Hello, and thank you all for joining the Karuna Therapeutics Webcast event today. Our session will focus on our ongoing development efforts around our lead product candidate, KarXT, for the treatment of schizophrenia, with an emphasis today on psychosis and Alzheimer's disease. Before we begin, please note that this conference call will include forward-looking statements made pursuant to the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995. Please see slide two of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements. Steve Paul, Chief Executive Officer, President, and Chairman of the Board of Karuna, will begin today's presentation, followed by remarks from Andrew Miller, Founder and Chief Operating Officer, and Ron Marcus, Senior Vice President of Medical and Medical Lead for Alzheimer's Disease Program. After the conclusion of today's presentation, Steve and Andrew will be joined by our Chief Financial Officer, Troy Ignelzi, for the Q&A portion of today's presentation, which will wrap up the call. Steve. Thank you, Alexis, and thank you all for tuning in to our webcast today. At Karuna, we are committed to push the boundaries of neuroscience to transform the treatment of mental illness. Our team is uniquely steeped in neuroscience, from drug discovery to clinical development and even clinical practice, with first-hand experience working with patients, their families, and caregivers. This provides us with a very unique perspective, allowing us to better understand the needs of those living with mental illness as we work towards our mission of developing and delivering transformative medicines for people living with serious psychiatric and neurological conditions. This is literally our North Star here at Karuna, which is why we're excited to share updates on our clinical development efforts for our lead investigational medicine, xanomeline-trospium, also known as KarXT. Now, before we begin, it's important to acknowledge the current state of mental health treatment and outcomes in the United States. The burden of mental illness is profound, with one in every five adults in the U.S. experiencing a diagnosable mental illness and one in twenty experiencing a serious, life-threatening mental illness. Even when there are available treatments, we see major deficiencies in the ability of the current treatments to provide meaningful, functional outcomes. For example, only 10% of people with schizophrenia are gainfully employed, despite more than 20 available treatment options. Nearly 30 years of life is potentially lost in people with schizophrenia compared to the general population, partly attributed to cardiovascular and metabolic disease comorbidities, and much of this due to current medications as well as, unfortunately, an increased rate of suicide. Many, if not most, people with schizophrenia are disabled by their symptoms for their entire adult life. As a society, we should understand that current treatments do not provide adequate solutions for those suffering, and we cannot ignore the burden of mental illness that still exists. As scientists, clinicians, and drug developers, we simply can't accept the current standards of care as adequate or good enough. Now, that's why at Karuna we're focused on developing and delivering medicines that work in entirely different ways and are potentially better than current treatments, so that people living with the most serious psychiatric conditions can find relief from burdensome symptoms and without burdensome side effects in order to live happier and more productive lives. The primary focus of our webcast today is to discuss our lead asset, KarXT, an M1 M4-preferring muscarinic receptor agonist, which arguably represents the first new approach to treating schizophrenia and psychosis in Alzheimer's disease in more than 50 years. We are taking a very deliberate approach to lifecycle management, utilizing our deep expertise in neuroscience, decades of preclinical and clinical research, and our unique understanding of the biology and pharmacology of muscarinic receptors. Our development efforts with KarXT are focused on evaluating its potential therapeutic utility in conditions where its mechanism of action could provide substantial relief to patients, such as dementia-related psychosis in patients with Alzheimer's disease. Many of you know, KarXT is currently being evaluated in phase III trials for the treatment of schizophrenia as a monotherapy through the EMERGENT clinical program and as an adjunctive therapy through the ARISE clinical program. Earlier this month, we announced that we have completed enrollment of our phase III EMERGENT-2 trial, which is a five-week inpatient trial evaluating the efficacy, safety, and tolerability of KarXT compared to placebo. We remain on track for a top-line data readout mid-year, specifically in the third quarter. We also expect top-line data from our second p hase III efficacy and safety trial, EMERGENT-3, in the first quarter of 2023. I am incredibly proud of the progress we made to date. The challenges we've been able to successfully navigate over the past two years as we look forward to significant milestones over the coming months, including the expansion of our development efforts in Alzheimer's disease, which we are excited to speak more about today. Now, this morning, we are shining a spotlight on psychosis related to Alzheimer's disease. We know that there is a tremendous unmet medical need in Alzheimer's disease, but some may not fully appreciate the true burden of this condition, particularly the behavioral and psychiatric symptoms for which there are currently no approved treatments. As Alexis mentioned earlier, Andrew will discuss KarXT's novel mechanism of action, reviewing key published data supporting this dual M1 M4 preferring agonist approach and how this translates clinically and what we've seen to date in clinical studies with xanomeline and KarXT. From there, Ron will share new details of our phase III program, the comprehensive clinical program evaluating KarXT for the treatment of psychosis in Alzheimer's disease. This includes two phase III trials evaluating the efficacy and safety of KarXT compared to placebo as an acute therapy as well as a maintenance therapy, and an open label extension of both trials, which will evaluate long-term safety. Finally, we'll end with some closing remarks and Q&A. Before handing it over to Andrew, I'd like to shed some more light on psychosis related to Alzheimer's to further underscore the critical unmet medical need of this condition. As many of you know, Alzheimer's disease is a type of dementia that affects memory, thinking, and behavior. It is the leading form of dementia worldwide, affecting approximately 6 million people in the U.S. Alzheimer's disease is progressive, meaning that memory and other functions deteriorate over time due to the continued loss of nerve cells, neurons, and synapses in key brain regions. Many of us have firsthand experience with Alzheimer's disease, whether it is a family member or friend, and have likely seen the devastating impact of this disease on the person afflicted, as well as their loved ones and caregivers. Memory loss and confusion are the better known symptoms of Alzheimer's, which worsen over time as the disease progresses. What many people, however, might be less familiar with are the debilitating behavioral symptoms associated with Alzheimer's, such as hallucinations, delusions, agitation, and aggression. These symptoms do not typically appear at the early stages of the disease. However, over time, they become more prevalent with increased disease severity. Eventually, 30%-50% of individuals with Alzheimer's disease develop these disabling behavioral symptoms. As you can imagine, the impact of these behavioral symptoms places a huge burden on families and caregivers and can often be a key factor in the transition from living at home to a full-time care-based setting. There are currently no approved treatments for the behavioral symptoms of Alzheimer's disease. Today, patients are often treated off-label with antipsychotic drugs and sedatives, despite FDA box warnings for their association with increased morbidity and mortality in the elderly. Existing antipsychotic drugs work through blocking dopamine and serotonin pathways, which are also associated with side effects such as extrapyramidal symptoms or abnormal motor movements, weight gain, metabolic dysfunction, sedation, and other adverse events, such as an increased risk of stroke and death in the elderly. Despite this, off-label use of these medicines is unfortunately very common as there are simply no other treatment options. Last year, The New York Times investigated the use of antipsychotics in nursing homes, finding that at least 21% of all residents are taking an antipsychotic drug. At its core, this underscores the dire need for increased awareness of the behavioral symptoms related to dementia, as well as the urgent need to develop new therapies that are both effective and safe. I'll now hand it over to Andrew Miller, Karuna's Founder and Chief Operating Officer. Andrew? Thank you, Steve. We have heard Steve discuss the significant need for new treatments for Alzheimer's disease. Let me now review with you why we believe KarXT could be a potential treatment for the behavioral symptoms of Alzheimer's that so many are living with today. KarXT has the potential to be the first medicine of its kind with a truly new and unique mechanism of action that doesn't rely on the dopaminergic or serotonergic pathways to treat the psychosis associated with schizophrenia and Alzheimer's disease. KarXT combines xanomeline, a muscarinic receptor agonist, with trospium chloride, an FDA-approved muscarinic receptor antagonist that does not meaningfully cross the blood-brain barrier. This design enables the preferential stimulation of muscarinic receptors in the brain to unlock the therapeutic potential of the xanomeline while ameliorating its peripheral side effects through the use of trospium. On this slide, you'll see how the use of trospium may work to reduce the side effects of xanomeline. The potential therapeutic benefit of KarXT is driven by xanomeline, which has demonstrated antipsychotic activity and pro-cognitive properties across three phase II studies in Alzheimer's disease and schizophrenia. The dual mechanism of action of xanomeline allows it to stimulate simultaneously both the M1 and M4 receptors in the brain. We believe this dual mechanism is an important and valuable attribute of xanomeline, and research has shown that activity at the M1 and M4 receptors affects brain networks involved in both cognition and psychosis. This unique pharmacology enables us to evaluate KarXT's potential use as a treatment for complex mental illnesses with multiple symptom domains, with psychosis and Alzheimer's disease serving as the logical next step in our development efforts in parallel with our ongoing efforts in schizophrenia. Clinical research exploring xanomeline as a treatment for Alzheimer's disease provided the first evidence of the pro-cognitive and antipsychotic properties of a muscarinic receptor agonist. This seminal study has served as the foundational research for the exploration of muscarinic receptor-targeted therapies in psychiatry and gives us a better understanding of xanomeline's properties, which informs our development efforts with KarXT. Let's take a deeper look at this study and its findings. The original clinical development of xanomeline focused on evaluating it as a pro-cognitive treatment for Alzheimer's disease. Eli Lilly conducted a six-month, double-blind, multicenter phase II trial evaluating the effects of xanomeline compared to placebo in 343 patients with mild to moderate Alzheimer's. In this study, patients were randomized to four parallel treatment arms where they received either placebo, 75 mg, 150 mg, or 225 mg of xanomeline daily. While the primary focus of the study was cognition, the trial did also capture effects on behavioral symptoms of Alzheimer's disease. Patients in the study weren't recruited based on these symptoms. However, some patients had behavioral symptoms at entrance into the study, and some patients developed them during the trial, which is expected given the nature of the condition and its progression, which Steve spoke to earlier. These effects were measured using the Alzheimer's Disease Symptomatology Scale, also known as the ADSS, which looks at psychiatric symptoms commonly found in these patients, such as hallucinations, delusions, agitation, aggression, and vocal outbursts. In this study, there was evidence of a cognitive benefit associated with xanomeline treatment in patients who completed the trial, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale, or ADAS-Cog. The magnitude of the benefit seen was similar to acetylcholinesterase inhibitors such as donepezil. The effects on behavioral symptoms were highly statistically significant, where xanomeline treatment was associated with a dose-dependent reduction and remission of behavioral symptoms and the prevention of the onset of these symptoms. Here you can see the dramatic improvements in a number of different symptom domains. The first figure looks at the percent of patients who had symptoms at baseline and then had a remission of these symptoms, i.e., they stopped experiencing these symptoms and did not experience them for the entire duration of the trial. To call out a specific example, let's look at hallucinations on the left. In both the placebo and high-dose xanomeline group, there were 17 patients who were experiencing hallucinations at baseline. In one of those 17 patients on placebo, or 6%, hallucinations remitted and were not experienced for the duration of the trial. This is in contrast to the high-dose xanomeline treatment arm, where nine of 17 patients, or 53%, had their hallucinations completely disappear during the trial. This analysis evaluates patients who had psychiatric symptoms at baseline. We can also look at patients who did not have psychiatric symptoms at baseline. The second figure looks at those patients and evaluates whether they developed symptoms during the course of the trial. One would expect to see psychiatric symptoms develop over the course of the trial in some patients as the prevalence of these symptoms increases with disease progression and severity. What we see in the figure is a significantly lower rate of symptom onset in patients treated with xanomeline. Xanomeline had prevented the onset of these symptoms, with onset rates in the high-dose treatment group being approximately two to five times lower than on placebo during the trial. As Steve mentioned earlier, symptoms of hallucinations, delusions, suspiciousness, agitation, and vocal outbursts are extremely burdensome for patients with Alzheimer's and their caregivers, so effective management of these symptoms can meaningfully improve their quality of life. In this trial, activation of muscarinic receptors was associated with both therapeutic benefit on cognition and the treatment and prevention of behavioral symptoms. The link between muscarinic receptor stimulation in the brain, particularly the stimulation of M1 and M4 receptors, and the reduction of symptoms of psychosis and improvement in cognition, has been very well studied following these trial results. However, a successful therapy targeting the receptors has not been developed due to the undesirable side effects that are believed to arise primarily as a result of stimulation of muscarinic receptors in peripheral tissues. What we are looking for is a way to stimulate both the M1 and M4 receptors in the brain, harnessing the benefits of xanomeline, but without the undesirable side effects that prevented the xanomeline successful development. This is where KarXT offers a potential innovative pharmacological solution to treat these symptoms by harnessing the therapeutic benefit of xanomeline while mitigating its side effects through the use of trospium. In our development, we set out to better characterize KarXT's potential tolerability and explore the dose and dose ratios of xanomeline and trospium in the elderly through a phase Ib trial. Previously, we implemented a similar approach to our development efforts in schizophrenia, where a phase I program in normal healthy volunteers informed the most appropriate doses and xanomeline to trospium ratio that we used in our positive phase II EMERGENT-1 trial in schizophrenia. Moving forward, the results of this phase Ib trial in healthy elderly volunteers will inform our phase III program for the treatment of psychosis associated with Alzheimer's disease. Our phase Ib trial in healthy elderly volunteers was a three cohort placebo-controlled trial that utilized a flexible dosing protocol over two to three weeks. Flexible dosing, similar to how we conducted the EMERGENT-1 trial, allowed the dose of KarXT to be titrated based on tolerability as determined by a clinician. Said a different way, the dose of xanomeline would be escalated if the patient was tolerating KarXT well, and if not, there was the option to not increase the dose of KarXT further or to go back to a lower dose if needed. The idea being that volunteers would end up at a dose of KarXT they tolerated well. This slide summarizes the key findings from the trial, and there are a few in particular that I would like to highlight, which helped inform the doses that will be used in the design of our phase III clinical program. First, we learned that a lower dose of trospium to xanomeline was better tolerated in the elderly compared to those ratios used in EMERGENT-1. The purpose of using trospium is to hopefully allow for the titration of xanomeline high enough to reach potentially therapeutic blood levels while still being well-tolerated. In this trial, the majority of people receiving KarXT titrated their dose to xanomeline total daily doses of between 150 mg and 200 mg. The doses where therapeutic benefits were observed in the original xanomeline trial in patients with Alzheimer's disease that we reviewed a minute ago. We must also take into account that based on our earlier phase I trials, we see approximately 10% higher xanomeline exposures with our co-formulation compared to a powder blend and capsule formulation like what Lilly used. This places the doses achieved in this healthy elderly trial squarely in the range that demonstrated therapeutic benefits in the original Alzheimer's trial. Importantly, and more importantly than dose levels alone, the average blood level of xanomeline achieved in this trial was comparable to the blood levels seen in the positive EMERGENT-1 trial in schizophrenia, suggesting that elderly patients could achieve potentially therapeutic blood levels or exposures with xanomeline doses that are approximately 20%-25% lower than the doses used in the EMERGENT-1 trial in patients with schizophrenia. In summary, results from our phase Ib healthy elderly trial suggest that potentially therapeutic doses of KarXT can be administered to elderly adults while maintaining a favorable tolerability profile. Findings from this trial were instrumental in informing the doses used and the trial design of our phase III development efforts. I will now hand it over to Ron, who will speak about the details of our phase III program. Ron? Thanks, Andrew. The ADEPT program evaluating KarXT for the treatment of psychosis in Alzheimer's disease will consist of two registrational quality phase III trials designed to demonstrate KarXT's utility as both an acute and maintenance treatment, as well as a third long-term safety study. In a few months, we will initiate our first phase III trial, ADEPT-1, which will look at the efficacy and safety of KarXT using a randomized withdrawal trial design. The second trial, ADEPT-2, will evaluate the efficacy and safety of KarXT compared to placebo as an acute treatment using a double-blind, placebo-controlled 12-week trial, which is expected to initiate next year. The third is a one-year rollover open-label study to provide long-term safety data for KarXT in this patient population. Patients who complete either efficacy trial may be eligible to enter into this long-term safety study. We expect that both efficacy trials will complete around the same time in 2025, though we'll continue to refine these timelines as the studies initiate and with a better understanding of enrollment projections. Now, let's take a closer look at ADEPT-1 and ADEPT-2. The phase III ADEPT-1 trial will evaluate the safety and efficacy of KarXT in adults ages 55 to 90 years old with moderate to severe psychosis related to Alzheimer's disease dementia in a randomized withdrawal design. In this trial, patients will be living at home or an assisted living facility. The primary objective of this trial is to evaluate relapse prevention as measured by time from randomization to relapse during the 26-week double-blind period. Secondary endpoints will evaluate the time from randomization to discontinuation for any reason, as well as standard safety and tolerability measures. As you can see here, this trial consists of a 12-week single-blind treatment period, followed by a 26-week double-blind period, where subjects will be randomized to receive KarXT or placebo. There is a 30-day screening period prior to entry into the single-blind portion of the trial in which we will conduct our routine screening assessments and exams, and patients will taper and discontinue prohibited concomitant medications such as antipsychotics. Those who complete the screening period and fulfill all the inclusion and exclusion criteria, of which select criteria can be found on the slide, will be eligible for the study. Eligible patients will enter the study actively experiencing symptoms of psychosis. They will hear or see things that are not actually there, have altered or false beliefs and perceptions, or have heightened levels of paranoia. Upon entering the study, they will receive KarXT for at least 12 weeks in the single-blind treatment period. Patients who meet the responder criteria at weeks 10 and 12, meaning that they have experienced a significant reduction in symptoms at both time points, and they've maintained this response to treatment between the two time points, will be randomized into the double-blind portion of the study. The relapse criteria for entry into the double-blind randomized withdrawal treatment period are based on two symptom domains, hallucinations and delusions. They're measured by hallucination and delusion domains within the Neuropsychiatric Inventory-Clinician scale, also known as the NPI-C H+D, and the Clinical Global Impression-Change scale, or better known as the CGI-C. For context, the NPI-C is a 14-symptom domain scale that is similar to the ADSS scale described earlier by Andrew and used in the earlier Alzheimer's trial with xanomeline. Both capture the presence and severity of the key behavioral symptoms associated with dementia with the NPI-C also capturing information about the frequency of these symptoms and the level of caregiver distress. The NPI-C is a well-validated scale in this patient population. The CGI-C is a global scale that is commonly used to assess how much of the patient's symptoms have improved or worsened over time. It requires the assessor to consider aspects of the symptoms of psychosis, including hallucinations and delusions, prior to providing a global assessment of change score. To have met the criteria for response, a patient must demonstrate at least a 40% reduction in symptoms on the NPI-C H+D scale compared to baseline and show a CGI-C score of one or two, which represents a clinically meaningful improvement in symptoms of very much improved or much improved at weeks 10 and 12. As I mentioned earlier, upon meeting this response criteria, patients will then enter the double-blind randomized withdrawal period where they will receive KarXT or placebo. Here, a patient must meet at least one of four criteria to be considered as having a relapse, including at least a 40% increase on the NPI-C scores compared to the end of week 12, and a CGIC score of six or seven, representing symptoms of much worse or very much worse to ensure that the relapse represents a clinically meaningful change. Other relapse criteria can be seen here on the slide. This randomized withdrawal trial design is commonly seen in clinical development programs as it helps researchers better understand a medicine's maintenance of effect, and in this case, at what rate the symptoms reemerge when treated with KarXT compared to placebo. This is an incredibly valuable information for patients, caregivers, and physicians. Now, let's take a closer look at how we're approaching dosing. As Andrew touched on earlier, through our studies to date with KarXT, we have learned that starting at lower doses of KarXT and then uptitrating allows for an accommodation period, and importantly, for us to find a well-tolerated and potentially therapeutic dose. The use of titration is commonly used in clinical practice today, particularly in psychiatry and in the treatment of psychosis. In medical school, we learned lower and slower when it comes to administering therapy to elderly patients, meaning that the lower doses of drug given over longer periods of time allows for this population, in particular, to better tolerate treatment in order to reach a maximally therapeutic dose. This approach has been successfully used with donepezil, which acts on the cholinergic system by inhibiting acetylcholinesterase. In a 2020 study, the use of dose titration before escalating to higher therapeutic doses of donepezil showed much better tolerability in terms of cholinergic adverse events in Alzheimer's disease patients. In addition to the use of flexible dosing in the study, you will see that we have introduced new doses of KarXT. These doses have a lower trospium-xanomeline ratio than those that are currently being used in our schizophrenia trials. This is based on the findings of a phase I study in healthy elderly volunteers, which Andrew discussed earlier. The doses represented here are ratios of xanomeline to trospium, which will be given three times per day. For example, patients will start off at 20 mg of xanomeline and 2 mg of trospium three times a day, resulting in a total daily dose of 60 mg of xanomeline and 6 mg of trospium. In the single-blind portion of the study, KarXT will be titrated up to a maximum of 200 mg of xanomeline and 20 mg of trospium total daily dose based on tolerability and therapeutic benefit. Titration based on tolerability and clinical response allows us to find the optimal dose for these patients. We do expect that we will see a larger distribution of clinically meaningful doses in this population, but this is not unlike what is commonly seen with other drugs, including the cholinesterase inhibitors in patients with dementia. Recall, as Andrew mentioned earlier, in our phase I healthy elderly volunteer study, we saw patients across various dose ranges, including those below 150 mg of xanomeline, achieving average blood levels or exposure levels of xanomeline comparable to those seen in the EMERGENT-1 trial, where the top dose was 250 mg of xanomeline per day. We feel confident that these doses and this dosing schedule will allow us to achieve potentially therapeutic exposures as seen in prior studies of KarXT. Overall, this trial will provide valuable insights into understanding the efficacy and maintenance and effect of KarXT for the treatment of psychosis, specifically hallucinations and delusions in patients with psychosis related to Alzheimer's dementia. In addition to these symptoms, we are gathering data on other prominent symptom domains such as agitation, aggression, and apathy, where we saw xanomeline show a benefit in the earlier Alzheimer's study, which will help characterize KarXT's potential effects on treating these other important symptoms, as well as inform our future potential development efforts. In addition to ADEPT-1, we will also be conducting a phase three trial evaluating the acute efficacy of KarXT in psychosis related to Alzheimer's disease. Here, you will see a preview of our trial design, which will evaluate the efficacy and safety of KarXT compared to placebo in a one-to-one randomized double-blind placebo-controlled trial. We anticipate the primary endpoint of ADEPT-2 will also be the NPI-C H+D. We plan to share further details of this trial as we approach its initiation next year. Together, these two trials will provide us with valuable information on the potential use of KarXT as both a maintenance therapy, understanding its ability to treat and prevent the onset of symptoms over time, as well as an acute treatment. We look forward to initiating our first trial in our program mid-year. Thank you. Thank you, Ron. To quickly summarize, we're extremely enthusiastic about the continued progression and expansion of our development efforts, which serve as a testament to our belief that KarXT has the potential to offer a new transformative therapy for people living with serious mental illness, including schizophrenia and dementia-related psychosis. Thank you all for joining today. Andrew, Troy and I will now take your questions. Thank you, presenters. Participants, we will now begin the question and answer session. To ask a question over the phone, you may press the star key followed by the number one from your telephone keypads. To withdraw your request, you may press the pound key. Again, that's star one to ask a question over the phone or the pound key to withdraw your request. Presenters, our first question is from the line of Salveen Richter of Goldman Sachs. Your line's now open. Good morning. Thank you for taking my question. With the Alzheimer's disease study, is it the relapse trial or the acute trial that has the lower bar here for success? Do you need both for approval? How comfortable are you with the safety profile here in the context of going up to higher doses in the Alzheimer's study than you did in schizophrenia psychosis? Salveen, this is Steve. Let me start, and I'll let Andrew comment as well. Thanks for your questions. I think it's too soon to tell what will be required actually for approval. Obviously, this will require additional discussions. What we feel very good about, however, is that we have a drug that, at least based on the Lilly trial, works both acutely, and I might add, pretty rapidly. You can check that out in the Bodick et al. paper, but also seems to work prophylactically as a preventative. We think we're going to see efficacy in both scenarios. Clinically, as a clinician, I think both are important. What often happens when patients get psychotic, the patients that have Alzheimer's, is they get, you know, they start hallucinating, they get delusions, usually persecutory delusions, they get agitated. That is, in essence, a bit of a medical emergency to be completely blunt about it. We like the fact that we have a drug that will very likely treat that without producing the profound sedation and other adverse events associated with, you know, the off-label use of antipsychotics and sedatives. We also like the fact that if patients remain on the drug, as you saw from the study that Andrew profiled, they're much less likely to have a psychotic episode over time. We think both features are really important, and we have data from a fairly large phase two study that supports that the drug will work in both scenarios. That's what our hope and expectation is moving forward. Andrew, do you wanna comment? Thanks, Steve. I can comment quickly on the dosing part of the question. Please I think from our perspective, we feel quite comfortable with the dosing scheme that we've designed into the ADEPT program, you know, on the basis of the historical efficacy data with xanomeline as well as KarXT and the safety and tolerability data from the phase one healthy elderly volunteer study. You know, fundamentally, in both schizophrenia as well as in dementia, and specifically Alzheimer's here, our goal is to use trospium and dose titration to allow xanomeline to be dosed high enough to see what we think would be therapeutic exposures. That's what we're able to achieve in the healthy elderly study. As we translate this now into patients with dementia, you know, our hope, our expectation is that the first few weeks of the ADEPT program, if it looks similar to what we saw in healthy elderly volunteers, we'll be able to titrate patients up to doses that provide them, on average, with exposure similar to what we saw in the successful schizophrenia program. I think that gives us confidence in this dosing scheme, and that we'll be able to achieve appropriate exposures to hopefully replicate some of the efficacy benefits that we've been discussing. Yeah. Just to comment again, as Ron pointed out, this kind of dose titration and flexible dosing is very common, particularly in the elderly. You know, we have a class of drugs, the cholinesterase inhibitors, where if you don't titrate, it's often very difficult to get patients to a therapeutic dose. If you do that, the vast majority will get there without very substantial cholinergic adverse events. This is pretty common. It's just good medicine. Again, we anticipate that patients will be on such a drug for quite some period of time. Thank you. Next question is from the line of Laura Chico of Wedbush Securities. Your line is now open. Good morning. Thanks very much for taking the question. I have two. The first question is on, I guess, the overall ADEPT programs, and I'm wondering if you could just clarify the safety database requirements here. Presumably, you'd have potentially an approval in the schizophrenia population prior to submitting an Alzheimer's disease psychosis. The ADEPT programs seems pretty large in terms of the number of patients being recruited. Just kinda curious, how do those requirements change in this second indication? Just with respect to ADEPT 1, I'm wondering if you could talk a little bit more around the rationale around the relapse definitions and perhaps maybe your assumptions on treatment effect in that population. Thanks very much. Andrew, do you wanna comment on the second question, and then we can work backwards? Sure. Thanks, Steve, by the way. From the sort of responder and then relapse criteria perspective. You know, I think we've crafted these kinda four criteria consistent with typical clinical practice, historical studies, not just in dementia, but also looking back into randomized withdrawal study designs in schizophrenia, which have been run historically. As we look across these criteria, I think they speak to ensuring clinical meaningfulness, a 40% reduction on NPI-C, as well as being paired with CGI-C score requirements. You know, we look at requiring treatment with other antipsychotics, discontinuation due to lack of efficacy or hospitalization. Those last three are really more outcome-based. I think those are pretty typical criteria established in the literature historically. Obviously, we feel good about the use of the NPI-C. It was specifically designed to assess psychiatric symptoms of dementia, including Alzheimer's. I think these criteria ensure that, you know, if we're able to demonstrate superiority over placebo, it will be a clinically meaningful change that we've seen. Yeah. Laura, on the first part of your question, what we wanted to do here is design a program that will get us a label, a good label, both for rapid acute treatment as well as preventative treatment. We also recognize that the database from our schizophrenia trials will be relevant. Just to remind everybody, the average age of patients in that trial, in those trials, I should say, you know, roughly between, let's say, 40 and 45 years of age. This is a much older population of patients. I think having additional safety data as we've designed here is going to be prudent and very important for the FDA. I do remind folks that in the Lilly xanomeline trial, we had 68 patients remain on the drug safely for at least 12 months, at least a year. We had a handful of patients that were on the drug for several years and doing well. We pretty confident that there will be good long-term safety, but we need that database and we wanna do something definitive as we move forward with this medicine. If Steve, I'll just add. That's super helpful. Sorry. Oh, sorry, go ahead. Sorry, Laura. I would just add quickly to that. You know, I think by collecting long-term safety data, it's a great opportunity for us to potentially differentiate from currently used medicines. You know, Steve referred to them in his presentation with a black box warning for increased mortality, in addition to a list of other problematic side effects. I think by collecting this data gives us an opportunity to really show a potential important differentiating feature of KarXT in this patient population. Got it. You know, if I could just sneak one in just related to Steve's comments there on site of care. Should we presume the majority of these patients are in long-term care facilities? I guess I'm just thinking about it from the perspective of the TID dosing. Thank you very much. Appreciate it. Well, my comment there, Laura, is if you've ever worked with a patient, even with early Alzheimer's disease, let alone, you know, mid to late stage disease, these aren't patients that are handed a bottle of pills and say, "Okay, take your medicine three times a day." That's not how it works. These patients, whether they're in an inpatient facility like a nursing home or frankly at home with a caregiver, they're given their medicine. Okay? That's, I think, the real you know, nice thing about this is they'll be given medicine, you know, maybe before each meal or what have you. It almost invariably will want their caregivers to help them manage their medication. As you know, they're often on multiple medications, not just for, you know, CNS conditions. Next question is from the line of Paul Matteis of Stifel. Your line's now open. Hey, thanks for the question. This is Alex on for Paul. Just a quick follow-up on the first question related to the bar for approval. I was wondering if maybe you could characterize your interactions with FDA as it relates to the design of these studies. Did FDA suggest running a relapse prevention and acute study? Maybe if you could talk a little bit more about that'd be great. Then for the relapse prevention study. I was wondering if you could talk a little bit about powering assumptions and whether or not there would be an interim analysis pending a certain number of events, and if the trial could stop early. Thanks. Andrew? Sure. So with respect to the overall kind of study design and enrollment assumptions as well as our design of the study, you know, I think from a statistical perspective, you know, we feel good with the target enrollment numbers we've given here for the ADEPT-1 trial. You know, again, I think it provides us an opportunity both to, you know, run a study that's significantly sized to provide important and definitive information with respect to safety, but also to be well powered in terms of separating from placebo in terms of the rate of relapse as well as time from randomization to discontinuation for any reason. I think similar to how we've approached the EMERGENT program, we've overall taken a somewhat conservative view of how we think about powering these studies, in part because as we've been discussing, you know, we believe that KarXT, you know, has the potential to be a safe and effective treatment, and we wanna make sure that we give ourselves the appropriate opportunity to see that, as part of the ADEPT program. Yeah. I think specifically with respect to regulatory conversations, I think what we can say at this point is, you know, like any sponsor, we interact with various regulatory agencies as we think about designing and executing clinical trials, and I think this program does reflect those conversations, and feedback that we have received. Haven't commented specifically on particular requests or particular aspects of those conversations. Yeah. You know, let me just underscore, as I said earlier, we want to design trials, a program here that will provide unambiguous results on the safety and efficacy of this treatment for dementia-related psychosis in patients with Alzheimer's disease, and something that is clinically meaningful and that if appropriately placed in the label, will allow prescribers, caregivers, patients, et cetera, to again have unambiguous evidence that this works and is effective. You know, we just would underscore that because there's no approved drug in this space, and the current standards of care that are being used off-label are pretty horrific in many cases, this should be of interest to regulators, here in the U.S. and around the world if we achieve the goals that you know, we are cautiously optimistic, I should say, that we'll see. Then that's helpful. Maybe one follow-up. Is the expectation for the single-blind treatment period that you get 150 patients up to a 150 mg dose, or would you move forward pending enough patients at the response criteria if they were at lower doses? Yeah, Andrew can comment. I'm pretty certain it's the response criteria we're looking for. One needs to think about exposures, blood levels rather than actual oral doses here, as I think Ron's comments underscored. It's really, you know, responses and tolerability at that point. Yeah. To emphasize that, Steve, you know, the entrance into the double-blind randomization period is not, you know, there's no consideration for dose as part of that. It's really about meeting the response criteria. Again, I think we have a lot of comfort with how we design the dosing strategy. I think important that, you know, it does allow for flexible dosing titration based, you know, primarily on tolerability up to the 150 mg xanomeline dose level, and then both tolerability and response, up to the 200 level. You know, I think the idea that there's flexibility on the part of clinicians and patients in the study to find what is the best tolerated and then hopefully efficacious dose to meet those response criteria. We don't take anything into account specifically. We think about their entrance into the randomization phase other than that clinical benefit. Great. Thank you. Next question is from the line of Cory Kasimov of JP Morgan. Your line is now open. Hey, good morning, guys. Thank you for taking my questions too for me. First of all, interested in your perspective as it relates to NUPLAZID or pimavanserin, and if you expect the upcoming FDA panel for that candidate to have possible read-through into the design that you laid out today or the outlook for your programs. The second question I have is, when you think about the tolerability profile that's been established for KarXT, are there any specific adverse events that have been seen in previous trials that would be maybe most concerning or we should be looking out for in a more elderly patient population with Alzheimer's as we get to results down the line? Thanks a lot. Andrew, I'll let you take the Acadia question and, maybe I'll provide some color commentary there as well. Sure. I mean, I think with respect to Nuplazid and the upcoming AdCom and PDUFA dates, you know, I think from our perspective, you know, we don't feel that the outcome of those is gonna have meaningful impact on how we think about designing our program and executing on our program. I think as Steve mentioned, you know, in response to the last question, our focus has been designing a program that, you know, gives us the chance to provide unequivocal data of a clinically meaningful benefit in an overall favorable safety and tolerability profile for KarXT. I don't think that's going to be impacted by whatever happens with other companies or other programs. We do, of course, follow those things closely to the extent we can glean information that's helpful to us. I don't think we anticipate any meaningful impact on how we're thinking about our development efforts. I don't know, Steve, if you would add anything to that. No, I think that's exactly what I would have said. Cory, by the way, thanks for your questions. On the first question, you know, we look at any of the AEs, the adverse events that we saw in the initial xanomeline trials, either the procholinergic AEs, which were mostly there because we didn't obviously have a flexible dosing or trospium. You know, things like syncope, which we've not seen in our phase Ib studies or any of our studies in adults, you know, in the case of the schizophrenia trials so far. You know, we look and monitor those. We think that the dose adjustments that we've made for the elderly, for the fact that they generally metabolize drugs and excrete drugs more slowly, less rapidly than younger people, will take care of the more problematic AEs. But all of the cholinergic and anticholinergics are monitored and, you know, so far, knock on wood, you know, we've seen very mild to moderate effects at the dose ranges that we expect to use in this study. We're again, you know, optimistic that we're gonna get, you know, the majority of patients on the therapeutic doses, therapeutic exposures of KarXT. Okay. Very helpful. Thank you. Next question is from the line of Neena Bitritto-Garg of Citi. Your line is now open. Hey, guys. Thanks for taking my questions. My first question is just around assumptions that you made on the discontinuation rate. I know that you mentioned earlier that Alzheimer's patients may have a higher discontinuation rate than what you would expect in schizophrenia. Maybe you can talk a little bit about that. Also I'm just curious if you are incorporating any sort of assessments on cognitive scales as well. Thanks. Andrew? Maybe to take that second part first with respect to cognition. We do have the MMSE, so the Mini-Mental Exam as part of this protocol. Maybe to pick up on the second part of that, you know, we don't have the ADAS-Cog as part of this protocol. The ADAS-Cog is not validated for use in patients who have an MMSE score of less than 11. And we have an MMSE range that includes patients below 11 in this study, reflective of you know, the idea that psychosis is more prominent with disease progression and disease severity in Alzheimer's disease. This, you know, is fundamentally a different population than you would recruit or enroll into an Alzheimer's study focused on cognition. That sort of talks to that first part. I think from a discontinuation perspective, I wouldn't necessarily make a direct comparison to, you know, schizophrenia patients living with schizophrenia as opposed to patients living with dementia. I think fundamentally, if you look at the ADEPT one study design, it is quite different than the EMERGENT -1, two, and three study designs, which are more similar to the acute ADEPT -2 study. You know, obviously, we're looking at the same types of symptoms, but with a single blind treatment period at the beginning and then a double blind randomization period that, you know, has patients overall in this protocol out to 38 weeks. We do have to make some different considerations about discontinuations. Again, I think we've taken an appropriately conservative approach as we think about the overall study size. You know, those are all things that we can monitor during the study. Again, I think we've taken an appropriately conservative approach as we think about the numbers we need to statistically separate from placebo. Got it. Thank you. Presenters, next question is from the line of Myles Minter of William Blair. Your line's now open. Hey, thanks for taking the questions. Just on ADEPT-1, I think you're using your response criteria of 40% and your peer with pimavanserin drug development was using 30%. Is that just in line with your sort of conservatism in getting responders in and powering the study? Or is there something behind that additional 10% responder criteria that you're implementing? Sure. I can take that one directly. You know, I think from our perspective, you know, 40% I think really goes to the point of ensuring that the difference is clinically or the effect is clinically meaningful. I think more importantly, it's really about that tie to the criteria is not just a change in NPI-C, but it is also a change on the CGI-C. Which again is really just a way to tie the benefits specifically to something that's clinically meaningful. You know, the CGI-C criteria is likely to be more stringent in some ways than a 40% reduction in NPI-C. I think they're gonna be closely correlated with each other. I think it really just allows us to ensure that we can speak to the clinically meaningfulness of the change that we see. Okay. Cool. Is there any reason to believe that the therapeutic exposures of xanomeline in an elderly population would differ on a concentration basis to that of the adult population? Because I know that a lot of the rationale here is that you're aiming to achieve exposure levels seen in EMERGENT-1, and I'm just wondering if that changes in an elderly population or maybe in the old Lilly study, you did some exposure work there that could give us more confidence of a direct comparison in this patient population. Thanks. Well, what we're saying is that we can achieve those therapeutic exposures seen in our schizophrenia trials, but also in the Alzheimer's trial of xanomeline at lower doses for a variety of reasons, which we elaborated on, including the exact formulation we're using. We're pretty confident that we're in a good therapeutic range with somewhat lower, just modestly lower doses in the elderly. Of course, we get the benefit of improved tolerability, particularly with the lower ratio of trospium. All of that, you know, was the purpose of our phase one B study, and it's so far working, I think, quite well. Okay. Thanks. Thanks for the questions. Terrific. Well, I think we're at time. Really appreciate everybody's participation and promise to keep everybody updated on the, you know, the ADEPT programs and trial execution, etc., moving forward. It's an exciting time at Karuna. As you can tell, we've got lots of things going on, and this is an exciting new dimension for this pipeline in a product, so to speak. Thanks, everybody. Have a great day. This concludes today's conference call. Thank you all for joining. You may now disconnect.