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spk02: Good morning and welcome to the Ceravel Therapeutics Third Quarter 2022 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 will now hand the call over to Matt Calistri, Vice President of Investor Relations. Please go ahead.
spk08: Thank you. Thank you. Good morning, everyone. We appreciate you joining us for our third quarter 2022 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. Dave Cisse, our President, will join us for Q&A. During our call today, please refer to our press release from this morning detailing our Q3 2022 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 achievement and outlook.
spk07: Thanks, Matt, and good morning, everyone. Thanks for joining us for our third quarter 2022 business results call. At Ceravel, we know our aspiration is to become the premier neuroscience company. Our recent financing of $599 million puts us in a strong position, and now with more than a billion dollars of capital on our balance sheet to fuel our pipelines. Here at Ceravel, we innovate across all aspects of our business, from drug development to clinical trials to capital formation, and our strategic and creative approach to financing following positive data from a peer is a prime example of this approach. We have more than doubled our financial resources, which we expect will fund our operations into 2025. We have multiple mid- to late-stage clinical trials across four therapeutic areas, along with several planned proof-of-concept and early-stage discovery programs. By advancing a broad neuroscience portfolio that we believe is unmatched among our peers, we seek to deliver potentially transformative medicines to the millions of people living with schizophrenia, Parkinson's disease, epilepsy, dementia-related apathy, panic disorder, and Alzheimer's disease psychosis. We have confidence in our deliberate and differentiated approach to treating neuroscience diseases through which we focus on three core elements. First, targeted neurocircuitry, which is developing a deep understanding of how the brain is wired. Second, receptor subtype selectivity, which enables us to narrowly target our therapeutic interventions. And third, differentiated pharmacology, which enables us to precisely design potential therapies for the diseases we're focused on. And our progress continues. In June, we initiated our robust phase two program for imbraclidine, our novel muscarinic M4 selective positive allosteric modulator, or PAM in adults living with schizophrenia. We're all aware that the patient need in this area is tremendous. More than two million people in the US live with schizophrenia, a disease that dramatically affects families, loved ones, and entire communities. At Cerevel, we are committed to advancing our Imraclidine program on an accelerated basis to bring this potentially transformative therapy to as many individuals as possible as soon as possible. And we believe Imraclidine has tremendous potential beyond schizophrenia. By the end of this year, we plan to initiate a phase one safety, tolerability, and pharmacokinetic trial in healthy elderly volunteers to support future development of imraculidine in Alzheimer's disease psychosis, or ADP. The behavioral and psychological symptoms of Alzheimer's, such as delusions, hallucinations, and paranoia, exert an enormous toll on patients, their loved ones, and the cost of care. I'm very pleased to share that in recognition of the significant unmet need in this particular syndrome, we recently received fast-track designation from the FDA for Imraclidine for the treatment of hallucinations and delusions associated with Alzheimer's disease psychosis. We're eager to explore Imraclidine's potential in this and other conditions. Our work with Imraclidine in schizophrenia and ADP is, however, only one part of the Cerebral story. Across our pipeline, we are bringing forward therapies for other serious neurological conditions by targeting new pathways with novel approaches. DERIGABAT, our selective alpha-235 GABA-PAM, is another Serovel program with multiple potential indications. The first of these is epilepsy, the fourth most common neurological disorder. As we recognize Epilepsy Awareness Month in November, we reflect on the fact that 1 in 10 people will have a seizure in their lifetime, and 1 in 26 will develop epilepsy. We're studying dirigibat and focal epilepsy through our Phase II REALIZE trial, which is on track to read out in mid-2023. And earlier this year, we announced positive acute anxiety data for dirigibat, The DERIGABAT trial demonstrated for the first time proof of principle in the clinic that a compound targeting alpha-2, 3, 5, and sparing alpha-1 can generate anxiolytic activity and at the same time may be able to minimize the side effects that limit benzodiazepines to only episodic use. We've selected panic disorder. as an additional indication for Darigabath, as panic is the second most common anxiety disorder and can be the most debilitating. We expect to initiate a phase two proof of concept trial in 2023. Let me turn now to our most advanced program, Tavapidon, the first D1, D5 partial agonist in development for the treatment of Parkinson's disease. We believe our registration directed Phase III program has the potential to establish Tabapadon as the cornerstone of therapy across the spectrum of Parkinson's disease, the preferred monotherapy choice for the newly diagnosed patient, and the ideal adjunctive therapy to leave Adelpa as the disease progresses. Although certain of our data readout timelines in this program are under review, All three of our phase three trials in early and late stage Parkinson's disease are ongoing, along with the corresponding open label extension. So, as you can see, CeraVel is advancing with clear purpose, and our late stage pipeline has the potential to deliver important medicines to individuals living with neuroscience diseases who need and deserve new treatment options. We believe CeraVel's future is bright, driven by the strength of our pipeline and our programs and our early-stage discovery initiatives, and we remain committed to changing what is possible in neuroscience. Now, let me turn the call over to Dr. Ray Sanchez, our Chief Medical Officer, to provide some added color about our lead programs. Ray?
spk04: Thank you, Tony, and good morning to all of you. As Tony has outlined, Cerevel is well-positioned to pave new paths in neuroscience, Our pipeline seeks to address some of the most challenging neuroscience diseases and brings forward new treatment options with enhanced tolerability profiles. Let's first turn to Imraclidine. As Tony mentioned, we recently initiated both phase two Empower trials of Imraclidine in adults living with schizophrenia. I am delighted that we are dosing patients in these two trials and am eager to see the results, which we expect in the first half of 2024. We are very encouraged by the robust results we saw in our Phase 1b trial as we move into a potentially registrational program. These two adequately powered three-arm trials are being conducted worldwide and will each randomize 372 adults living with schizophrenia and experiencing an acute exacerbation of psychotic symptoms. The first trial will test Imbraclidine, 10 milligrams and 30 milligrams once daily versus placebo. And the second trial will test Imraclidine 15 milligrams and 30 milligrams once daily versus placebo. Running these two trials in parallel enables us to fully explore the therapeutic dose range of Imraclidine while minimizing the number of treatment arms with the hope of reducing the variability observed in clinical trials as well as placebo response. These trials also reinforce CeraVel's commitment to diversity and the needs of individuals living with schizophrenia with the focused inclusion of groups often underrepresented in clinical trials. In order to potentially accelerate a registrational package for enraclidine and schizophrenia, we recently initiated a 52-week open-label safety extension trial, known as Empower 3. Moving now to the potential of enraclidine as a treatment for Alzheimer's disease psychosis. As Tony mentioned, we plan to initiate a phase one trial evaluating the safety, tolerability, and pharmacokinetics in elderly healthy volunteers 65 to 85 years old by the end of this year. The design of our multiple ascending dose trial will evaluate five doses in five cohorts lasting 14 days each and will allow us to delineate a dose range for later stage trials. We are pleased to announce today that FDA has granted FAST-TRACK designation for enraclidine for the treatment of hallucinations and delusions associated with Alzheimer's disease psychosis. FAST-TRACK is an FDA process designed to facilitate the development and potentially expedite the review of drugs to treat serious conditions and fill an unmet medical need. The designation will allow for early and more frequent communication and meetings with the FDA regarding the development of this important program. Turning now to DERIGABAT, our alpha-235 selective GABA-A receptor positive allosteric modulator currently under development for epilepsy and being designed in panic disorder. As Tony mentioned, November is Epilepsy Awareness Month, and we are pleased that our ongoing phase two focal epilepsy trial, known as the REALIZE trial, is on track to read out in mid-2023. More than three million Americans live with epilepsy, but despite its prevalence, there are still many myths and misconceptions, and the stigma can lead to discrimination, isolation, and negative perceptions. The stigma can have a trickle-down effect into all aspects of a person's life and the lives of their caregivers and loved ones, while the physical consequences of unmanaged epilepsy can be devastating and can even lead to death. Data show that at least 1 million people in the United States have uncontrolled epilepsy, and we aim to bring a new treatment option to fill the significant unmet need. As we discussed last quarter, we also plan to pursue Derigabed as a potential treatment for panic disorder, which is the second most common anxiety disorder. Panic disorder is characterized by panic attacks and presents with a range of debilitating symptoms, including a rapid heart rate, a sense of impending doom, weakness, dizziness, disorientation, and even chest pain, which can make some people feel like they are experiencing a heart attack. We are developing a phase two proof of concept trial for panic disorder, which we plan to initiate in 2023. We will provide additional updates, including the trial design, once we have completed our interactions with the FDA. As a reminder, the program follows the very encouraging positive data from our DERIGABAT phase one healthy volunteer hypercapnia trial in acute anxiety earlier this year. These results provide strong evidence of DERIGABAT's potential to be a differentiated daily maintenance treatment for anxiety-related disorders while minimizing tolerability concerns in contrast to benzodiazepines. Now turning next to Tabapadon, our D1-D5 partial agonist, which we are developing for Parkinson's disease as both a monotherapy and adjunctive treatment to leave a dopa for symptomatic motor control. We believe that Tabapadon could serve as a potential monotherapy early in disease, while for the more advanced Parkinson's patients, Tavapidon could be a preferred adjunctive treatment with Levodopa. With Tavapidon's longer half-life, potentially improved tolerability profile, reduced incidence of dyskinesias, adjunctive treatment may allow for 24-hour motor symptom control and delay the need for L-DOPA dose escalation. We continue to dose in all three of our Phase III trials and the 58-week open-label extension trial known collectively as the TEMPO trials. Additionally, we are encouraged by the high rollover rate of 95% in our open label extension program. Tony mentioned earlier that we're currently evaluating data readout timelines for Tababadon. Enrollment in the Temple trials has been impacted due to residual post-COVID landscape challenges and other factors affecting clinical trials and other related organizations. We therefore anticipate a delay in the TEMPO3 readout beyond the first half of 2023, and we're currently conducting a review of the timelines of the full TEMPO program and will provide an update on the timing of the data readouts for all three trials in the first quarter of 2023. Turning to CBL871, our second D1, D5 partial agonist. As you will recall, in the second quarter of 2021, Cerevel received fast-track designation from the FDA for the development of CVL871 in dementia-related apathy in recognition of the significant unmet need in this area. We are currently conducting a Phase IIa exploratory trial in this novel indication. Dementia-related apathy affects 50 to 70 percent of people with the disease and is associated with worsening outcomes and increased burden on caregivers. The post-COVID landscape challenges in clinical trials are also impacting CVL871, and as a result, we no longer expect the data to read out in the first half of 2023. We are reevaluating the timelines for our trial and will provide an update timeline in the first quarter next year as well. I am pleased with the progress we are making across our portfolio and am confident that Cerevo will bring forward important therapies to address the significant unmet needs of so many people living with devastating neuroscience diseases. With that, I will turn it over to Dr. John Renger, our Chief Scientific Officer, to review our early stage portfolio. John?
spk05: Thank you, Ray, and good morning, everyone. I'd like to begin by providing an overview of our earlier stage clinical and preclinical programs. First, we have an active program to identify and enforce selective full agonist clinical-ready molecule as part of our goal of creating an industry-leading M4-selective therapeutic franchise. We believe this novel program will provide additional clinical indication optionality as we consider the therapeutic potential of this mechanism of action and its demonstrated utility in treating psychosis. This additional program will give us an opportunity to complement our emiraclidine program and expand our presence in additional neuroscience indications. We will be presenting preclinical data characterizing the in vitro profiling, in vivo efficacy data, and EEG biomarker data across both the Society for Neuroscience meeting in November and the American College of Neuropsychopharmacology meeting in December. Second, I'd like to highlight our Kappa Opioid Receptor Antagonist Program, CBL354, which continues to progress in our ongoing phase one single and multiple ascending dose trials in healthy volunteer subjects. We believe this mechanism of action has the potential to address major depressive disorder and substance use disorder based upon prior clinical and preclinical data generated with compounds that selectively target the CABA opioid receptor, such as our compound CBL354. Preclinical data characterizing the in vitro and in vivo data in CBL354 will be presented at both the SFN meeting and the ACNP meeting. These presentations will include non-human primate PET imaging data characterizing the selectivity of CVL354 receptor occupancy at the Kappa opioid receptor over the Mu opioid receptor, as well as efficacy results showing reduction of oxycodone withdrawal symptoms preclinically. We are also carefully evaluating a series of PDE4D sparing compounds. a well-established small molecular target profile with a therapeutic potential in multiple disease areas, including major depressive disorder, schizophrenia, and neuroinflammatory conditions. Our selected PDE4 inhibitors spare the PDE4D receptor subtype, which is believed to contribute to the GI side effects that have historically hindered the development of non-selective PDE4 inhibitors in neuroscience indication trials due to the limitations on exploring the full therapeutic dose range that has been capped by intolerable side effects such as nausea and emesis. Our teams continue to have an ongoing presence at key medical meetings, which is an important part of our drug discovery efforts. Most importantly, team members attended the 14th Annual Parkinson's Disease Therapeutics Conference hosted by the Michael J. Fox Foundation. This conference focuses solely on Parkinson's drug development and creates an opportunity for top Parkinson's researchers and business development professionals to convene and learn about what is new in Parkinson's disease therapeutic space. On full display with the Parkinson's Progression Markers Initiative, a large foundation sponsored cohort study aimed at identifying biomarkers of disease onset and progression. Sarah Bell recently became a partner member of the PPMI initiative, and we look forward to the great insights that will be gleaned by this cross-industry group. Overall, we continue to build our robust drug discovery engine in our research labs in Cambridge Crossing, with additional ongoing discovery stage and pre-IND programs focused on areas of large unmet patient need. We are leveraging our differentiated understanding of disease-based neurocircuitry and world-class chemistry to develop and explore the therapeutic potential of small molecules with selective receptor activity and potentially improved efficacy and tolerability. We believe our research engine, which is driven by a team of incredibly dedicated and talented scientists, will fuel future innovation for many years to come, and we look forward to keeping you updated on our progress on these earlier stage efforts as appropriate. I'd now like to hand it over to Cerebell's Interim Chief Financial Officer, Mark Bodenreiter, to review our financial performance for the third quarter.
spk03: Mark? Thank you, John. Good morning, everyone. As Tony mentioned earlier, during the third quarter, we completed a $599 million financing, and we now have over a billion dollars in cash with runway into 2025. This impressive capital raise is just one example of our judicious and strategic approach to funding and prioritizing our broad and deep portfolio programs. and investing in ongoing discovery efforts to replenish our pipeline. I'm pleased to provide an overview of Cerevel's strong financial position in our third quarter 2022 financial results. Please refer to this morning's press release for the full details of our financial update. For the third quarter, total operating expenses were approximately $95 million, which includes R&D expense of $71 million and G&A expense of $24 million. Relative to the third quarter last year, R&D expenses increased by approximately $31 million. This increase was primarily due to the continued advancement of our Tavapadon, Imraclidine, and Dregabat programs, investment in our preclinical and discovery efforts, and increased personnel and other infrastructure costs as we expand capabilities to advance our pipeline. As expected, R&D expense was relatively consistent on a sequential quarter basis, and we expect it to remain relatively consistent through the rest of the year. G&A expense for the third quarter increased by approximately $9 million over last year. This was primarily due to higher personnel costs, including equity-based compensation, as we support the continued growth of our organization. G&A expense may increase slightly for the balance of the year. As of September 30, 2022, our cash, cash equivalents, and marketable securities totaled $1.03 billion. In closing, we remain well-capitalized, We expect our cash resources to fund our current operations into 2025. We look forward to multiple value-creating data readouts over the next couple years, and we will continue to think creatively and opportunistically about further strengthening our balance sheet. With that, I'll hand the call back to Tony for closing remarks. Thanks, Mark.
spk07: As you can see, we're advancing our broad and diverse set of programs and building what we believe is rapidly becoming the premier neuroscience company with the potential to deliver significant value for both patients and for shareholders. We're advancing novel programs across a wide range of neuroscience diseases, Parkinson's, schizophrenia, epilepsy, dementia-related apathy, just to name a few. We have the pipeline, the people, and the capital we need to truly transform what's possible in neuroscience, and we're proud to be on the leading edge of the next great frontier in medicine. Thank you for joining us this morning. I want to thank our teams whose dedication and commitment make all of this possible. I also want to extend my deepest gratitude and appreciation, as I always do, to the clinical trial participants and investigators who contribute to the development of these important therapies.
spk02: with that operator let's open the call for questions thank you to ask a question you will need to press star 1 1 on your telephone please stand by as we compile the q a roster one moment please for our first question our first question will come from umir raffet of evercore your line is open hi guys thanks for taking my question
spk10: A couple here, if I may. First, I think there's a little bit of investor confusion around how exactly the blood pressure is being measured in the ongoing study for amyloctin. And specifically, the question is really around how the timing of two-hour measurement, which was shown for some of the prior studies, versus how the 24-hour sort of average for the day is measured for this trial and to what extent that would or would not have ramifications on the way the statistics are structured versus relative to baseline, if you could just speak to the timing of measurement. Secondly, the trial, this eight-week study was fully enrolled as of July as per clintrials.gov, so I would have thought we should be getting an update by now. So if you could speak to timing if the data is in-house already, et cetera. Thank you very much.
spk07: Okay, Omer, thanks for the question. The first one's really very, very easy. We did use two different methodologies, one for the Phase 1B study in terms of cuff measurements and the ambulatory blood pressure process that we're using for that Phase 1 study. Ray, why don't you actually just break down the really simple distinction between those two and Omer's question specifically about timing, and maybe take the second half of his question as well regarding our expected study conclusion.
spk04: Right, right. So, Umar, good morning. So, you know, in the Phase 1B trial, we actually just, as Tony mentioned, did cuff measurements, you know, a couple times a day. But in the ambulatory blood pressure monitoring trial, in fact, at baseline, at week four and at week eight, we monitor blood pressure every 20 minutes during the waking hours and every 30 minutes during the time that they're asleep. So it is a 24-hour assessment where then you get a mean. So then you will look at the mean change from baseline at week eight around that 24-hour cycle, which, as you know, will give you a more precise reading in terms of the sustained systolic blood pressure effects over time. And then in terms of the data readout, so the trial is still ongoing, and we will – have that data available later in the year when we conclude the trial. We will also share that data at the appropriate time and really at an appropriate venue as well, so stay tuned for that.
spk07: Okay, Omar, thanks for the question. Operator, we'll take the next question.
spk02: Thank you. One moment for the next question. Our next question will come from Michael Yee of Jefferies. Your line is open.
spk14: Hey, guys, thank you. Good morning. Two questions for us. On Tavapadon, obviously, you're commenting on the potential change in timeline. Can you just be a little bit more specific about what you mean by a post-COVID landscape challenge and other factors, and maybe put a little more meat on the bone as to what the different compounding things are and how much of a delay you're talking about? Because I guess it's sort of related to enrollment completion. And then second question was the other announcement around Derigabat and anxiety. Just comment on what sort of drove that. Is that a better comfort with the tolerability safety profile, as I remember from the first readout that caused a little bit of investor concern, and obviously in the fact that you have another ongoing study going on at the same time, so maybe there's some learnings from what you're seeing there. Maybe just comment on anxiety. Thank you.
spk07: Okay, Mike, I think just really quickly by way of context for the trial delay, this is nothing new across the industry. We've actually been researching the particular set of challenges that companies are facing and actually looked at some metadata insights information suggesting that 80% of trials have been delayed in 2022. So we think that this is exactly on par with what's happening in many instances across the industry. I'm going to ask Ray to give more comment, but I will quickly note that our inpatient trials, as distinct from the outpatient trials we're discussing for Tavapidon and 871, our inpatient trials continue to enroll well. So there is no interruption or delay we're expecting for any of the Imbraclidine Empower studies. And Ray's already commented on the ABPM study, which has enrolled very well, and we expect that to conclude this year. So just draw the distinction between our inpatient studies for us, and these two outpatient studies as well. And this is a phenomenon we're finding across the landscape, but I know Ray will have more details because his team's right hip deep in this particular topic. Ray, why don't you take that one, and then we'll come to the de Rigobat anxiety question.
spk04: Good morning, Michael. So as you know, and I think Tony's mentioned, that there has been a residual effect of due to the COVID era, and you're seeing basically the effect at the trial site level, as well as at the CRO levels and other associated organizations. And there's a bolus of trials that really are trying to catch up, but the personnel really can't catch up as quickly. So we're seeing delays due to those reasons, as well as individual hesitancy at times in certain populations to participate in trials. all of which have been captured as Tony mentioned in the data insights article that metadata provided recently. So we're working very diligently to come up with plans to try to catch up as quickly as we can and really some risk mitigation plans without diluting the quality of the data. So we'll stay tuned for that. But again, I think a challenge that the landscape is experiencing that we're trying to obviously bridge that gap as well.
spk07: And I know, Ray, you provided some color in your prepared remarks on the choice of panic for DERIGABAT, our ongoing conversations with the FDA, but what would you add to try to amplify Michael's question?
spk04: So, Michael, you know, just that, as you know, there hasn't been a drug approved for panic disorder since 2005, so it's been 17 years. And so we are currently in process of designing a trial that's very consistent with the precedent that has been set in the landscape historically. but want to get the alignment from the agency in order to ensure that we have a viable program moving forward, so stay tuned for that as we go through that process and then be able to clarify to all of you what that trial design and timeline will look like, but we will start the trial in 2023.
spk07: The good news is that we think we've got a winning compound for this particular opportunity, and clinical development just takes time, and our approach design the trial correctly the first time, and this input from the FDA we think is going to be very important. But so far, so good. The data looks good, and hopefully we can address some of what we saw in the Phase 1 study in healthy volunteers. Okay, operator, we will take the next question.
spk02: Thank you. One moment. Our next question will come from Paul Matai of Stiefel. Your line is open.
spk11: Great. Thank you very much. I just want to clarify something. On the ABPM timing of the disclosure, is that going to be disclosed still this year or is the study just completed this year? And then beyond that, I just had two other sort of prepared questions. One on Imraclidine. There's some data out there that suggests around a quarter of schizophrenia trials for effective drugs fail. You know, given you have more money in the bank now, have you thought about initiating a third pivotal study as a hedge given – just to mitigate the downside risk on bad luck and what that could mean for filing and launch timelines. And then on the CAPA program, you reference external data, and I know that there's the J&J study as it relates to POC and depression. How closely are you watching the trial readout from Newmora? And, you know, if those data are positive or negative from their MDD study, How much would that influence whether or not you actually start a POC trial in depression? Thank you.
spk07: Okay. Paul, thanks for those. I'd say on the ABPM study, which was your first question, what you hear us saying, what we're guiding to is that the study we expect will conclude this year. Obviously, I don't know yet whether it will be early or late December, but we expect or even later this month. So give us the opportunity to wrap the study, understand the data, and as it will not be uncommon, we'll make the best decision about when and how to disclose those particular data. So stay tuned for that. We know that everyone's very interested in this data. We are as well. And it will be our duty to get this to you as quickly as we understand what we see in the data. I will add and underscore a really important point, and I've said this before, Ray has said this before, and we'll continue to reiterate this. The results of the ABPM trial we do not believe will be gating to a review or an approval of an NDA, and I want to underscore that and make that very clear. Those results, we do believe, will inform and help labeling negotiations when we get to that point with the FDA. And so I want to branch this as a matter of what we expect will provide a high-quality label and instruct physicians on how best to use Imraclidine in all patients. Obviously, the fact that we're doing this particular trial and that we've received fast-track designation for Imraclidine in ADP, obviously an older, more vulnerable population, suggest that there are not significant concerns about this particular topic. Otherwise, the agency and others wouldn't be as supportive as they have been of us moving these programs along. So I just add that context because sometimes we get very focused on the micro point, and I'd like us to zoom out and understand the significance of this and the relevance of this in terms of what we expect will be a great therapy to treat patients. Let's take the second question. that Paul's posed about umbraclidine and whether we would consider a third study as a hedge. I know you have some thoughts on that.
spk04: Yeah, so Paul, it's a good question. We really want first to see what the phase two data readout looks like on both of those trials. Obviously those trials are positive. They do have potential for them to be pivotal, but to your point, obviously you may need additional trials to ensure that you have the two registrational trials you need to submit an NDA. So I think that's something that we definitely are considering and have considered moving forward, but we do want to focus really on completing those phase two trials first before we take any further steps.
spk07: And J.R., if you would take the core question and talk a little bit about the landscape. And it might actually be useful because everyone may not be up to speed as Paul is, but just share perspectives on the J&J data that they've released, the promise of this particular mechanism in MDD, and talk also about what we know about the other competitors.
spk05: Sure. Thanks, Tony, and thanks, Paul, for the question. So, you know, the cap opioid receptor antagonist approach has been actually one that's been sought after for quite a long time. There's been previous compounds that have had activity as, let's say, non-selective cap opioid receptor antagonists in the past that have shown some evidence for having antidepressant effects. I think that we've seen other companies try to pursue through multiple pharmacology approach the opportunity to go after the cap-alkaloid receptor antagonism as a depression target. There was complications with that multiple pharmacology approach, but most excitingly and most recent has been the reported data that has come out of Johnson & Johnson around the approach that they've taken with having a selective compound, which is a compound that we're very familiar with. That compound showed effects in treating major depressive disorder. Consequent to that, what we've seen, or subsequent to that, what we've seen is that actually J&J has now announced that they're actually initiating their phase three program. They have started one of those phase three studies. There's likely to be another one. And then they also announced the start of an open label. And so J&J seems to be very convinced on the action of that molecule and the potential there. As mentioned, another competitor in the field is Nemora. As you know, that was a compound that was picked up from Blackthorn as part of the formation of Nemora. Yes, we are very interested in seeing what that study reads out. I would say that what we're cognizant of is the inclusion-exclusion criteria and how those trials have been designed and the differences between what J&J approached as a positive proof of concept that they've demonstrated versus the inclusion criteria that Newmora has incorporated in their study, looking, you know, putting a lot of emphasis on anhedonia as part of their enrollment. And so we are watching very closely. We know a lot about both molecules, but we also know very well our molecule Plus, we have internal preclinical data that's helping us make decisions on how we're going to pursue next steps after we get through the phase one studies that we're in. Part of that data, as I mentioned, we will be talking about at some conferences that are coming up about what we've learned, particularly about our receptor occupancy selectivity to kappa over mu, which is obviously something that we're interested in as well as other companies and regulators. And so I think that data will be exciting when it's publicly available. But we do see a lot of potential for this mechanism. It's one that, you know, has been validated clinically. Although with non-kind of ideal compounds, J&J clearly is convinced. We're looking forward to seeing how the anhedonia inclusion criteria for Nemora plays out. But we also have some strong data internally pre-clinically there. It's also helping us direct our investment in this program. But overall, it's an exciting opportunity because of the multiple areas that this mechanism could play a role in.
spk07: Suffice to say, we are excited about the prospects here because if we can add major depressive disorder to schizophrenia, to Parkinson's, to epilepsy as yet another indication we're working on, that would be great for patients. Operator, let's take the next question.
spk02: Thank you. One moment, please. Our next question will come from Tazeem Ahmad of Bank of America. Your line is open.
spk12: Hi, good morning. Thanks for taking my question. Maybe just to follow up on a comment you just made, as regards to the results of the blood pressure study, how does it in any way impact your commercial opportunity? Because we have seen other drugs with labels of schizophrenia that do contain language on on blood pressure increases, do you think it would impact the opportunity negatively at all if you were to see a signal? And at this point, just based on the mechanism, would it be surprising to see a one to two point elevation in mercury in the end results of your upcoming study? Thanks.
spk07: Tadim, thanks for the question, and it's a great pickup because that was exactly the message that I was delivering in my earlier comment. We actually don't think, well, let me say what we do think. We do think that this is a mechanism-related phenomenon so that the muscarinic agents are likely to induce a pressor effect. This is what competitive data appears to show. From a labeling point of view, there might be some provision that the FDA would provide if there is something to consider there. But commercially, we don't expect to be put at a disadvantage because of what we find and expect that given the efficacy and the relatively clean side effect profile for this compound, in addition to the once daily dosing, the no need for titration. And what we think is a unique advantage, which is the selectivity of the M4 receptor subtype interaction, that those all provide a really compelling argument for a strong commercial potential, as well as a really important therapeutic benefit as a differentiator for patients. So physicians will obviously make their minds when all of these agents come to the market. But this presser effect increasingly appears to be mechanism-related, and we think there are significant distinctive benefits that Imrakladine will have in the marketplace that will bear out. So we don't expect an impact on the commercial opportunity. I think that's it, JR, unless you want to add anything else on the mechanisms.
spk05: I would disagree, Tony. We do believe it's mechanism-based, but maybe relevant to the question is the fact that what we also think is that it's transient increases and that the increase tolerates. And so both our preclinical evidence as well as what we've seen clinically suggests that While there is a pressure effect, it seems to be very transient, and it tolerates. And, you know, what the agency is interested in in the ABPM study is whether there's sustained effects. That's not what we've seen in any study preclinically or clinically, that those effects would equate to an effect over the period of dosing that we're performing in these studies. Good. Thank you, JR.
spk07: All right. Thanks for the question. Operator, pick the next one, please.
spk02: Thank you. Hold on a moment. Our next question will come from Matthew Harrison of Morgan Stanley. Your line is open.
spk13: Hi. Thank you for taking our questions. This is Max Skor on for Matthew Harrison. I was just wondering, how should we think about the potential risk and tolerability profile of Imraclidine in 65 to 85-year-olds, and do you expect dosing to be significantly different compared to younger individuals? Thank you.
spk04: Okay. Thanks, Max. Ray? Yeah, so, you know, we, as you know, we are going into the Alzheimer's disease population, an older population, 65 and older. You know, we really don't expect emiraclidine's profile to be any less tolerated by that population than the younger population in schizophrenia. We are going to start multiple ascending dose trials we mentioned earlier later this year that will delineate the dose range. we probably most likely will achieve a similar dose range, but we don't expect any of the characteristics that we know about imraclidine to inhibit our moving forward in any way in that older population or for there to be any significant effects in terms of side effects or tolerability.
spk07: Can I add just right to that? Importantly, and this is, I think, a really key thing, we don't expect any of the GI or cholinergic effects that are associated with M1. And I I just underscore that because it goes to the central thesis of what we do as a company with targeted receptor selectivity. If we're right, and we think we are because we have clinical data to support that, both scientific and clinical data, which suggests that the cholinergic and other GI-related side effects that you see with some agents aren't likely to be a factor here. So it's a great question. Obviously, cholinergic side effects are a real problem in the elderly, and you have to dose adjust to address for those things. So our expectation is that the once-daily dosing from a targeted M4 PAM, like imraclidine, should be beneficial. But we'll collect the data, and we'll see, and we will govern ourselves accordingly. Operator, why don't we take the next question?
spk02: Thank you. One moment. Next question will come from Madhu Kumar of Goldman Sachs.
spk09: Your line is open. Hey, guys. Thanks for taking our question. This is Rob on for Madhu. First, for miraculine, how should we think about the importance of psychosis versus cognition endpoints, particularly in Alzheimer's? And then for derigabat and epilepsy, how do you think about the development landscape in this disease and sort of where the drug fits in? Thanks.
spk07: Okay. Ray, I think you can take both of those, if you will, notably the importance about psychosis versus cognition in ADP.
spk04: Right. So, you know, they are different, as you know, that we are really evaluating psychosis in this population, which is seen in up to 40% or maybe even a little bit over 40% of the population that suffers from Alzheimer's disease in terms of hallucinations and delusions, really. And so that's where we're really focusing on a very different approach to evaluating cognition, which would be a different patient population and a different endpoint and trial design and so forth. So our objective really is to address a very debilitating syndrome in patients with Alzheimer's disease psychosis moving forward?
spk07: Jera, inherent in that question, though, is a question about the M1 component, which most people are linking to potential cognitive benefit. So if you would just go through the M4, M1 distinction, because I think that's inherent in the question. And operator, we're going to ask you to reopen the line for Goldman Sachs because the second question we could not hear. So Max will ask you to come back in the queue momentarily. So while JR is answering that, operator, if we can queue up the second question after the next couple. Go ahead, JR.
spk05: Sure, Tony. Thanks. Thanks for the question. Yeah, I think when you're looking at the treatment, as Ray said, there's very different designs to the studies that you would want to perform to demonstrate the difference between the psychotic benefit and the cognitive benefit. I think there's been discussion about the potential for treating cognition, particularly in Alzheimer's disease, with the muscarinic approach. Historically, the M1 receptor has been one that in preclinical models, primarily rodents, What's been demonstrated is that compounds that are M1-selective activators, whether PAMs or agonists, have demonstrated cognitive benefit in rodent models. What's not been demonstrated at all, to my knowledge, is the fact that once you get into the clinical setting and you look at populations that demonstrate cognitive deficits, like Alzheimer's patients, that in fact the compounds that activate and show cognitive benefit in rodents don't translate to a benefit. And one of the references I use for that is a compound that was developed by Merck that was highly selective. It was about 1,000-fold selective for M1 over the other muscarinics. It was a really well-performed set of data that they'd gotten to show target engagement and activity. However, when that compound went into an Alzheimer's population, and both cognition and activities of daily living were looked at, there was absolutely no benefit in an Alzheimer's population as far as cognition. And so that's probably one of the best quality molecules that I can point to that's gone into that transitional study from preclinical to clinical, and it's not actually demonstrated a cognitive benefit. And to the point about the endpoints, I don't think that in the populations that have psychosis, that M1 has ever been really taken into a study in patients with psychosis to actually demonstrate in the appropriate design study a benefit on cognition, because it would be a very different study design than the typical kind of PAN study that is typically done to show an antipsychotic benefit. Really, I think that there's no strong evidence that M1 supports a cognitive benefit either alone or in a cognitive deficit population like Alzheimer's or in a combination of looking at a psychotic population and showing a cognitive benefit in an appropriately designed study. So I think that could M4 show cognitive benefit? I think the answer is potentially. We do have preclinical data that says that the M4 mechanism alone with selective compounds does benefit cognition. But again, the translational piece into the clinic and actually doing the appropriate study has not been done.
spk07: But just to flesh this out, the combined answer for both of you, cognition is not what we're looking for in ADP. That's right. What we're looking for is an improvement of psychotic symptoms, not cognitive benefit. And so we have to separate the two and keep them really distinct, because this is not an anti-Alzheimer's therapy to improve cognitive benefit. This is a therapy to diminish the delusions and the hallucinations associated with psychosis. And that's a really important distinction that we will come back to time and time again. So I appreciate the question, and we'll keep framing it so everyone really does understand what the therapeutic benefit and goal is here.
spk04: And Tony, if I could add that If you wanted to evaluate cognition, you would not want to do it in a patient population that was experiencing psychotic symptoms. So this is a very, even within the Alzheimer's group, it's a very different population than the one we would evaluate for cognition.
spk07: Okay, good. Thanks, Ray. Operator, we'll move on to the next question. I know you're trying to open the line of Matthew Kumar so they can ask their second question if they're still there. But let's take the next question in the queue while you're working on that.
spk02: Thank you. First of all, to Rob Palermo of Goldman Sachs, if you could please hit star 11 again to get back into the queue so you can ask your second question. Our next question will come from, we'll hit Ben Sal of Wells Fargo. Your line is open.
spk15: Great. Thank you very much for taking my question. So a couple for my side. One is that, so your initial trial in schizophrenia was in inpatient trial while the blood pressure study is outpatient. Do you think it will have any ramifications on the outcome there? Also, your competitor also noted that there was increases treatment adverse events, related adverse events of hypertension were resolved over a period of time. So does this give you confidence that over a period of eight weeks it will probably be a more modest impact if there is any? And last one is on M1 and its impact on cognition. I understand that these trials are probably five weeks or six weeks long, so you may not see any benefit on cognition. But do you think in longer term the delta on cognition could show up if there is indeed a benefit of M1 on cognition? How do you think about that? Thank you.
spk07: Okay. Ray, you can take both. I'll have a comment on the second one. But in terms of, please draw the distinction and provide the description between the inpatient versus the outpatient question on BP.
spk04: So both trials, both the six-week Phase II trials and the Phase IB trial are all inpatient trials in patients with an acute exacerbation of psychotic symptoms. The ambulatory blood pressure monitoring trial is also an eight-week inpatient, not outpatient, but inpatient trial, and the reason for that is to ensure that we minimize the variability so we can get a more precise and accurate reading over the eight-week period. So just to ensure that everyone understands that all of these trials are inpatient trials, not outpatient.
spk07: So that's a really important distinction, and to date, In the phase 1B, we saw no treatment emergent AE that was associated with hypertension. And I think that was implied as the second part. But bear me out on that, Ray.
spk04: So we only, in the 30 milligram group, which we're evaluating in the phase 2 program as our top dose, we only saw one treatment emergent adverse event of increased blood pressure out of 27 patients, or roughly 4%. There were actually two patients on placebo, roughly 7%. So, again, a really minimal number of treatment emergencies due to increased blood pressure, as I just outlined.
spk07: But no difference between placebo. So two placebo and one in the treatment arm? And one in the treatment arm. And that's really an important distinction because we're obviously always comparing the placebo in these placebo-controlled trials, and that was the point I was making. As to cognition, I think it's really important to follow Ray's line of thinking here that if you are testing for cognition, you can't do it in a psychotic patient. That's right. And that's a really important thing. So with the duration of these particular trials, you've got to focus neatly on the scales that help you assess the improvement in psychotic symptoms, delusions, and hallucinations, and and then separately answer a cognition question, right?
spk04: And just to add to that, that invariably when you have a psychotic patient that gets better, the cognitive score is also going to improve. The pseudospecificity of that is very different from having a patient population that has residual cognitive deficits and is stable, and then you see improvement from that vantage point. So again, a very different approach, a very different patient population, and also may I add a very different regulatory path forward to get that indication.
spk07: Okay, good. Thank you. Operator, we will take the next question.
spk02: Thank you. One moment. And next we have Rob Palermo. Your line is now open to ask your second question.
spk09: Hey, thanks for reopening my line. Just a quick question on DERGABAT. Like, how do you see the treatment landscape and epilepsy moving forward?
spk07: Okay. I think, Abe, you can start with that one. I'll have some thoughts, but if you would, that'd be great.
spk06: Sure. Well, thank you for the question. So first off, this is a patient population that I think we're all aware has significant unmet need. Many of these patients are refractory patients, patients that are in need of additional therapy. One of the opportunities that we clearly see with the Rigabat is the opportunity to really have benzo-like efficacy. However, given the alpha-1 sparing nature of our compound, really be able to potentially transition this marketplace from a PRN-based market to really a chronic-based market, which would be a substantial opportunity, obviously for Darigabab, but also a substantial shift in the way that epilepsy patients are managed overall. So we see that as a major opportunity. Thank you.
spk07: Thanks for the question. Operator, we have time for just a couple questions more. How many more do we have in the queue?
spk02: There are two left. Okay, perfect.
spk07: We'll take the next question.
spk02: Thank you. One moment. Our next question will come from Charles Duncan of Cantor Fitzgerald. Your line is open.
spk01: Super. Good morning, Tony and team. Thanks for taking our questions. I had just two, one on emiraclidine and one on derigabat. With regard to emiraclidine, I know that you just started the Amparo 3 trial, but could you provide us any information on the enrollment in that open-label extension program? Or do you plan to talk about that in the future? Persistence could be a pretty interesting observation on raclodine.
spk04: Right? Yeah. So, you know, the Empower 3 trial recently started only because the patients who are currently in the Phase 2 program have the option to roll over. So it's in early days. We do plan in the new year to also include de novo patients in order for us to meet the ICH-mandated safety exposure that is needed to file an expedient NDA when those trials potentially read out in the future. So stay tuned for that, but that's something that obviously we're monitoring very closely to ensure that it's not really limiting to our submitting an NDA down the road.
spk07: Okay, very good. But obviously, we're very excited that the program's really going quite nicely and really excited to see what happens there. Aubrey, we will take the next question.
spk02: Thank you. One moment, please. And just a reminder, to ask a question, please hit star 1-1 on your phone. Our next question will come from Douglas Stout. of HC Wainwright. Your line is open. Hi, good morning.
spk16: Thanks for squeezing me in. Just a couple quick ones. First, Tony, maybe if you could just talk about what the financings that you, you know, completed, you know, does that open up new opportunities for the company? Just be curious to hear that. And two, maybe on the panic disorder study, I know, Ray, you referenced, you know, sort of to the most part following the you know, sort of the precedent, but obviously, you know, the precedent was some time ago, and just given the sort of unique characteristics of Drogobet, are there sort of tweaks to the study design that you're making to help better characterize the profile, the unique character of the drug, or do you think those would be sort of borne out in sort of the sort of more, you know, sort of traditional study design, for lack of a better phrase? Thank you.
spk07: Okay, just on the, Ulrich, why don't you take that one, and then Mark and I will take the financing question.
spk04: Sure, so thanks for that question. So in terms of the panic program, obviously we're currently designing that trial. We are designing it relevant to what the precedent has been set, even though it's been a while since that precedent was set 17 years ago, but there's not a lot of latitude really when evaluating panic disorder and the trial design. There's nothing unique in terms about the design, or we're not doing anything differently because it's DERIGABAT, but what we do hope is, like we saw in the hypercademia trial, that the alpha-2,3 selectivity will obviously give us the opportunity to show the benefits of a chronic dosing of Derigabat to be like a benzodiazepine, but without the alpha-1 side effect issues and issues that limit chronic dosing that will hopefully help us with moving the program forward, but also showing the benefits of the great need that there is in this population.
spk07: And just quickly on the financing, so we will conclude on time. You know, with a billion dollars on the balance sheet, we clearly have the opportunity to fund the ongoing operations into 2025 and several data readouts in that timeframe. But Mark, why don't you talk specifically about what we think that this recent raise will do for the company in transforming it?
spk03: Yeah, sure. So, you know, with the proceeds from this offering, You know, we really feel that we have the opportunity not only to continue to develop the development of imraculidine, but we have the ability to evaluate the potential of imraculidine in other populations such as ADP. We have the opportunity to advance dirigivate and panic as well as our earlier stage programs such as, you know, CVL 354, our core asset. But it will also give us an opportunity to accelerate registrational enabling and market development activities for our lead programs. But again, as Tony said, is, you know, we have enough to fund our current operations into 2025.
spk07: I think the only thing I would add is that we are obviously looking forward to understanding competitive landscape and the market landscape, how these diseases are currently treated. So we will be paying attention to the evolution of that landscape, what prescribers are interested in, what patients need, and really trying to get market insights that will help us provide better opportunities. Operator, that's all the time we have for questions, and so I will apologize in advance to anyone we did not get to today. Thank you guys for listening. It's been a full conversation. Thank you for your questions. Thank you for your attention. We are clearly optimistic about the prospects of not just what's happening with schizophrenia and rachladine, but with the recent fast-track designation from the FDA on ADP, as well as what's happening across the portfolio with the rigor bat and the news that we're expecting there in the middle of next year, and the other programs that we have ongoing, including Trapadon, to help transform the Parkinson's landscape. We've got a lot going on. But really focused, really excited, and thank you for your support and your attention. Good morning.
spk02: Thank you. This concludes today's conference call. Thank you all for participating. You may now disconnect and have a pleasant day.
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