Great. Good morning, everyone. My name is Jessica Fye. I'm a large-cap biotech analyst at JPMorgan, we're continuing the conference this morning with Cerevel. A little different format this year, we're not gonna do the whole switching rooms thing for Q&A. After Tony's presentation, we're gonna go straight into Q&A in this room. There's two ways to ask a question. You can raise your hand, someone will bring you a mic, you can submit your questions electronically, they'll send it to an iPad, I'll read the question for you. With that, let me pass it over to Cerevel CEO, Tony Coles. Thank you, Jess, and good morning, everyone. It's certainly terrific to be back in San Francisco for one of the first large in-person JPMorgan's. I'm happy to be here and to be with you this morning to tell you the tale of the improbable story of the company of Cerevel that is really working to do something that's very hard, which is to unravel the mysteries of the brain. The story begins with the spin-out at Pfizer of all of Pfizer's neuroscience portfolio, and that with the intensive focus, the experienced leadership team, and the support of the capital markets, is the beginning of our conversation today. Before I get started, I will be making some forward-looking statements, so please do refer to our various SEC filings for the various provisos that will support these statements. Let's talk a little bit about why it is that we believe we can actually do what we've set out to do. It's quite aspirational. It's quite bold, and that is to unravel the mysteries of the brain. We know that in order to treat the diseases that we are focused on, epilepsy, Parkinson's, schizophrenia, anxiety, dementia-related apathy, and a number of others, that we really have to understand how the brain functions and how it works in disease. We start with what we know today with regards to neurotransmitters and neuroreceptors and build upon that with a specific and nuanced understanding of receptor subtypes and where it is exactly that we understand how the brain is wired, how these neurotransmitters conduct themselves, and the interaction with the neuroreceptors. The central unifying thesis for all the programs we'll talk about today is the selective focus of specific receptor subtypes that we expect will be the business end and drive the efficacy for these programs or these compounds, and for then that will avoid the on-target side effects through that selective interaction. It involves a keen understanding of targeted neural circuitry or the brain's wiring, receptor subtype selectivity, and very specifically, and this was the gift that a decade of research and $1 billion at Pfizer gave us, a keen understanding of the differentiated pharmacology for these potential new medicines and the chemistry that allows this targeted focus on specific receptor subtypes. You'll see what I mean in just a moment. Cerevel, as I have said, wants to unravel the mysteries of the brain and, in doing so, actually become the premier neuroscience company. Why do we think that this is possible? Well, first of all, the pipeline we have that is the focus of all of our work to address the diseases I've mentioned just a moment ago, but I'll add schizophrenia and Alzheimer's disease psychosis to that list, gives us an opportunity to actually cover the broad beachhead that we consider to be neuroscience. Neurodegenerative diseases, neuropsychiatric diseases, and even in the case of epilepsy, neurology diseases. Since the company's public introduction at the end of 2020, we have delivered incredible data for our lead programs each year. In 2021, it was data for schizophrenia for emraclidine. In early 2022, it was data for anxiety in healthy volunteers that is forming the basis of the expansion of our opportunity for darigabat. You see this continues in 2023 with a mid-year readout for epilepsy and with darigabat, and in 2024, where we expect the pivotal data for emraclidine in schizophrenia and more beyond that. Let's talk about the progress that we continue to make with the pipeline beyond those specific data readouts I've mentioned. For emraclidine, which is the subject of great interest for many investors, there's an ongoing, quite large, 650 or so patient phase II program across two studies testing three specific doses of emraclidine in schizophrenia. This will, we expect, and we hope, if the data are supportive, form the basis of an NDA application for emraclidine. Of course, our job is to deliver the data and let the FDA make the decision about the acceptability of the filing. That, in addition to our recently announced positive ABPM or ambulatory blood pressure monitoring data that we delivered last month, really clears the deck for what it is that we think we need to do. We have proven that this question around a potential pressure effect is now no longer an issue, and we see a clear path to delivering what we expect and what we hope will be impressive efficacy data. As a second indication opportunity in Alzheimer's disease psychosis, the FDA has granted us Fast Track designation for that particular new indication, and we announced in our press release yesterday that we are beginning a phase I healthy elderly volunteer study to enable the development in this new indication opportunity. We'll talk a little bit more about that opportunity and the reason to believe in just a moment. For darigabat, positive phase I data delivered a year ago in acute anxiety has encouraged us to pursue a phase II program in panic disorder, the second most common anxiety-related disorder. We announced yesterday, and I'll present today, that we expect to initiate that particular phase II program in the second quarter of this year. All of this would be impossible without the support of the capital markets, without creative deal-making, which is the hallmark of the way the company was originated in 2018 in the unusual transaction and innovative transaction between Pfizer and Bain. The strong balance sheet that we have, the opportunity to steward the capital of investors and put all that to work on behalf of patients. You can see that as of the end of the third quarter, we have a balance sheet with over $1 billion or so. Our job, as experienced, pharmaceutical executives, is to be disciplined with our spending, use the capital wisely, deploy it for the next best incremental opportunity. Very importantly, with this balance sheet, we expect operations can be supported into 2025. I'll emphasize there that that is just beyond the critical readout for emraclidine. We think that it's quite possible that we can support our operations through that pivotal data point. Let's get into some of the details. I'll spend about 15 minutes or so with prepared comments. We'll open it up for questions. This is the pipeline and the portfolio for the company. You can see that across the programs here, there is one phase III, three phase II programs, one phase I program in Alzheimer's disease psychosis, and then the darigabat panic disorder program about to enter phase II as well. Importantly, we've guided that there will be data in the first half of 2024 for emraclidine and schizophrenia, data at the middle of this year in epilepsy, and the two trial initiations that you can see on the far right-hand side of this particular slide. We've also suggested that the tavapadon and CVL-871 studies are under review in terms of timeline guidance, we expect this quarter to provide an update for when we expect data for those two particular programs. That's to say nothing of the early stage of preclinical programs. Quite interestingly, we're very excited about the core opportunity, where stunning data in major depressive disorder has recently been delivered that gives us hope that we might actually have an opportunity in that additional indication on top of everything that we're focused on today. Let's start with emraclidine. We've added to schizophrenia, the new indication opportunity for Alzheimer's disease psychosis, t he thought behind these two opportunities is that the differential benefit of focusing selectively on the M4 receptor subtype will provide a distinct and a competitive advantage in this space. Let's talk a little bit about schizophrenia. Well-known, well understood by many of us, 20 million patients worldwide. One of the things that has excited, I think investors and providers alike, is not just the large size of this particular patient population, but the important notion that for the first time in 50 years, there's a potential new mechanism on the horizon beyond what we were using in the late 1950s and 1960s. This has generated a fair bit of interest and excitement across the treatment landscape and by providers. We believe emraclidine has the opportunity to be a best-in-class therapy, not just because of this new potential mechanism for the treatment of schizophrenia, but because with its once-daily dosing and with its no need for titration, two really important differentiators in this treatment population. Why? Mostly because something quite unusual happens with schizophrenia patients. Schizophrenia patients require the maintenance of their therapy in order to control their symptoms. What often happens is that when side effects occur, treatment is stopped by the patient, and that lack of compliance actually begins an inexorable worsening of their disease. 77% relapse at one year, 90% at two years. We know is that with every relapse, the prognosis for schizophrenia patients worsens. Compliance, side effect profile, each of those things matters enormously in addition to the efficacy benefit from these therapies. It's the combination of the potential efficacy benefit, which we'll discuss in a moment, the improvement in tolerability, the once daily dosing, the no need for titration, is a complete package that gives us a great opportunity to potentially be best in class with this new mechanism. Let's look at the data. These were the story data that really did provide the first validation proof point at Cerevel for that central unifying thesis of targeted receptor selectivity that I mentioned a moment ago. This is the PANSS total score. This is in the orange, the 20 mg twice daily dose of emraclidine, and in blue, the 30 mg once daily dose for emraclidine. You can see that these curves compared to placebo separate early within the first week and continue to separate out to the 6 weeks of treatment in this particular study. This is what I think has excited providers and investors alike about this potential new opportunity. Clinically meaningful and statistically significant improvements in PANSS total score. Interestingly enough, which is very hard to do, meaningful improvements in both the PANSS positive and PANSS negative subscales with an appropriate tolerability profile. All of these data were recently published in The Lancet, so I'll refer you to that particular publication for a full disclosure and full set of the data and the information that we obtained in phase I. That has actually led us to be quite encouraged to build the large phase II program that I mentioned a moment ago, which we'll read out in the first half of 2024. On to the second indication opportunity for emraclidine, Alzheimer's disease psychosis. On the right side, under the potential for differentiation, I'll draw your attention to the fact that nearly 6 million patients are diagnosed currently with Alzheimer's disease, and that figure is as high as 10 million by some estimates on a worldwide basis. What's quite interesting to appreciate is that 97% of Alzheimer's disease patients present with some kind of neuropsychiatric symptomatology, mood disorder, agitation, anxiety, and importantly, hallucinations and delusions, which is the subset that we consider the psychosis of Alzheimer's disease. That occurs in about 40% of patients with Alzheimer's disease. The need is large, and there are no currently approved treatment options. Think of the caregiver burden attached to having a patient who is cognitively deficient and actively psychotic, and the complexity of trying to care for those individuals, either in a home setting or even in a long-term care facility setting. The fact that there are no currently approved treatment options, I think has encouraged the FDA to provide the Fast Track designation in this particular indication opportunity so we can raise these new therapies forward. It's not just the caregiver burden of the psychosis of Alzheimer's disease. There is actually an increased mortality associated with Alzheimer's patients who have these symptoms. If you think about the nearly 2.4 million or 4 million patients who have the psychosis of Alzheimer's disease, the need is certainly great and new solutions are required. Our phase I MAD trial is up and running. We've announced that it began enrolling last month, and that you can see here we're testing dose ranges from 2 mg-30 mg in patients who are 65-85, and this will give us much needed both PK, safety tolerability data that will enable the development of this important new indication opportunity. We complement schizophrenia with an important new additional chance to make a difference in the treatment landscape for patients. Let's turn our attention now to darigabat, the second program I'd like to talk about. darigabat is a GABA positive allosteric modulator. Think of it, if you will, as having the potential benefit of benzodiazepines from an efficacy point of view, with some really important distinctions, but without the side effect and with a much better and much improved tolerability profile. We'll talk about that in great detail. Like emraclidine, there are two indication opportunities that we are pursuing here, one in epilepsy and one in panic disorder, based on the positive phase I data that I talked about at the top of my comments. Let's start with epilepsy and start with where the real opportunity may lie in this treatment landscape. Many people will say we have enough antiepileptic drugs, but let me draw your attention to the notion that there are about 3 million patients in the U.S. with epilepsy. 60% of them have focal epilepsy, which is the target or the subject indication that we are pursuing in this phase II study. Nearly 90% of those patients are treated because going without treatment is not consistent with either a good life or even potentially with continued life in many instances. One-third of the nearly 2 million patients who have focal epilepsy actually continue to experience treatment refractory seizures. That's the important opportunity here. Yes, while we do have a number of antiepileptic drugs, nearly one-third of patients break through and could use better efficacy for these for their seizures. If you ask specialists who treat epilepsy, epileptologists, they will tell you their preferred therapy by far and away is a benzodiazepine. While benzodiazepines are used in the acute setting to break seizures or to treat patients acutely, there are side effects of dependence, withdrawal, and overall poor tolerability prevent their chronic administration. If you think carefully about the opportunity that darigabat provides with its very specific receptor focus at the alpha-2/3/5, if you will, the business end or the efficacy end of the GABA receptor, and the fact that it spares alpha-1, which benzodiazepines don't, that actually gives the efficacy profile we expect and the potential for an improved tolerability profile that will make a difference in this potential population. Do keep in mind this notion of targeted receptor selectivity. It is akin to the M4 focus for emraclidine, the business end for efficacy, and the fact that emraclidine spares M1, which we actually think is the on target side effect subunit responsible for those effects. This is alpha-2/3/5 for the efficacy or the business end, and alpha-1 sparing to avoid the side effect profile that you commonly see with benzodiazepines. The opportunity in this case to transform the landscape has everything to do with the fact that if you can use a benzodiazepine-like agent with a better tolerability profile, you can transform what is today an acute market with benzodiazepine use to a chronic therapy market for the benefit of patients. Let's look now at the data that encouraged us to pursue this phase II opportunity. On the left side, you can see the results from a photosensitivity trial. What's hard to read a little bit is in gold or in yellow amongst the gray and the orange lines is the lorazepam line. Given what I've said about lorazepam as a benzodiazepine in the treatment of seizures, you can see comparable benefit in this proof of principle trial for two different doses of darigabat. That has led us to pursue the 150 patient study that will test two dose levels of darigabat in the focal epilepsy population. We do expect those data in the middle of this year. This is additional reason to believe for darigabat in panic or in particular. one year ago, I mentioned that we delivered healthy volunteer data in our hypercapnia model, another proof of principle study, which suggests that there was a potential benefit for darigabat in anxiety-related disorders. We've chosen panic disorder because that's where the need is great. Many of the current treatment standards include benzodiazepines for this particular population. What you'll notice is on the left side, you'll notice that the two dose levels of darigabat delivered efficacy that was quite side by side, much better than alprazolam. This is encouraging to us, highly statistically significant, and of course, needs to be validated in a much larger population. This suggests that the underlying thesis of focusing on alpha-2/3/5 sub-subunit receptors can derive the benefit that we're expecting in a variety of conditions, anxiety-related as well as epilepsy. Nearly two-thirds of patients receive pharmacological therapy for panic disorder. This sets the stage for an important contribution in the treatment landscape. Let's move now to the third program I'll discuss, tavapadon, where we are running a very large phase III program with over 1,300 patients or so, and looking at the initiation of tavapadon as a D1/D5 agonist, and we'll talk more about the specificity of that and the importance of that. In the earliest stages of that particular disease as monotherapy, where we're running a fixed dose and a flexible dose trial, and as an adjunct to L-DOPA, which is the current standard of care in the later stages of treatment for Parkinson's disease. We get a lot of questions about, can we really make a difference in Parkinson's, and what would be required to launch a successful Parkinson's drug? Let me set the stage, if I can, to describe the current standard of care, which are MAO-B inhibitors and the D2/D3 agonists, and contrast that with tavapadon as a D1/D5 agonist. What does all of that mean? I'm gonna give you three potential reasons to believe that tavapadon can make an important difference in this treatment landscape. First, the fact that it is a D1/D5 selective partial agonist for the dopamine receptor. In our rubric where M4 is the business end, alpha-2/3/5 is the business end for darigabat. D1/D5 is the business end for the effect of tavapadon in terms of efficacy or benefit. Extending that same analog where M1 is spared to avoid the on-target side effects. alpha-1 is spared for darigabat. It's actually the other dopamine receptor agonist, D2/ D3, that tavapadon does not interact, which we think drives much of the side effect. The first reason to believe that tavapadon can make an important difference is specific with regards to the mechanism. The second reason to believe is that the tolerability or the side effect profile observed in studies to date supports an improved tolerability profile. The third, and very importantly, has everything to do with the efficacy benefit that we see. You can see from the phase II study that was the basis of our thinking for this large phase III program in orange, the dose of tavapadon. Again, note the early separation of the curves and the continued separation of those curves, and an absolute reduction or improvement in the UPDRS Part III, which is the motor subscale of nine points. Compare that to current standard of care of the D2/D3 agonists, which is about five points. On a placebo-adjusted basis, you can see the 4.8 point difference, and that compares favorably to the 2 or 3 points that the current standard of care delivers. If we can replicate these findings, if we can leverage our understanding about the mechanism and the distinction of the mechanism, and offer these patients an improved tolerability profile with enhanced efficacy benefit, we think we have an important drug here for tavapadon, and that it could potentially change the treatment landscape. One of the other opportunities is that there are no therapies that patients begin with at the beginning of their diagnosis and that they end with. To start with and stay with opportunity for tavapadon from the beginning of their disease throughout and as an adjunct to levodopa, provides an important treatment opportunity for providers and for patients. In sum, the pipeline has built an incredible amount of momentum. We have the broad set of offerings across neurodegenerative diseases, neuropsychiatric diseases, and neurological diseases. The progress we have made in the clinic has been at lightning speed with pivotal and important data each of the years since we've been public, and that's expected to continue for the next 18-24 months. As well, as I mentioned in my opening, none of this is possible without access to capital, a strong balance sheet, and important data catalysts that will occur before or that will occur and can be supported by our current balance sheet. With that, I'll end my formal comments and we'll invite questions. Joined at the podium today are Dr. Ray Sanchez, our Chief Medical Officer, and Dr. John Renger, our Chief Scientific Officer. Jess, with that, I will turn it over to you. Great. Thanks Tony for the presentation. As a reminder, if you have any questions, just raise your hand or you can use the portal. I don't see any on the portal. Again, we'd love to use the time to kind of address your questions. I will start. You recently read out the phase I blood pressure data. Love you to spend a little more time elaborating on that because it's just such a focus for investors heading in. How should we think about the absolute mean decrease in 24-hour blood pressure from baseline over the 8-week trial? Let me... I'm gonna ask Ray to cover this in substance, but let me address and set some context. The FDA's provided guidance for companies that have therapies that may have a potential blood pressure effect. This is new guidance started in 2018, and every company where there's a potential blood pressure effect has to submit to this particular guidance as part of the registration package. We knew this. We've known this. It's well known in the development of drugs, and we volunteered to do this particular study at this particular time, so we could ask and answer the question early and inform the rest of the development. That's really, I think, important because, Ray, I think you should probably talk a little bit about what we found in that trial as a result. Right. Good morning, Jess, and good morning, everyone. When we were first sensitized to the mild and transient increase in systolic and blood pressure, but in blood pressure in general, in phase I-B, we were very proactive in really wanting to understand that phenomenon and really characterize that, as Tony has mentioned, in terms of the guidance that the agency has put out that was finalized in early 2022. What we conducted, and we worked closely with the agency in designing the trial, was an 8-week trial that looked at the change from baseline in systolic blood pressure, and the mean change over 24-hour periods. That means that we monitored blood pressure for 24 hours at baseline and monitored it again at week 8. What that allowed us to do is really characterize the actually the effect and see if we could rule out or rule in a pressure effect. The conclusion is that with chronic dosing, emraclidine does not have a pressure effect. What gives us that confidence is the data that was generated that if you look at the mean change from baseline in systolic blood pressure, we achieved a -0.27 mm of mercury for the 10-mg dose and a negative 0.4 mm of mercury for the 30-mg dose. Importantly, and what the agency's really focused on and what the guidance is really focused on is really the upper bound of the 95% confidence interval. If you look at the -0.3 for the 10 mg and the 2.1 mm of mercury for the 30 mg, it rules out 3 mm of mercury which is per guidance, allows you to make the conclusion that you do not have a pressure effect. Taken together, it really gives us the confidence to continue to robustly execute on the schizophrenia program but importantly also execute on the Alzheimer's disease psychosis program. It's because of this outcome, it gives us great confidence for those programs moving forward and the compound in general. Thanks, Ray. Really important de-risking and clearing event for the company. Can you also talk about the strategy behind dose selection for the phase II EMPOWER-1 and EMPOWER-2 trials? Maybe remind us historically in schizophrenia, has the FDA required hitting on the same dose in both studies to file? Maybe what we'll do because the focus on mechanism is so important. J.R., if you'd be kind enough to talk a little bit about receptor occupancy that we see from those various doses, the 10 mg, the 15, and the 30 mg, which are the three doses of interest in the phase II program, and how it is that we got to that, and Ray you can make additional comments as you like. Sure. Thank you, Tony. Thank you, Jess. Thanks everyone for showing up. The dosing was determined in a couple different ways. First of all, we had, you know, being that this is a brand-new mechanism of action being selective at M4, what we relied on at first was the preclinical data that demonstrated that across the various preclinical models, it was consistent, and we needed 70% receptor occupancy or greater to maximally affect the outcome of those preclinical studies. When we went in with the initial study, what we did was we picked two doses, the 20 mg BID and the 30 mg once a day, so that we could examine whether or not this mechanism of action, which was new, was working off either an AUC effect or whether it was working off a Cmax effect. You guys have just seen the data that showed that a once-a-day dose was sufficient and actually superior to the twice-a-day dose. That, you know, defines that a once-a-day dose is capable of being achieved in this population and effective and well, very well tolerated. The next thing that we had to do is with that dataset was, part of having two kind of registrational quality studies is you have to examine the from the minimum effective dose to the dose, you know, that is give you the best benefit and the minimum, you know, for the top what you're trying to do is examine where does the maximal benefit become achieved without achieving other side effects. The 30 mg, based on our analysis of the first dataset, showed us that when we looked at the PK analysis and saw some patients that had variability and were actually higher exposures, we didn't actually get better efficacy. The 30 mg was deemed from the dataset that we had to be a maximally effective dose. We didn't feel like we needed to go higher there based on the data set from looking at the PK/PD kind of response there. Using the preclinical data and using the PET data. In parallel to that study, we'd actually done a human PET study. We're able to determine the doses that would give us a bracket around 70%. 10 mg gives us approximately 68% receptor occupancy, and 15 gives us 78%. What we have is a nice, you know, plus or minus variability. We've got a nice bracket around that 70% receptor occupancy in order to demonstrate across the two trials the minimum effective dose. The agency wants to know what is your effective dose range for informing physicians on how to use the drug. It was determined both on the data that we had and also on the PET studies that we had did, you know, completed in parallel to actually inform the dose range. Thank you, J.R. Ray, anything to add? No, just one thing, and that's inherent in your question, Jess. I think is, you know, these two trials have registrational potential in that they characterize the full dose range from, as John mentioned, the minimum effective dose to the top dose of 30 mg. Historically, you don't have to replicate doses in trials, but you do have to show that they statistically separate from placebo in when you submit the data package. I just wanted to give that clarity, because that gives us a confidence that if the data reads out as we hope it will, that we could actually have a potentially registrational program. Of course, that's in the purview of the FDA ultimately and empirically driven. Thank you. Just to clarify that a 2little bit. Is that to say if the high dose only hits in one study, that, but both studies have a positive dose that you could file based on that? Potentially, yes, of course. You know, I don't want to speak for the agency, and of course it's empirically driven. That scenario would potentially lead to a registrational program. Historically, that has been done. I just wanna make sure that we look at that data and then have that discussion with the agency. Question in the audience. Hi. Another one on emraclidine. You have a competitor in development a little bit behind you, M4 agonist. Can you just talk a little bit about the difference in MOA, with emraclidine being a positive allosteric modulator versus just an agonist and what that might show up like in the data? Sure. It's, it's an important question because obviously we're so focused on mechanism of action as the central unifying thesis. J.R., if you'd be kind enough to quickly walk through the distinction between an agonist and a positive allosteric modulator, and why we think there's a benefit in schizophrenia from a positive allosteric modulator. Sure. Thanks, Tony, thanks for the question. Give you a little receptor pharmacology course, mini course cliff notes here. Yeah, the way that the PAM is designed is it actually amplifies the ability of a synapse to have a signal that is transferred. A PAM relies on the presence of the ligand. As you know, in the nervous system, the signaling, how messages are encoded in the nervous system is the speed at which neurotransmitter is released or not. There's information carried along with the presence or absence of the ligand. What happens when you have a full agonist is as long as the drug is present, it will activate the receptor. There's a loss of temporal information in the nervous system when you have a full agonist. If you think about what it is that you're actually trying to do is correct a dynamic neural network, PAMs are usually better able to do that because they don't overactivate the receptor. You don't lose the information encoding in the nervous system, you know, with a PAM like you will with a full agonist. It's really about the duration of effect of the drug at the synapse that you're really trying to correct in disease. That's the benefit of actually having a positive allosteric modulator versus an agonist is that duration of effect. J.R., if you could, 'cause inherent in the question is the question about M4 selectivity. Talk just a little bit about that as distinct from a non-selective approach. You know, as many of you realize, the history here was started with a non-selective muscarinic agonist called xanomeline. What people are familiar with the literature will know is that the very first study that was done was in an Alzheimer's disease population. What they noted with the, with xanomeline was that it was dose dependent and had statistically significant effects across a number of you know, psychiatry-related measures. There's vocalizations, outbursts, but importantly, delusions, hallucinations were also dose dependently reduced and significantly reduced. It was the first data set that pointed towards muscarinic as being an effective mechanism of action in treating psychosis in that AD population. What people familiar with the literature also know is that about 50% of the patients dropped because of the GI issues and because of the non-selectivity of hitting the M1 receptor that's expressed in the GI tract. You had a very high rate of nausea and vomiting that caused the patients to actually drop out in that study. The whole concept around the importance of selectivity, of getting to the M4 action and eliminating the M1 was we believe that the M4 receptor that's highly expressed in the striatum, which is the part of the brain that we're trying to modulate here, because of the role of D2s that have been demonstrated by the typicals and atypicals. The M4 is actually a break on the cholinergic system. When you activate it reduces excitation, reduces dopamine release. Ultimately, it acts in a very similar biological way to the atypicals. What it does is it avoids binding directly to the D2 receptor that's associated with all the side effects. The extrapyramidal symptoms, the metabolic, the hormonal effects that you get with D2s are all avoided because we're not blocking the D2. With this selectivity to M4, we've gotten away from the xanomeline demonstrated effects of having M1 activity. That's why we had a really beneficial side effect profile. What we've been able to do is maintain the efficacy of the M4 target and its ability to reduce dopaminergic activity and provide that antipsychotic benefit. That was the whole concept. We were the first company to actually demonstrate the ability to achieve that by having this highly selective molecule. Thank you, J.R.. Jess, I wanna make sure that this side of the room doesn't have any questions and that we're clear. I'm not sure you can see them. I can, but I think you're clear for your next question. Oh, there's one in the audience. I was just gonna ask on the M4 agonist then, you know, what disease areas do you think that one is more suited towards? Ray? You know, if you look at positive allosteric modulators as John was mentioning and then the M4 agonist and potentially the need to treat certain populations more aggressively, you would look at a potentially a bipolar disorder population, especially bipolar mania, where they need to be aggressively treated. That's one option as well. Those are considerations that we've been discussing in terms of how to differentiate the PAM from an M4 agonist in terms of the populations. That's still, of course, hypothetical until we actually do those trials. That's one example of where an M4 agonist would probably have great treatment effect. I will hasten to point out that we obviously like the mechanism quite a lot. We also have an M4 agonist in the early stages of late stages of discovery, that we're quite interested in. Our approach is on a portfolio or franchise basis. If we have a positive allosteric modulator that's selective for M4 and have an M4 agonist, we should be able to cover a broader number of indication opportunities for the benefit of patients. We are learning more, but our goal is to become the foremost expert on the muscarinic pathway. Jess, I think you're clear. Another question? Can you also talk about what gives you confidence to go into Alzheimer's disease psychosis? Sure. We have just under two minutes left. Ray, I'm gonna actually ask you to cover this, very, very quickly. J.R. may have some mechanistic rationale comments as well. Right. I think the fact that we saw such a robust antipsychotic effect, Jess, you know, gives us the confidence that this will also work in treating patients with Alzheimer's disease, where the manifestation of psychosis in that population is very different from that in schizophrenia, but still under the umbrella of treating psychosis, mostly hallucinations and delusions. We believe that it will also have an opportunity to show robust results as well. I'll just reiterate what I said about xanomeline having a benefit that was dose dependent and also statistically significant in the original AD study, where they actually showed that delusions and hallucinations were reduced, as well as the other things like paranoia and outbursts. I think there's a nice demonstration and clinical validation of muscarinics in that disease population. You know, from a drug discovery guy, I like clinical validation, I'll say that. Very good. Okay. I think we're about out of time, so we'll leave it there. Thank you. All right. Thank you, Jess, very much. Thank you.