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spk05: Good morning. Welcome to the Ceravel Therapeutics fourth quarter and full year 2021 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. I'll now hand the call over to Matt Calistri, Vice President of Corporate Strategy and Investor Relations.
spk10: Thank you. Good morning, everyone. We appreciate you joining us for our fourth quarter and full year 2021 earnings call. 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 Bodenrader, our interim chief financial officer. During our call today, please refer to our press release from this morning, detailing our 2021 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 Dr. Tony Coles, chairperson and CEO of Ceravel, to provide an overview of our achievements and outlook.
spk04: Thanks, Matt, and good morning, everyone. Thank you all for joining us for our fourth quarter and full year 2021 business results call. Ceravel is well on its way to achieving our aspiration of becoming the premier neuroscience company. We've got the pipeline, the people, and the capital we need to transform what's possible in neuroscience. And we have seen that borne out with the two positive trial results we have recently announced in schizophrenia and anxiety. First, in June of last year, we announced positive phase 1B data in schizophrenia for Imraclidine, our M4 selective positive allosteric modulator, or PAM. We're eager to bring this potentially transformative therapy to as many patients as possible, as soon as possible, and are working aggressively and creatively to do so. Earlier this year, we shared the details of our comprehensive phase two program in schizophrenia, which we expect to initiate in the middle of this year. And just two weeks ago, we announced positive anxiety data for DERIGABAT, our selective alpha-235 gabapam. This trial demonstrated, for the first time, Proof of principle in the clinic that a compound that targets alpha-2, 3, 5 selectively and spares alpha-1 can generate anxiolytic activity and minimize the side effects that limit benzodiazepines to only episodic use. Benzodiazepines are widely known to be non-selective gabapams and have a challenging side effect profile, including sedation, withdrawal, and abuse potential. These impressive clinical results support the distinct Cerebell approach to treating neuroscience disease, an approach that is grounded in a deep understanding of neurocircuitry, is focused on targeted receptor subtype selectivity, and which is distinguished through differentiated pharmacology as illustrated on slide eight of our corporate presentation. We've grown our dynamic, innovative, and experienced team of employees, bringing forward these and the rest of our clinical programs We've almost doubled in size from 104 employees at the beginning of 2021 to 200 at the beginning of this year, with the majority, over 70%, working in research and development. Another strength of Cerebellum is our robust financial position, which we bolstered in 2021 through innovative deal-making. In April, we announced a non-dilutive financing deal for Tevapidon that secured funding for our most advanced program through NDA submission. And we raised $250 million to a follow-on offering in July after the announcement of our positive and miraculous data. As a result, we're very well capitalized to fund our operations into 2024. Now, turning to our pipeline, which is slide nine of the presentation, we'd like to highlight the depth and the breadth of the late stage programs in the Cerevel portfolio. With two important readouts already completed, We're rapidly advancing the rest of our pipeline in the hopes of addressing the unmet needs of patients suffering from not only schizophrenia and anxiety, but also epilepsy, Parkinson's, dementia-related apathy, and other neuroscience diseases. Slide 10 highlights the upcoming milestones for our lead programs. In the second half of this year, we're looking forward to Phase 2 proof-of-concept data from our ongoing trial of DERIGABAT in focal epilepsy. In the first half of 2023, we anticipate having data from our ongoing Phase 2A trial of CBL871 and dementia-related apathy. Also, in the first half of 2023, we expect to have Phase 3 tabapadon data in late-stage Parkinson's with early-stage Parkinson's data to follow later in the year. And in the first half of 2024, we expect to have data from our two recently announced Phase 2 trials of imraculidine and schizophrenia. We also have a robust early clinical and discovery pipeline that we are actively advancing, leveraging the state-of-the-art laboratories at our Cambridge Crossing facility. In sum, Cervell is in an enviable position, bringing together a strong pipeline, a talented team, and a robust financial position to advance the treatment of neuroscientific diseases. Now, let me turn the call over to Dr. Ray Sanchez, our Chief Medical Officer, to review the key updates for our lead programs.
spk12: Thank you, Tony, and good morning to all of you. As Tony has outlined, Cerebral truly is poised to transform what is possible in neuroscience. Our pipeline is one of the most exciting I've seen in my career, and it is a great privilege to be part of this organization. The last year in particular has been momentous for us as we had two positive data readouts, which have created a lot of excitement in the physician provider community. Let's first turn to imraculidine, formerly known as CVL231 or M4 positive allosteric modulator. In June of last year, we announced positive phase 1B data in schizophrenia outlined on slide 13. The results of that trial are very impressive. Both doses of imraculidine demonstrated clinically meaningful and statistically significant antipsychotic effects. with no meaningful differences in gastrointestinal side effects, extrapyramidal symptoms, or weight gain compared with placebo. The 30 milligram once daily group demonstrated an absolute improvement versus baseline of 19.5 points, while the 20 milligram twice daily cohort showed an improvement of 17.9 points on the PANS total score. Relative to placebo, both treatment groups had statistically significant reductions of 12.7 and 11.1 points, respectively. We were very encouraged by these robust results, and we are moving rapidly into our next stage of development. This past January, we were pleased to announce the details of our comprehensive Phase II program in schizophrenia, which will begin by the middle of this year. Now, as you can see on slide 14, this program will consist of two adequately powered placebo-controlled Phase II trials running in parallel. Running these two trials in parallel is meant to fully explore the therapeutic dose range of Imracildine while minimizing both the placebo effect and the increased variability that can result from having four or more arms in a single trial. We designed these trials to potentially meet the criteria necessary to serve as pivotal based on what we expect the agency will examine in a registrational package. The data we generate will determine whether these trials are sufficient And ultimately, the final decision on the approvability of the data package will be up to the FDA. As you'll see on slide 14, the first trial will evaluate imraclidine 10 milligrams and 30 milligrams once daily versus placebo. The second trial will evaluate imraclidine 15 milligrams and 30 milligrams once daily versus placebo. Each phase two trial is 90% power to detect a placebo-adjusted change in the PAMS total score of seven points or greater at week six. We expect top-line data from both of these trials in the first half of 2024. In conjunction, we plan to initiate an open-label extension trial, which will accept both rollover and de novo patients in order to begin generating the required safety database to support the NDA filing. Beyond schizophrenia, we also plan to evaluate this mechanism and other indications and populations, including dementia-related psychosis. Now, moving on to DERIGABAT. Two weeks ago, we announced positive top-line data from our Phase I Healthy Volunteer Trial in Acute Anxiety, another great proof point for Cerebel's differentiated approach to neuroscience. I was thrilled by these results and believe they represent strong evidence of DERIGABAT's potential as a differentiated therapy that might be a daily maintenance treatment for anxiety-related disorders in contrast to benzodiazepines. As Tony mentioned, benzodiazepines are non-selective GABA PAMs and are limited to episodic use due to their tolerability issues. This data readout supports our thesis that DERIGABAT may optimize anxiolytic effect by selectively targeting the alpha-2, 3, and 5 subunits of the GABA-A receptor while minimizing the alpha-1 associated tolerability concerns. We were very encouraged to see clinically meaningful and statistically significant anxiolytic effects after eight days of treatment for both doses of DERIGABAT tested. We were also pleased to see that DERIGABAT was generally well-tolerated with no serious adverse events, no treatment-related discontinuations, and no incidents of withdrawal symptoms in the DERIGABAT treatment groups. Now, a couple of points I would like to highlight about the trial design before I discuss the specific results. This trial was optimized to show in healthy volunteers an anxiolytic effect over a relatively short duration of treatment, approximately one week, and alprazolam was used solely to ensure sensitivity of the hypercapia model, which occurred. Second, we utilized a very quick four-day titration regimen for both doses, as again, the purpose of this particular trial design was to detect an anxiolytic effect rather than elucidate the safety and tolerability profiles. With that in mind, I would like to turn your attention to slide 20 of the corporate presentation. As you can see here, the DERIGAVAT 7.5 milligram and 25 milligram twice daily doses demonstrated statistically significant improvements of 3.9 and 4.5 points on a placebo-adjusted basis, with p-values of 0.036 and 0.008, respectively. We stated previously that a two- to three-point placebo-adjusted improvement in the panic symptoms list, or PSL4 total score, would be considered a clinically meaningful reduction in anxiety symptoms. So the robustness of our results are quite impressive and clearly exceeded expectations. The clinical effect seen with alprazolam of 1.6 points was within the range of expectations for this model, and again confirmed the validity of the model for detecting angiolytic activity. Although this was a trial in healthy volunteers and not patients, we were quite pleased by the tolerability profile we observed in this study. Both doses of Derigavac demonstrated anxiolytic effect, and 97% of adverse events reported were considered mild. The incidence and temporal pattern of these AEs appear to be related to the dose and speed of titration. So in future trials, a longer titration period may help us better understand the actual adverse event profile we might expect to see in the relevant patient populations. Later in the presentation, Dr. John Renga will provide some details on what we learned about the relationship between drug exposures and anxiolytic activity from the trial, and we look forward to presenting additional details on this trial at future scientific conferences. As a reminder, In the second half of this year, we expect the results from our Phase II proof-of-concept trial in focal epilepsy. We're also conducting a corresponding open-label extension trial, which continues to have a very high rollover rate. Turning next to Tabapadon are D15 partial agonists, which we are developing for Parkinson's disease symptoms as both a monotherapy and adjunctive treatment. We continue to dose in all three of our phase three trials, known collectively as the TEMPO trials, and all remain on track with our expected timelines. We expect data from TEMPO 3, the adjunctive trial in late-stage Parkinson's, to read out in the first half of 2023, and data from TEMPOS 1 and 2 in early-stage Parkinson's to read out in the second half of 2023. Turning to CVL871, another D1, D5 partial agonist. which we are currently evaluating in a phase 2A exploratory trial in dementia-related apathy. We expect data in the first half of 2023. In June of last year, we received fast-track designation for CVL871 in this indication, which enables early and more frequent interactions with the FDA as well as the potential for rolling NDA submission and priority review. We are looking forward to interacting closely with the agency in determining the best path forward for developing a treatment in this novel indication. Before I hand the call over to Dr. Renger, I wanted to address the war in Ukraine and any questions you may have on the impact to our trials. Our thoughts are first and foremost with the investigators and patients at clinical trial sites and indeed with all the people of Ukraine. Specifically for Saravel, we do not believe our clinical trial timelines are impacted at this time, but we are acutely aware that this is a grave humanitarian crisis in an important country for clinical research and development. Among our ongoing trials for Tavapidon, we have a small number of clinical trials for the Phase III TEMPO program, less than 10% of all sites that are located in Ukraine. We are proud of the meticulous approach we take to trial execution. And in fact, we began planning for geopolitical uncertainties and potential disruptions in the region a while ago. For example, in January, we started taking mitigation measures as a contingency, including pre-shipment of additional clinical drug product and supplies to the country. As we have in the past with the COVID-19 pandemic, and as with any rapidly evolving crisis, we are constantly evaluating clinical operations across our portfolio to ensure we continue to meet our goals with respect to data integrity, enrollment quality, and trial timelines. I'd now like to turn the call over to Dr. John Renger, our Chief Scientific Officer, to speak about our early stage portfolio. John?
spk03: Thank you, Ray. Good morning, everyone. First, I really do want to emphasize that the recent data from our acute hypercapnia panic trial on healthy volunteers represents an important scientific and medical breakthrough for scientists, clinicians, and especially patients who are desperately seeking new mechanisms for the treatment of anxiety-related disorders. These data are the first clinical validation in humans to demonstrate that robust anxiolytic benefit can be achieved by selectively targeting the alpha-2, 3, and 5 subunits, while at the same time sparing the alpha-1 subunit containing GABA receptors. In this particular clinical trial, we evaluated a broad range of drug exposures in the concurrent receptor occupancies to best inform future dose selection and for confirming the necessary drug levels required to reduce antialytic symptoms. As context, our preclinical studies have previously shown the receptor occupancies of at least 50 to 60% were sufficient to demonstrate anxiolytic activity with DERGOVAT. In this healthy volunteer trial, The 7.5 milligram twice-daily dose achieved 50% receptor occupancy at the alpha-2 subunits of the GABA-A receptor, while the 25 milligram twice-daily dose achieved approximately 76% alpha-2 receptor occupancy. Importantly, as a reminder, this is relative to less than an estimated 15% or lower alpha-2 receptor occupancy achieved with alprazolam at the 1 milligram twice-daily dose. a dosage level that is on the low end of what is typically prescribed as the starting treatment for the reduction of anxiety symptoms in patients in the clinical practice setting. Our goal of this study was to push the upper bounds of receptor occupancy selectively at the alpha-2, 3, and 5 subunits in order to more fully investigate the maximal level of drug activity to retaining high levels of alpha-2, 3, 5 receptor occupancy well beyond what is achievable with non-selective benzodiazepines, which are dose-limited to the side effects of sedation, motor discoordination or ataxia, and cognitive impairment, such as amnesia. The extended range of high receptor occupancies achieved in this trial were multiple folds higher than the 15 to 20% that's normally achieved for the non-selective benzodiazepines at clinically used dosages. Our data give us great confidence in sparing the GABA alpha-1 receptor and selectively targeting the GABA-alpha 2, 3, and 5 receptors at these occupancy levels may provide anxiolytic benefit while avoiding the issues that underlie dose limitations associated with benzodiazepines. From this data, we also have gained important insights into the exposures needed to be achieved for exploring beneficial effects, and the culmination of this information will enable our teams as we consider future options for alternate dosage formulations. We're eager to keep you updated as we pursue the development of DERIGABAT as a potential daily dose therapy for the treatment of anxiety disorders, giving patients who are counting on Cerevel the potential for new options for maintenance therapy. Within our early pipeline, I'd first like to highlight CVL354, our highly selective kappa opioid receptor antagonist, as a potential therapy for the treatment of both major depressive disorder and substance use disorder. The FDA recently accepted our IND for this program, and we are currently conducting phase one, single, and multiple ascending dose trials in healthy volunteers. We're very excited about the potential for this program to be differentiated in multiple areas of high unmet patient need, particularly due to recent clinical validation by others in a phase two depression study and an extensive amount of our internal preclinical work that supports the potential for this mechanism of action. We are also well positioned as the scientific leader in identifying and progressing a host of selective M4 muscarinic receptor-directed compounds with a range of pharmacological profiles, complementing our promising M4 PAM and miraclidine. Our teams of scientists are actively evaluating additional highly potent muscarinic M4 receptor-selective full agonists and allosteric modulators to potentially advance into the clinical setting to expand upon our lead molecule, imraclidine. These additional molecules are expected to expand the clinical utility that we've already demonstrated with imraclidine in multiple additional psychosis-related therapeutic indications, potentially further increasing our lead in the targeted M4 muscarinic receptor therapeutic area space. As you can see, 2021 has been an extraordinarily productive year for CeraVal, We are looking forward to many exciting updates in 2022 and beyond. I'd now like to turn it over to Mark Bodenrader, our Interim Chief Financial Officer, to review the specifics of our financial performance and our outlook for this year. Mark?
spk11: Thank you, John. I'm pleased to provide an overview of Saraville's strong financial position, which was bolstered by our capital raises in 2021. I'll start by discussing our 2021 financial results, and then I'll spend a few moments on our cash position expected runway. Full year 2021 total operating expenses were approximately $220 million, which includes R&D expense of $162 million and G&A expense of $58 million. R&D expense for 2021 increased by approximately $59 million over 2020, primarily due to the continued advancement of our later stage clinical programs, increased investment in our early discovery efforts, and an increase in personnel and other infrastructure costs to support the continued growth of our pipeline. R&D expense for 2021 also included $9.2 million of equity-based compensation expense versus $3.2 million last year. G&A expense for 2021 increased by approximately $12 million over last year, primarily due to a full year of public company operating costs and higher personnel and other costs to support organizational growth. G&A expense for 2021 also included $14.7 million of equity-based compensation expense relative to $7.3 million for 2020. As of December 31st, 2021, our cash and marketable securities totaled $618 million compared to $384 million as of December 31st, 2020. Our cash position was bolstered by the $350 million follow-on offering completed in July shortly after the announcement of the positive Phase 1b data for Imraclidine and Schizophrenia. In addition, we received approximately $55 million in the third quarter from the redemption and exercise of our public warrants, and in April we received the first funding payment under our Tevapidon financing agreements of $31 million, and we anticipate receiving an additional $37.5 million under these agreements in the second quarter this year. Looking forward, We expect R&D expense to continue to increase this year as we initiate our comprehensive phase two program for Imraclidine, continue to advance our phase three program for Tavapadon, and continue to invest into Rigabat, CVL871, and our early discovery efforts. In addition, we expect R&D personnel costs to continue to grow this year to support the advancement of our pipeline. We also expect G&A expenses to increase as we support the continued growth of our research and development efforts and initiate pre-commercialization activities. In closing, we remain well capitalized. We expect our cash resources to fund our operations into 2024. We look forward to multiple value creating data readouts over the next couple of years. And finally, we continue to think creatively and opportunistically about further strengthening our balance sheet to support our extensive pipeline. I would now like to hand the call back to Tony for concluding remarks.
spk04: Thanks, Mark. At Cerevo, we continue to advance our mission to improve the lives of people living with neuroscience diseases. We've reported two successful data readouts in less than a year, continue to make progress and rest of our extensive pipeline of both clinical and preclinical programs, and we've secured the people and the capital we need to continue our journey to become the premier neuroscience company. Our programs are focused on addressing high unmet needs for millions of patients with neuroscience diseases, including schizophrenia, anxiety, epilepsy, Parkinson's, dementia-related apathy, and now depression. At Cerebell, we're leveraging our unique expertise in neurocircuitry to advance our deep portfolio and ultimately to bring new medications to the patients who need them. Before I conclude, I'd like to, as I always do, thank our employees who are so committed to making a positive impact on patients' lives and live that mission every day. To the physicians, caregivers, and participants in our clinical development programs, we say thank you. And I also want to thank you, our investors, for your support and belief in our mission. And I can tell you that we truly couldn't do this without you. With that, Sarah, let's now open the call for questions.
spk05: Thank you. We'll now begin the question and answer session. As a reminder, if you would like to ask a question, please press star 1 on your keypad and wait for your name to be announced. And to cancel that request, you can press the hash key. So star and 1 for questions. Your first question today is from the line of Michael Yee from Jefferies. Please go ahead.
spk08: Hey, good morning, Tony and team. Thank you. We had a question on Darigabat. Appreciating the recent exciting data I think you've presented in anxiety, I know there's a little bit of debate there, but I think we all agree there was proof of concept and proof of biology. We were wondering how you have thought about that data now that it's out there and how you think about the translation to the epilepsy study later this year, both on an efficacy scenario standpoint and a safety tolerability standpoint, what you think the bar is for efficacy and how to think about those scenarios. Thank you so much.
spk04: Okay, thanks, Michael, and good morning. The first point I'd like to make is we are really excited, as Ray said in his prepared remarks, by these results because they demonstrate that it is possible to achieve the efficacy that we see with benzodiazepines, the non-selective GABAs, without any Alpha-1 activation. So that's a really important demonstration of the power of this particular mechanism and it's being alpha-1 sparing. And now we've seen this clinically for both epilepsy in our earlier studies and anxiety. The other thing I'd like to do is highlight this, is further validation of this selectivity that I've just spoken about. And it complements all the work that we're doing, both in healthy volunteers, which was this study, and in patients. I don't think I'd specifically read through either safety tolerability or efficacy findings from the anxiety trial. There are some important differences. I'll ask perhaps Ray to comment or JR to comment in just a moment. There are some really important differences in healthy volunteers as distinct from patients. And we've discussed this previously because obviously healthy volunteers, this particular trial for healthy volunteers was drugged shorter duration and had a much more rapid titration than we would expect to be in either common practice or in clinical trial in patients with anxiety. So I think in some, Mike, we really are excited about the mechanism, its potential across multiple disease opportunities, and what this could mean, and we'll know soon about epilepsy. But, JR, let me turn it over to you for any additional detail.
spk08: Specifically on the bar, how you're thinking about the bar there for efficacy and whether we should just compare to other data sets out there.
spk04: Mike, I'm sorry, you broke up on my end. Would you just repeat the second half of your question?
spk08: Yes, specifically on how you think about the bar for efficacy, assuming it could be positive, what magnitude and what reduction of seizures would you like to see, and should we just compare that to other data sets out there for other drugs?
spk04: You mean for epilepsy specifically?
spk08: Yes, yes.
spk04: Yeah, okay, okay. So, JR, why don't you provide some additional detail, and we'll have Ray answer that part of the question separately. JR?
spk03: Sure. Thank you, Tony. Yeah, so, Mike, I think, you know, you're referencing the data and how we interpret it. You know, I can speak to that, and then Ray can speak to the clinical meaningful difference for the treatment in epilepsy and how we designed that trial and powered it. I just want to reemphasize that this is really the very first time that a selective compound has demonstrated the ability to achieve a resolution of panic symptoms. And even though this is a healthy trial, we think that it has a very strong read-through to the potential for demonstrating efficacy in anxiety-related disorders. Of note, the receptor occupancies that we targeted in this study were very similar, identical, in fact, to the ones that are being used in the epilepsy trial. So what we know is that the dosages that we've used have, again, demonstrated efficacy in the dose ranges that are also being used in the epilepsy trial. So as you know, in the photoepilepsy study, we've shown efficacy in treating epilepsy previously. In this one, this is a second indication now looking at different neural pathways in the brain that underlie the feeling of panic that patients can have. We've also demonstrated with the same dosage range efficacy in treating those symptoms in this healthy study. So What this indicates to us is that we understand the effective dose range and we believe that, you know, in either population that we're actually covering the important receptor occupancy range that we want to cover to demonstrate CNS activity. So I'll let Ray speak actually to the design of the epilepsy trial and what we've empowered to see there. Ray?
spk12: Thank you, John. Good morning. Good morning, Michael. Thank you for the question. So as you know that the ongoing epilepsy trial is 80% power to show a reduction of 31% in seizure frequency. To give you some juxtaposition in terms of the other therapies in the landscape, Keppra is about 28% is what they demonstrated. We're hoping to show at least 31%, if not higher, given the selectivity of the mechanism, but also the data that's been generated to date in the proof of principle photosensitivity trial. We'll stay tuned for that data later this year, but we're encouraged by what we've seen in anxiety and what we've seen in epilepsy to date and hoping that we can see the benefits of this therapy in the epilepsy population as well.
spk08: Thank you very much.
spk04: Good. Thank you, Ray. Michael, thank you for the question. Sarah, we'll take the next question, please.
spk05: Thank you. The next question is from the line of Matthew Harrison from Morgan Stanley. Please go ahead.
spk07: Great. Good morning. Thanks for taking the questions. I have two. So first on schizophrenia, can you just comment on the trials and the potential to pool those? So for example, could you have the 30-meg dose in two trials? Would you be able to pool them if the effect size was smaller than the seven-point delta that you were assuming? And then second, just on to Vapidon, can you remind us how you're imputing for missing data there and sort of what percentage of dropouts you were expecting in the original staff plan. Thanks.
spk04: Okay. Ray, why don't you, if you would, take both of those. But I'd really appreciate you perhaps underscoring that part of your prepared comments about how we design these trials and what we think that they can do in terms of answering the essential registrational questions. We all know that the agency is going to be looking for a full characterization of the dose range for Imraclidine. They'll want long-term safety. And there are, of course, two adequately powered placebo-controlled trials. So we think we've got the right, we're asking the right questions for the FDA to evaluate what we know they'll be looking for in registration. But Ray, why don't you just expand on that and speak to the specific question about the possibility of pooling data for the effect size, and then take the tab question.
spk12: Right, right. So good morning, Matthew. So as you know, as Tony has mentioned, and I've said I think before as well, that these two trials were designed to potentially be pivotal in nature, really looking at the full dose range of the top dose of 30 milligrams and the minimum effective dose of 10 or 15 milligrams. In order for them to be registrational in nature, they each have to – separate from placebo, as you know. So the opportunity to actually combine the data is probably not the approach that the agency will likely accept. They've not done that historically in very few cases, but with very different populations and different trial designs. So we'll stay tuned to present the data that we generate. to the FDA at our end of Phase II meeting to see the viability of the program in terms of its registrational potential. But the plan is not to pool that data moving forward in order for them to be registrational in their potential. The second question you asked about Tavapidon and in terms of imputation of data, we're using a mixed model of repeated measures, the MMRM approach, as you know. We anticipate when we design the trials approximately a 27% discontinuation rate. We'll obviously see how that fares versus what, you know, what the trial actually produces once it reads out. But that's our assumption going into it based on historical trials and precedent from other trials in Parkinson's disease.
spk04: Okay. Very good. Thank you, Ray. Sarah, we're ready for the next question.
spk05: Thank you. The next question is from the line of Paul Matisse from Stiefel. Please go ahead.
spk01: Great. Thanks so much. I had two questions on the M4 program. One, on the cardiac safety study that you're doing, can you just maybe talk a little bit more about why you decided to do this study and why And I guess maybe just sort of set it up. What are you hoping to sort of describe? And, you know, do you view the cardiac changes that you see, changes in blood pressure, changes in heart rate, as things that are, you know, likely maybe more labeling or monitoring issues? Or how should we sort of be thinking about this? And then just separately, I was wondering if you could talk about any plans you have to go into the elderly with things like Alzheimer's psychosis. Thanks.
spk04: Okay. Let me just, I'm going to ask Rita to take the question, but let me just make a couple of quick comments, Paul. I appreciate the question, but this ambulatory blood pressure monitoring study isn't really a cardiac safety study that would be designed very, very differently. This is to look at the more narrow questions specifically of heart rate pressure. As we showed in the phase 1B, we did not have AEs associated out of proportion to placebo. And what we did observe is, as you certainly know, tolerated over time. So I just don't want the notion that this cardiac safety study, we're answering a pretty specific and narrow question that, you know, the agency will ask about blood pressure and heart rate. So I want to make that distinction. But, Ray, why don't you add to my comments in any way you like?
spk12: Yes. Yes. Thank you, Tony. Good morning, Paul. So, Paul, as you know, and I think Tony mentioned here that, you know, we were very encouraged at the end of our six-week trial, the Phase 1B trial for imbraclidine, where we saw negligible increases in really heart rate and blood pressure versus placebos. But really what's of interest to the agency is really the sustained effects in blood pressure, not so much heart rate. And that's why we're conducting the ambulatory blood pressure monitoring trial as outlined in a guidance that was developed in 2018. But really to understand, is there a sustained increase or a sustained effect in systolic blood pressure? And that's what the ABPM trial does. In fact, it's an eight-week trial, as you know, and it's 90% powered to rule out a greater than three millimeter of mercury effect that is sustained in systolic blood pressure over the baseline. So patients get recorded at baseline, they get recorded at week eight, at 24-hour monitoring, and then the blood pressure sustained effects are evaluated, and of course it's powered, as I mentioned, to rule out greater than three millimeters of mercury. So That's what we're trying to understand and better elucidate, but based on the phase one B results at six weeks and the study being at eight weeks, we don't have any concerns, but again, it's something that we have to do in order to characterize the effect per the FDA and per guidance as well.
spk04: Yeah, the only point I'll underscore there, Ray, is that the FDA only recently instituted this guidance, say the last two or three years, for ambulatory blood pressure monitoring studies. So this is part of the registration package that any company in our situation would have to do. I know, Paul, you asked a question about dementia-related psychosis. I think, J.R., if you would take the first part of that, because there's a clear mechanistic rationale that we should go through, and then A.C., our president who has responsibility for commercial is, is, uh, available to answer questions. Abe, why don't you take the second half of that?
spk03: Sure. Thank you, Tony. And good morning, Paul. Thanks for the question. So, um, yeah, so absolutely. So we, we completely and fully appreciate that, uh, there's a, you know, potential for the inform mechanism, uh, to work in dementia related psychosis. As you, as you well know, one of the first studies that, um, was actually completed with zanomaline, was actually done in an AD population, and showed a benefit in treating the psychotic symptoms in an AD population. As you know, the interpretation of that study was somewhat confounded, however, because of the high dropout rate, because of the tolerability issues. And so we do believe that the dose-responsive effect that they saw there really demonstrated that the muscarinic approach, which we've refined with our in-force selectivity with imrancladine, is an appropriate and very promising and potentially validated way to approach that indication, and so we're absolutely aware of that and focused on that. But what I want to emphasize is that we like to proceed very thoughtfully and carefully here because what we want to do is fully understand the dose range that we want to take forward in that population, but we also have to establish the tolerability and safety profile of the compound. we have to think about the most efficient approach and the best approach to demonstrate in an elderly population the appropriate dose range, the safety tolerability profile, and then really go after replicating what we believe is the clinically validated approach of using the muscarinic pathway as a way to treat psychotic symptoms there. So absolutely in line with what your question is getting to, and we're actively pursuing that. Abe, I don't know if you would like to take over the second part.
spk04: Actually, JR, I've just been informed that Abe doesn't have a speaker line this morning, so let me take the second half of it. I think we all see the great potential and the potential benefit that we can bring to elderly patients with the miraclidine. I think JR has made the point about ensuring that we have good handle on both the dose range and the safety profile in the elderly population. which is work that will be ongoing. And this is 50 million people who suffer from dementia globally with 10 million new cases every year, and it's quite debilitating. So this is of the utmost urgency for us to figure a path forward and to do that as we sort through the schizophrenia requirements for registration. So it's very important to us, and we will figure this out. Sarah, we'll take it.
spk05: Thank you. The next question is from the line of Douglas Sell from H.C. Wainwright. Please go ahead.
spk09: Hi. Good morning. Thanks for taking the question. So first on miraculity, and I was just curious, I think in the 1B study, the patient population was enriched for certain types of schizophrenia or certain symptoms. I was just curious if you're going to be enriching the population for the phase 2 studies. And then I guess my second question is from a big picture standpoint, how are you prioritizing or thinking about prioritizing assets in terms of, you know, sort of advancing new drugs versus expanding the ones that you have which have broad utility into new indications? And then also maybe sort of related follow-up, you know, advancing individual assets into new indications versus potentially tuning them further, which you've shown an ability to do, to achieve greater effect or specific effect for certain indications. Thank you.
spk04: Very great, Doug. Thank you for the question. Ray, if you could take the American question about population enrichment, and I'll answer it in a second.
spk12: Thank you, Tony. Good morning. So in the Phase 1b trial, we didn't enrich the population per se, but what we did do is make sure that the patient, like we do with all our trials, that the patient profile was was actually the one that could be sensitive to detect drug signal. And we did that by making sure that we had a population that was a bit more severe, so the severity played a role. And then we did that also by breaking it down in terms of the positive symptoms, that they actually met a certain threshold in terms of individual positive symptoms on the PANS score, subscale scores. So not enrichment per se, but I would say refining the patient population is something that's critical across all trials regardless of population, but that's what our approach was in the 1B, and our approach will also be in the Phase II program as well.
spk04: And then, Doug, I think the second half of your question, which is a really important one about asset prioritization, Let me just make a couple of contextual points. First of all, we've built an internal capability to analyze the portfolio, to assess different opportunities, to try to figure out where to place our next annual dollar, and to do the kind of trade-offs that companies that have a portfolio like ours need to do. So that function is very much alive and well and really guiding the strategic decision-making for the organization. I'll also comment that we're in a strong cash position and are clearly well capitalized. You heard Mark's report on our year-ending cash balance. And the current operating plans we have really are driven by following the science. And that is what I'd say. You know, when we took over these particular programs at the formation of CERVO from Pfizer, we realized that there were some new opportunities. Anxiety is a great example. That had not been fully exploited previously. So I think not only our track record of designing the trials and really trying to pay very careful attention to what the science is telling us is really how we'll think about this. To the extent that there are multiple indication opportunities for the same asset, we'll pursue those if that makes sense. But we also know that given the richness of the portfolio and the pipeline that we have, and we have an extensive, for instance, Muscarinic program with a number of M4 agents, or Agnes and Alistair. We've got additional opportunities to really build and deepen a franchise, and we'll be thinking about that as we prioritize both. I love the fact that we're well-capitalized. I love the fact that we've got a really strong and well-integrated portfolio analytic approach to how we invest the dollars. And importantly, we will just follow the science and really do so on behalf of the benefit of patients. Great. Thank you. Yep. Thank you. Okay, operator, we'll take the next question.
spk05: Thank you. The next question is from the line of Madhu Kumar from Goldman Sachs. Please go ahead.
spk02: Hi, this is Omari from Madhu. Good morning. Thanks for taking our questions. So first, how do you think about the efficacy and tolerability in initial pivotal studies in schizophrenia compared to long-term OLE studies in terms of product profile?
spk04: Okay. And did you have more than one question? Because we'll take both together, please.
spk02: Sure. And then the second question is, can you swap us through the expectations for a duragabat in realizing epilepsy?
spk04: Okay. Sure. You know, I think on the, I just want to make sure I answer the first question. I think you're asking about what we see as the potential differentiation for imraculidine versus currently available therapies or other agents to So I'll ask Ray to talk through both what we believe mechanistically and also about the potential efficacy tolerability profile, which is what I think the thrust of your question was. So, Ray, if you would take that one, that would be terrific. And then we'll come back around to the Derigabat question just to clarify and make sure we're answering it.
spk12: Sure. So thank you for the question. You know, as you know, that there's a great need in the schizophrenia population for novel therapies. other than the D2 antagonists or partial agonists that don't have the side effect profile that can be quite malignant for patients with schizophrenia. And so we have an agent here that actually has shown a very favorable tolerability profile in our Phase 1B trial to date, but with also very robust PANS total score reductions of close to 20 points, And so that's something that very excites us because it gives us the opportunity to provide a therapy that not only has an efficacy profile that is very exciting and encouraging, but also safety tolerability profile that is relatively benign compared with what's available on the landscape. In terms of your question of acute versus long-term, we are doing, as you know, starting the acute trials later this year. And, you know, we powered them accordingly to show at least a seven-point placebo-adjusted difference. And that's really based on the landscape and what's been shown historically. But we hopefully expect to see a more robust outcome. In terms of the long-term effects, that would be something that the agency would most likely require for us to show in a phase four commitment to understand the longer-term maintenance treatment effect. But it's not something that we will be including in the immediate NDA package. It will be a subsequent approach. The open label extension, as you know, and I think you mentioned that, is really more to collect longer-term safety and tolerability data as required by the agency at six months and one year. But it's very difficult to really ascertain any efficacy longer-term from an open label extension, as you know, So that's our approach, and we're excited about the potential for this therapy and how it will be transformative to the landscape.
spk04: And, Ray, thank you, Ray. And then I think that the second half of Omari's question really had to do with what we might consider success from the DERIGABAT epilepsy phase 2 study. Obviously, Omari, we're hoping to extend what we saw in the phase 2A in the photosensitivity epilepsy study. But, Ray, I think if you don't mind, just touch on the 31% difference in how we powered the study, please.
spk12: Right. So the trial was powered 80% to detect the 31%. seizure reduction. We're hoping that with what the data that we've been seeing today in the photoepilepsy trial that it suggests that it actually could be even more robust. I mentioned in an earlier question that you see about a 28% seizure reduction with Keppra. As you know, it's used quite often. And so we're hopeful that we can see even greater benefit than what we powered for, but Obviously, later this year, we'll have more clarity in terms of how DERIGAVAT performs in the focal epilepsy population.
spk04: Thank you, Ray. Thank you, Omari, for the question. Operator, I think we've got time for just one more question.
spk05: Thank you. The last question is from the line of Corey Kazimov from J.P. Morgan. Please go ahead.
spk06: Hi, guys. Thanks for the question. This is Tiffany on for Corey. Just one that we get a lot of investors' questions on. How might you be thinking about Corona Phase 3 data readout mid-year? So, obviously, it's a similar MLA, and it could potentially provide some positive readthrough to Miraclidine if it's active, but just any initial thoughts or feedbacks on market research there? And then a follow-up to that, just thinking about the required safety database and OLE, is this anticipated to be the gating factor for filing? Thanks.
spk04: Okay. I think on the Karuna question, I'd make a couple of really quick comments. Obviously, we're focused on what is our most important next clinical data milestone, which is the Derigabed Epilepsy Program, and that's certainly going to be an important catalyst for the company. Clearly, we're rooting for Karuna's success and certainly support innovation in the antipsychotic space where there's, as we've said a couple of times, really great unmet needs, We know there's plenty of room for multiple players in the market, but we have a deep belief that the Musk Winning Pathway has a lot of potential as an exciting new mechanism. Having said all of that, there are some important features that make our M4 selective approach particularly interesting, including the reduced GI side effects, the once daily administration, and the no need for titration. And those are features that we hope to both confirm and leverage. as we do move to the phase two program. So clearly for patients, it would be wonderful if we can document success anywhere and add new therapies, but we've got strong reason to believe that we've got a differentiating profile with Imraciline, and that's where we're focused at the moment. The second question about the OLA, Ray, do you mind just taking that one and what we're looking for there?
spk12: Sure. So you are correct. The open-label extension is needed for registration. We have to have three patients exposed at six months at least and at least 100 patients at one year. Our approach is always to exceed those numbers, of course, per FDA. And we're going to be using an approach where we not only have the patients roll over from the pivotal trials, but we're also adding additional sites for de novo exposures And so that will get us the exposures we need by the time we file the NDA. So in terms of rate limiting, that's something that, of course, we've always thought about. So it doesn't become the critical path, the open label extension. And I hope it is that it will not be. And so that we will have all the data that will be necessary if indeed the both phase two trials are positive and we're expecting our other preclinical and other CMC work and so forth to try to get this medicine to patients sooner than later, but we'll have to wait and see how that all transpires once the data reads out.
spk04: Thank you. Thank you, Ray, and Tiffany, thank you for that question. I think that's going to wrap it for us. Thank you guys for joining us. We're off to a really strong start on the year with the great anxiety data that we've talked about. We'll close the year with in the second half with the epilepsy data. So a lot of really important value drivers both coming up this year and in subsequent years. The balance sheet is strong. The team is strong. So I think we've got all the right elements to continue to deliver great results, and we appreciate you guys in the conversation this morning. I think we've given a good perspective about how confident we are about our ability to change the landscape. So thank you guys for joining, and have a good day.
spk05: Thank you. That does conclude the conference for today. Thank you for participating and you may now disconnect.
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