarter last year.

Speaker 4: As Tony mentioned, we reduced our plan 2023 operating expenses while maintaining a rigorous focus on key priorities and timelines, including executing and achieving emaraclidine timelines in appropriate NDA-enabling readiness activities, as well as driving tavapidon-dorigabat clinical execution and trial completion. To achieve these reductions in plan spending, we shifted certain activities commensurate with our changes in timelines, gated incremental spend pending the achievement of top-line data, and reduced plan headcount growth for this year. We will continue our focus on fiscal discipline and monitor our expenses for additional opportunities to manage and gauge spend where possible.

Speaker 3: out of the work our team is doing in the pursuit of bringing much needed medications to patients living with some of the most debilitating neuroscience diseases.

Speaker 3: We're executing a smooth leadership transition and are pleased to welcome Ron as the next CEO at a time when our underlying business fundamentals are healthy and strong. We have continued momentum in our emiracating program in adults living with schizophrenia and look forward to a robust set of data catalysts in 2024 and are pleased to announce the expected Derrickabat results in the middle of next year.

Speaker 3: and tempo three results in the first half of next year. We remain fiscally disciplined with cash and to fund our operations into 2025 and deliver the next inflection point for each of our lead assets. And we remain open to new opportunities to maximize the value of the pipeline to creative deal making, especially under Rons' leadership given his track record of partnerships and collaborations in his prior roles. Let me also add, since this will be my last quarterly call as CEO .

Speaker 3: that this has been a tremendous privilege to lead Ceregal through such an exciting time. I took on the additional role of CEL more than three years ago with a very specific set of goals to launch this new organization to raise sufficient capital and prove the Ceregal Scientific thesis that are focused on your circuitry, receptor subtype selectivity,

Speaker 5: and differentiated pharmacology could advance important new medicines for patients facing vexing diseases.

Speaker 5: And with those objectives met, I've done what I came to do. Now is the time to return to my role as chairperson.

Speaker 5: And I am proud of all that we've accomplished today. I'm grateful for the tremendous team we've assembled, and I look forward to partnering closely with Ron, the team and the board as we continue on our journey to become the premier neuroscience company. And with that operator, I'd like to open the floor for questions. Thank you. And the reminder to ask a question, you will need to press star 11 on your telephone.

Speaker 2: Also, please limit your questions to one question pretendy only. Please send by while we compile the Q&A roster.

Speaker 2: Your first question comes from the line of Paul Matisse from Stifel. Your line is now open.

Speaker 6: Hey, thanks so much for taking the questions and I appreciate it and Ron, it's great to reconnect through view again and Tony before to continuing the dialogue. Ron, I want to use after you a question now stepping in a CEO , right or wrong, one of the investor concerns on Seridil has been a number of pipeline delays and if there's an underlying execution issue or if there's something that I guess operationally...

Speaker 6: needs to be fixed. So I would just curious your perspective on that and what you might be kind of looking at as you step in and what you might look at to do differently. And I guess to that end just on the miraculous being specifically, is there anything you can convey on a more granular level that can help solidify confidence in the investor community?

Speaker 6: that first half 24 is fully on track. Thanks so much.

Speaker 5: I hate to disappoint you Paul, but Ron is actually not on the call. He doesn't begin his tenure with the company until the middle of June . That's quite alright. But I appreciate the sentiment in your question, and so let me address that.

Speaker 5: You know, I have reflected on all of the accomplishments that we've had in the business and obviously the lens to which I look at this is over the last four years or so. So I think we'd be harder pressed to find a company that has raised the amount of capital, delivered the kind of data and proved the underlying thesis for the company, particularly in neuroscience. And as CEO as I reflect on all of these things.

Speaker 5: You control the things you control and you make the best of everything you can't control. And in this case, when we did have disappointing news surrounding clinical trial timeline delays that we've announced earlier this week, obviously no one likes that. But we can't let a simple matter overshadow the key achievements of a business that has been as valueably created as this one.

Speaker 5: So what we expect from Ron's great leadership, and this is one of the things I'm looking forward to is that he'll bring his own unique style of leadership, his own particular insights and his long track record of success and make the company even better than it is today. That's what a great CEO does, and that's what a great leader does.

Speaker 5: And let me reassure you on Imraquedine as well. Everything is on track with Imraquedine as of today. The kinds of things that have impacted the industry in terms of some of the trial timeline delays don't seem to be impacting our inpatient studies and this is evidenced by the ABPM study we announced in the fourth quarter of last year, which finished ahead of time.

Speaker 5: mine's back on track.

Speaker 5: So in all, as I reflect on the thrust of the question, I'm really proud what the team has done. We can control the things we can control, and we make the best out of things that we can. Let's take the next question operator. Your next question is from the line of Omer refot from Evercore ISI, your line is now open. Hi guys, this is Mike DeFury on...

Speaker 7: for Omar. There's two for me. Tony, it's been an absolute pleasure working with you and we certainly wish you continued success in your role as chairman.

Speaker 7: Tony, it's been an absolute pleasure working with you and we certainly wish you continued success and in your role as chairman.

Speaker 7: Okay, so here are my questions. An SEC filing recently surfaced, which said that your SPAC sponsor is currently engaging in preliminary discussions about a potential strategic transaction. Tony, if you could offer any color on this, and is this in any way related to your stepping down a CEO ?

Speaker 7: And separately, on the coronavirus emergency phase three results, we saw that the placebo response...

Speaker 7: increasingly improved over the course of their three trials. So remind us what is cerebral doing to mitigate the risk of an outsize placebo effect.

Speaker 5: in their phase two and power trials. Thanks, Bob, for the question, Mike, and on the SEC filing from one of our investors, this was a filing that perceptive me. There are no strategic transaction conversations underway, so I can dispense with that, and I can't.

Speaker 5: they did retract and issue an update the following dates. I'll refer you to their SEC, full-sub-SEC violence. As to the emergent three question and a placebo response, Ray, why don't you take that one? So, Ray, thank you for the question, and you are correct that placebo response is something that really plagues.

Speaker 8: a lot of the CNS landscape. And so it's really driven by so many factors, but this is what we're doing to mitigate the risk. And that is really one, we're ensuring that the right patients are enrolled in the trial, because that ultimately really drives the success of a trial and we have methodologies in place to achieve that. We're limiting the number of sites.

in each of the trials to no more than 25 to 30 sites per trial. And we're also limiting the number of countries that we're going into with and raclidding that also mitigate the risk of receive a response. And finally and importantly, we're also implementing a placebo mitigation protocol that each site

So thank you for raising that.

Thank you for the question, Mike and thank you Ray. Operator will take the next question.

Next question is from Joseph Solm from D.D. Collin. Your line is open. Hi there. Good morning and thank you for taking my question. Maybe one on the the Dirk about epilepsy study. Maybe what are you seeing in terms of recent enrollment trends like gives you confidence in issuing that you know mid-2024 readout guidance and when we look forward to the phase three do anticipate that you'll be able to.

include patients on concomitant excal-free or kind of what were the decision points that would go into that. Thank you.

Yeah, let me just make an introductory comment on that. We monitor all of our clinical trial timelines very, very carefully and get updated regularly by the clinical operations team. So we are clear about our expectations. We thought long and hard about the various permutations.

But I'll let Ray speak to the impact in the momentum that some of our mitigation planning has created, right? Yeah. Thank you, Tony. Yeah. So, to despite the industry headwinds we've seen increased momentum in our epilepsy program, which is extremely encouraging, we're confident that we can deliver that data by mid-year next year. And we've implemented several mitigation approaches to achieve that. Regarding the A3 program, we will be conducting a drug drug interaction trial that'll give us clarity in terms of how we can design that A3 trial to allow for.

the CIF-384 endoosters that are the rate limiting really medicines that are limiting the patient enrollment. We have an approach that in Phase 3 that we're now using, we'll be using the VDI trial to be able to clarify that when we forward. We don't anticipate the same enrollment challenges that we've seen in the proof of concept crop.

Great. Thank you. Next question. Next question is from Michael Yee from Jeffries. Your line is open.

I thank you. Good morning and thanks for the question and thanks Tony on behalf of a lot of us appreciate all the work you've done here. I know we're going to miss you. Thank you Michael. Yeah absolutely. We had a question on a Maraclidine you mentioned in the press release of course as a reminder there's also.

necessary non-clinical and clinical pharmacology studies ongoing. Can you just remind us what those are, the timing of those, and really the question is around assuming very strong data in the first half of 24, you know, how quickly you could get this all together, filed, assuming very strong data.

J.R., why don't you talk about some of the other enabling work that's ongoing and where you may actually just comment as you will on the regulatory approach as we think about bringing all this together. J.R., Sure. Thanks, Dwayne. And thanks for the question, Michael. So, yeah, so what the objective is for all the work that we're doing, as you mentioned, is to minimize the time between data readout and the potential for submitting our NDA. And so, as you're fully aware of much of the work that we have to do is to complete all of the talk studies, preclinical studies, evaluation and modeling of all the clinical pharmacology studies. We have a significant amount of work that we need to do to make sure that we have all of this.

They explore the full dose range and we also will have the safety exposures that are needed per ICH at 300, at 6 months, 100 at one year at least. And so collectively the path forward for schizophrenia, schizophrenia indications clear and meet the FDA criteria. So we're hopeful that if these trials, we're not as we hope they will.

that we will have a comprehensive package to go to the FDA with when the trials re-out. Thank you guys. Next question operator. Next question is from Jessica Fye from JP Morgan. Your line is now open.

Hey guys, good morning. Thanks for taking my question. With the emiracating trials and 10-po-3 now all expected in the first half of 2024, I'm curious which you expected to read out first. Can you remind us should we anticipate the empowered trials reading out concurrently or in sequence? Thank you. Ready you want to take that one? Sure.

So Jessica, what we can say is that the trials will read out in the first half of 2024. We don't have any more specifics at this time. In terms of the readout for empowers 1 and 2, they're enrolling very well and they will come in with a short amount of time within

next question operator.

Thank you. Next question is from Greg Zuvanovich from Mizua Securities. Your line is open. Hi Greg.

Hey Tony, how are you? Thanks so much and I appreciate the time that you spent with many of us and we'll miss you as well. So thanks again and good luck in focusing on the chairperson's role. I did want to pick up on that. I was curious as you go back to just being the chairperson, just quote unquote, are there any.

You know, a cerebell related activities or initiatives that you feel that you'll be able to maybe better prioritize or will be able to spend more time on versus, you know, before in the past when you've had to have dual roles. That's kind of my first question. And then my second question is just more broadly on the MRACLADINE program and the accelerator.

the FDA will in fact accept the data package and they won't, for example, require any additional late-stage studies. I think we've been getting a lot of questions as to what level of confidence you have an investor's thus should have in your Empower 1 and 2 studies being sufficient.

for an approval. Thanks. Thank you, Greg, for the question. Why don't we start with the second question first and I want to comment on one chair. Yeah, so Greg, good morning. So we feel very confident that these two trials, two in power trials meet all the requisites of the FDA.

has historically put forth in terms of the registration potential. Obviously, it's in their purview to request additional data. And we can't speak for the FDA, but we are very confident that in fact the two trials, and all the additional work that's being done, that John described earlier.

are requisites that need to criteria for registration, but again, it'll be data driven and we'll have that discussion with the agency, but we feel confident about the criteria that are being met here.

And as to chair, I think what I'd say is, you know, I think it's really important that when Ron joins as CEO that he have full range and full ability to lead the company to continue to build a company on the strong foundation that the team and I have put into place today, and to really work to continue to unlock and create value for patients and obviously for

values-based leader, I think that partnership will be a really effective partnership both across the board as I lead the board and as I work with Ron and the team to realize everything that we always wanted for the company. So no new projects, my job will be to lead the board in great fashion and that's where I expect to do it. Thank you for the question.

predictable, I would say that you see quite a number of companies entering this space to try to take advantage of new knowledge that's been created in the field. I do think that as a company, we always focus on what we call best in class. And so what that means to us is having highly effective compound as a really beneficial side effect profile for patients. And I think that what you've seen us achieve through our chemistry is importance, selectivity and receptor pharmacology that's delivered in both efficacy and benign side effect profile today. And so I think that, you know, thinking about what it is that the patients, the physicians are seeking, thinking about what we're looking at as far as having a meaningful medicine for patients to treat the symptoms of schizophrenia.

I think we really get the mark. I think that it is going to be, while there's a lot of excitement, it's going to be very difficult for a company to come in and try to usurp us in best in class. I really have a lot of confidence in our molecule. You've seen the side effect profile and the efficacy to date. And so, while I expect a lot of entrance into this area, particularly into Alzheimer's, as you mentioned,

We will have a second act with an M4 agonist. So if we're right about the selectivity of M4 and we believe that we are having both a PAM and an agonist that can be brought through development into patients later, gives us a broad portfolio opportunity to really build a strong franchise in this area and leverage it. So I just make that comment because Jay reminds of

factors that are important for patient adherence. As you know, patient adherence is something that's critical and really lack of adherence leading to recidivism. And now we have a class of therapies that have a benign side effect relative to standard of care currently. So we're delighted to have this best in class approach and really have this franchise upon.

the value of having two of them and not just commercially but also scientifically. Thank you. Okay. Jarel, why don't you take that one? It is, of course, early days on the Info Agonist, but we can speculate a little bit on how this might play out. Go ahead, Jarel. Thanks, Tony. And do things for the question, soon.

From a scientific perspective, so the difference between a compound like a miraclodene, which is a positive elastomeric modulator, and the molecule that we're bringing up behind that, which is the full agonist, is really how long does the drug have an impact on the receptor system that we're targeting, which is in this case the M4.

And as long as the molecule is present in concentrations that are effective, it will be activating the receptor that it's intended to go after. And so what you're thinking about is with a full agonist is treating a condition where you want to really push the mechanism as hard as you can continuously. Could you just give a shot of thatop 2000'sDial seairse media in the haze

by keeping the molecule levels high all the time. So what we've learned about schizophrenia in this case with the PAM approach is that it's really provided something that's been very effective and has been able to actually take advantage of the endogenous activity of the system that's overactive.

in schizophrenia patients and be used to actually correct those symptoms. If you think about the most severe cases where you actually start to think about things like prevention of psychosis or you think about the most difficult to treat types of psychotic breaks, what you're thinking about in that situation is really dampening and preventing what could happen in the occurrence of a psychotic break and really getting the system to a halt.

to actually have a drug that's going to work in a way that doesn't actually have to be there all the time in fully activating a system. Because the downside of a full agonist is when you push a system continuously very hard, you kind of remove the effectiveness of that system because you're overactivating it. But there are cases where treating specific diseases, that would be a beneficial thing. And so, as we've always said, we're thinking about indication expansion.

We're not thinking about a backup position for the agonist. We're not thinking about an insurance for for MRACAD. And this is really about taking the best molecule for the best disease state. And so that we get the best treatment to the right patient group.

And I agree with all of that. I think that's terrific. And as I acknowledged a moment ago, from a commercial business point of view, the opportunity to bring patients both, the M4 and MRAQVITY is obviously a great appeal to us. So stay tuned for more. We are excited about the M4 franchise. Our party will take the next question. Thank you.

in place of healthy population in the phase one. Great, thank you. I think the question has to do with the proof of principle phase 1B study that was done in healthy volunteers, that particular design, and the phase two. So, Greg? So as you know, the proof of principle trial that read out in February of last year was a hypercapnion trial that was in healthy volunteers.

The proof of concept trial that we're going to be conducting this quarter, the phase two trial, will be in patients with panic disorder. We're currently finalizing that design with the FDA, so stay tuned as we reveal what that design will look like in the near future. But that trial is very consistent with what's been done recently or historically I should say.

And it's been about 15 years or so since the last ventilate vaccine was approved in panic disorder. So we want to ensure that the agency agrees with what we're doing and we're working very closely with them. So stay tuned for that design, reveal us.

15 years or so since the last venlafaxine was approved in panic disorder. So we want to ensure that the agency agrees with what we're doing and working very closely with them. So stay tuned for that design reveal soon. Opry will take the next question.

Next question is from Charles Duncan from Cantor Fitzgerald. Your line is open. Hi, this is Elaine Kim on for Charles Duncan. I just wanted to ask how enrollment is going into the open label extension for empower and specifically what color can you provide on treatment compliance for persistence. Thank you. Thank you for the question. Brady want to take those and operator, I think this has to be our last question.

And so we're confident that we can meet the exposures that are needed to ensure that they're not rate limiting to our NDA filing at any point. And the way we're doing that is really by having a high volume of trial sites to ensure that we get the needed exposures. It's a very different population, a very different dynamic.

As I said in my prepared remarks, this has been a remarkable experience and it's been a wonderful way for me to cap my 30-year career in the industry. 15 of those years I was reflecting this morning have been spent as CEO and in that time I have watched a significant amount of evolution in the industry that people have changed, the faces have changed, but the essential mission of what we have to do hasn't.

which is to do the work that we do well and on behalf of patients and in that create value for you as our shareholders and those who really do care about bringing new therapies to to patients. So it's been a great pleasure for me to cap my career in the biotech industry with this particular experience where I believe

We are just at the beginning of making a significant difference in neuroscience. I thank my teammates, I thank the employees, I thank the board of Saraval, and importantly, I thank you guys because I have truly enjoyed all of our interactions and the opportunity to describe and discuss with you all the exciting things that I think we can do to enhance lives and make families and those affected by these diseases.

live a better existence. Thank you. And this does feel a little bit like a news anchor sign off. It really isn't. I just wanted to reflect more openly than I usually do about how you guys have impacted me. So thank you very, very much. And thank you for all the well wishes, the text, the emails. They are deeply, deeply.