Good morning, and welcome to the Karuna Therapeutics Conference call. I'll now hand the call over to Alexis Smith, Director of Investor Relations. Hello, and thank you for joining our call today. This call will focus on the top-line results from our phase III EMERGENT-2 trial evaluating our lead investigational therapy, KarXT, in adults with schizophrenia. 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 the forward-looking statements. Steve Paul, Chief Executive Officer, President and Chairman of the Board, will begin today's presentation, followed by remarks from Stephen Brannan, our Chief Medical Officer, and Andrew Miller, our Founder and Chief Operating Officer. Steve Paul and Andrew Miller will then be joined by Troy Ignelzi, our Chief Financial Officer, for Q&A, which will wrap up today's call. I'd now like to turn the call over to Steve. Thank you, Alexis. At Karuna, we are committed to pushing the boundaries of neuroscience to transform the treatment of mental illness. Every day, we are working towards developing transformative medicines for psychiatric conditions, an area that is in dire need of innovation. We need new, more effective, better tolerated and safer therapies. Today, we are thrilled to be sharing with you the positive top-line results from our phase III EMERGENT-2 trial evaluating our lead investigational therapy, xanomeline and trospium, which we refer to as KarXT, in patients with schizophrenia. As many of you know, KarXT is an oral M1/M4-preferring muscarinic receptor agonist. Unlike all current therapies, it does not rely on dopamine or serotonin receptors to treat the symptoms of serious psychiatric and neurological conditions such as schizophrenia, allowing patients relief from their debilitating symptoms without experiencing most of the very troubling side effects associated with dopamine-targeted therapies. For example, sedation, weight gain, and extrapyramidal motor symptoms. KarXT represents a completely new approach to treating schizophrenia, the first in arguably more than 70 years, and if approved, will usher in an entirely new class of medicine, perhaps a new standard of care for treating schizophrenia and other psychotic disorders. These positive results, which we'll discuss in more detail shortly, further validate M1/M4 muscarinic receptor-targeted therapies and their role in the treatment of serious mental illness, and importantly, strengthen the existing body of evidence demonstrating KarXT's potential to offer an entirely new and differentiated treatment for those living with schizophrenia. Now, having successfully completed two positive registrational studies, EMERGENT-1 and EMERGENT-2, we have a clear path forward to submitting our new drug application for KarXT in schizophrenia in mid-2023. First, let me briefly speak to the severity of this psychiatric condition and its complexities, as this will help further contextualize the significance of our results. Schizophrenia is a chronic and often debilitating mental illness that impacts how one thinks, feels, and behaves. It is characterized by three primary symptom domains: positive, negative, and cognitive symptoms. The most widely known are the positive symptoms, which include symptoms of psychosis such as hallucinations, delusions, and paranoid ideation and thinking. As I mentioned, these symptoms are quite disabling. As a result, only 10% of patients with schizophrenia are gainfully employed. Most patients also experience negative symptoms such as difficulty enjoying life, lack of motivation, and social isolation, as well as cognitive symptoms such as deficits in memory, concentration, and executive functions. Antipsychotic medicines are the only currently approved treatment for schizophrenia. However, they only treat positive symptoms and are often accompanied by burdensome side effects such as sedation, weight gain, and involuntary motor movements. Moreover, 10%-30% of patients with schizophrenia are refractory to current antipsychotic medications, and an additional 50%-60% only achieve a partial response. There are also no currently approved treatments for the negative or cognitive symptoms of schizophrenia. Now, I've spent nearly the entirety of my career in psychiatry, over 40 years, from working as a physician treating patients with serious mental illness at a state psychiatric hospital to developing therapies for psychiatric and neurological conditions at a major pharmaceutical company, and continue to see firsthand how debilitating schizophrenia can be despite the available medicines. While we have seen some incremental advances in treatment, the field has not seen true innovation in decades. Which is precisely why we are thrilled to share today's results, representing what we believe is a significant step forward in the treatment of this disabling disorder. We believe that KarXT, via its novel dual M1 and M4 muscarinic receptor mechanism of action has the potential to offer a completely new and differentiating therapy that could address all three symptom domains of schizophrenia without the troubling side effects of the current standards of care that often lead to poor compliance and have now been shown to contribute to the increased morbidity and mortality and the 20+ year reduced life expectancy of patients with schizophrenia. The EMERGENT program evaluating KarXT in schizophrenia was intentionally designed to gather data on all three symptom domains of schizophrenia, but with a focus on the positive and negative symptoms as is reflected in our primary and secondary endpoint measures. These are the data we are sharing with you today from the EMERGENT-2 trial. KarXT's effects on cognition are also being evaluated as an exploratory endpoint, data for which we look forward to sharing at future medical meetings. Now with this, I'll hand it off to Stephen Brannan to discuss the results from the EMERGENT-2 trial. Thanks, Steve. The phase III EMERGENT-2 trial is a five-week inpatient trial evaluating the efficacy, safety, and tolerability of KarXT compared to placebo in adults with schizophrenia. In the trial, patients were randomized one-to-one to receive a flexible dose of KarXT or placebo twice a day or BID for five weeks. Patients received KarXT orally in a co-formulated capsule of xanomeline and trospium. On days one and two, patients received either placebo or a dose of 50 milligrams of xanomeline, 20 milligrams of trospium, which we refer to as 50/20 KarXT twice a day or BID. On day three, all patients escalated to a dose of 125 BID, and starting on day eight, patients could further increase to 125/30 BID based on the clinician's determination of tolerability. The primary endpoint of the trial was changed from baseline in the Positive and Negative Syndrome Scale or PANSS Total Score through week five. If unfamiliar, the PANSS Total Score is a well-validated medical scale used for measuring symptom severity in schizophrenia and has been used as the primary endpoint in registrational trials in schizophrenia for the past several decades. Key secondary endpoints included change from baseline in PANSS Positive, PANSS Negative, and PANSS Negative Marder factor subscales. These three subscales were all derived from the PANSS Total Score that, as indicated by the name of each scale, focus specifically on either the positive or negative symptoms. Now, let's take a look at the data from EMERGENT-2. A total of 252 adults in the U.S. between the ages of 18 to 65 with schizophrenia enrolled in the trial. Participants had a diagnosis of schizophrenia and were experiencing symptoms of psychosis at the time they entered the trial. In order to meet the inclusion criteria, patients needed to have a PANSS Total Score of between 80-120 at the time of randomization. As you'll see here, the mean baseline PANSS Total Score was approximately 98 in each arm. Additional baseline characteristics such as age, race, and sex can be found on this slide. As you can see, there are no significant differences between the groups, and the demographics and baseline characteristics are in line with our phase II EMERGENT-1 trial, as well as historical U.S.based trials. Now, let's turn to the efficacy analysis. I'm pleased to share that the trial met its primary endpoint with KarXT demonstrating a statistically significant and clinically meaningful nine point six point reduction in the PANSS Total Score compared to placebo through week five with a p- value of less than 0.0001. That's right, 0.0001. KarXT demonstrated a 21.2-point reduction from baseline to week five, compared to an 11.6 reduction from baseline to week five for placebo. These results are not only highly statistically significant but also represent a clinically meaningful improvement of symptoms. Consistent with our phase II trial, we saw KarXT separate from placebo early, starting at the first time point of assessment, which was at week two, with a sustained reduction throughout the trial at all time points. We, of course, are extremely pleased to see that these results reinforce and confirm what we saw in our positive phase II trial. The Cohen's d effect size in this trial was 0.61 compared to 0.75 in our phase II EMERGENT-1 trial, both of which compare very favorably to the effect size of commonly prescribed antipsychotic medicines. For those who may be unaware, Cohen's d is a measure used to describe the difference in efficacy between drug and placebo. It's important to note that we have not evaluated KarXT in head-to-head studies with existing antipsychotic medicines, so this should not be considered a comparative analysis. Moving on to secondary endpoints. KarXT showed consistency as well as strength by meeting key secondary endpoints in the trial, demonstrating a clear reduction in both positive and negative symptoms of schizophrenia. As measured by the PANSS Positive, PANSS Negative, and PANSS Negative Marder factor subscales. As I mentioned earlier, these subscales are derived from the PANSS total score and are used to inform symptom severity within the positive or negative symptom domains of schizophrenia. The first key secondary endpoint measure is the PANSS Positive subscale, which specifically looks at the positive symptoms of schizophrenia, such as hallucinations and delusions. Here we see KarXT demonstrate a statistically significant and clinically meaningful two point nine point reduction in the PANSS Positive subscale compared to placebo at week five, with a p-value less than 0.0001. The next two secondary endpoint measures look specifically at the negative symptoms of schizophrenia, such as motivation and apathy. The first is the PANSS Negative subscale. Here we see KarXT demonstrate a statistically significant and clinically meaningful one point eight point reduction in the PANSS Negative subscale compared to placebo at week five, with a p-value equal to 0.0055. Next, the PANSS Negative Marder Factor subscale measure, which is a similar measure to the PANSS Negative scale that focuses on certain key negative symptoms. As you can see, there's a statistically significant and clinically meaningful two point two reduction in the PANSS Negative subscale compared to placebo at week five, with a p-value equal to 0.0022. As currently available treatments are only approved for the treatment of positive symptoms, we believe these data further underscore that KarXT represents an important advancement in the treatment of schizophrenia to potentially successfully address both positive and negative symptoms. Moving on to a summary of our safety and tolerability. KarXT was generally well-tolerated with a side effect profile in line with our phase II trial. Overall discontinuation rates were similar between the two groups. 25% for KarXT versus 21% on placebo, which is consistent with the rates we saw in phase II. The incidence of treatment-emergent adverse events, also known as TEAEs, were 75% in the KarXT arm and 58% in the placebo arm. The discontinuation rates related to TEAEs were similar between the two groups at 7% and 6% respectively. There were two serious TEAEs in both the KarXT and placebo groups, none of which were determined to be drug-related. The most common KarXT TEAEs, so those that occurred in at least 5% of patients in the KarXT arm, were mostly cholinergic in nature and similar to what we saw in prior studies. Rates for some AEs, such as headache, abdominal discomfort, and diarrhea, were comparable to the placebo rates. No events of syncope were reported. Importantly, and just like our phase II study, the most common AEs in the KarXT group were mild and moderate in severity, and most were transient in nature. Although TEAEs of increased blood pressure were recorded, the mean blood pressure measures for KarXT were similar to placebo at each time point throughout the trial. This is in line with previous trials of KarXT in healthy volunteers, healthy elderly volunteers, and patients with schizophrenia, where mean blood pressure measures were similar to placebo. Furthermore, baseline to endpoint blood pressure measures were similar even in a small subset of patients with a reported TEAE of increased blood pressure. This suggests that there was not a significant sustained blood pressure increase in patients that reported a TEAE of increased blood pressure, and importantly, these did not lead to trial discontinuation, nor was there any additional monitoring for blood pressure required in any of these patients. Heart rate changes were also similar to prior trials where an increase in heart rate was associated with KarXT treatment at the beginning and decreased in magnitude by the end of the trial. While we are conducting additional analyses, it appears that a majority of the most common AEs were transient in nature and resolved during the trial, consistent with prior trials of KarXT. We'll plan to share more details on the onset and duration of AEs at upcoming medical congresses. It's also important to emphasize that KarXT was not associated with common problematic side effects of current therapies such as somnolence, weight gain, or extrapyramidal motor symptoms. These are incredibly meaningful attributes for patients and their overall quality of life. With that, I'll hand it over to Andrew. Thanks, Stephen. As you have heard, the results from the phase III EMERGENT-2 trial are incredibly promising and support the potential for KarXT to offer a new option for the treatment of schizophrenia. This is especially important because of the immense burden schizophrenia has on patients and caregivers. Despite this condition affecting more than 21 million people worldwide. We believe there is a lack of understanding around this serious mental illness and the inadequacy of current medicines. People with schizophrenia require lifelong treatment. However, because not all people living with schizophrenia present in the same way, it has always been a very difficult condition to treat and manage. Antipsychotic medications are the only approved treatments for schizophrenia, but they all rely on the same pathway and approach, inhibiting dopaminergic and serotonergic signaling in the brain. While they can be effective in managing positive symptoms in some patients, many patients have only a partial response, and no current therapies are approved for treating negative or cognitive symptoms. Additionally, these medicines are accompanied by severe side effects, including movement disorders, sedation, and weight gain. As scientists, clinicians, and drug developers, we simply cannot accept the outcomes associated with current treatments as sufficient, and we must aspire to improve the lives of patients living with schizophrenia. The goal in starting Karuna was to create and deliver transformative medicines that work differently from current treatments so that people living with the most serious psychiatric conditions can find relief from their burdensome symptoms. We are focused on tapping the potential of the brain to accomplish this goal, and today represents a significant step forward toward this goal. With this in mind, I will now walk through our next steps for bringing KarXT to patients. The U.S. Food and Drug Administration, or FDA, has indicated that positive results from the registrational EMERGENT-1 trial, one additional registrational efficacy and safety trial, which we are presenting here with EMERGENT-2, and additional long-term safety data would be acceptable to support the submission of a new drug application, or NDA, for KarXT as a treatment for schizophrenia. Therefore, we will continue to gather long-term safety data from the ongoing EMERGENT-4 and EMERGENT-5 trials and plan to submit an NDA to the FDA in the middle of 2023. Top line efficacy and safety data from the EMERGENT-3 trial are expected in the first quarter of 2023. Again, based on our prior discussions with the FDA, we believe we do not need additional efficacy data to support our NDA submission beyond what we already have from the EMERGENT-1 and EMERGENT-2 trials. In addition to the EMERGENT program, we are currently enrolling the phase III ARISE trial evaluating KarXT as an adjunctive treatment for schizophrenia, with top-line data expected in the first half of 2024. Given the unique mechanism of action, we are excited about the potential of using KarXT in conjunction with existing treatments. The antipsychotic benefits of xanomeline were first discovered in patients with Alzheimer's disease. Having demonstrated that trospium allows for potentially therapeutic doses of xanomeline to be administered to healthy elderly volunteers, we are eager to progress KarXT into trials in Alzheimer's disease. We are on track to initiate our phase III ADEPT program evaluating KarXT for the treatment of psychosis in Alzheimer's disease this quarter, Q3 2022, starting with the ADEPT-1 trial. This trial will evaluate the safety and efficacy of KarXT in 400 adults with moderate to severe psychosis related to Alzheimer's disease dementia using a randomized withdrawal design. Overall, we look forward to advancing our efforts to improve treatments and care for serious mental illness with the goal of bringing the benefits of KarXT to patients and families around the globe. I'll now turn the call back over to Steve for final remarks. Thanks, Andrew. To summarize what has been discussed this morning, we are confident that the top-line results from our phase III EMERGENT-2 trial further demonstrate the potential for KarXT with its novel and unique mechanism of action to potentially change the standard of treatment in schizophrenia and, more importantly, the lives of millions of patients, their families, and care partners who are living with the devastating effects of this serious mental illness. The results from both EMERGENT-1 and EMERGENT-2 support the promise of KarXT, allowing patients relief from their debilitating psychotic symptoms without experiencing the very troubling side effects associated with current treatments. With two positive registrational trials in hand, we look forward to continuing to gather long-term safety data to support our submission of a new drug application with the U.S. Food and Drug Administration for KarXT as a treatment for schizophrenia, which we now expect to submit in mid-2023. Now, before closing today, I would be remiss to not thank all of the people living with schizophrenia who participated in the EMERGENT-2 trial, their families and caregivers, the trial investigators and their teams, as well as all of my colleagues at Karuna who made today's news possible. This is truly a momentous day for us and, most importantly, for patients, and we would not be here without them. Thank you for your participation in our call today. I now invite Troy Ignelzi, our Chief Financial Officer, to join Andrew and me for the Q&A portion of this webcast. If you'd like to ask a question, please press star then one on your telephone keypad, and please limit yourself to one question. The first question is from Salveen Richter with Goldman Sachs. Your line is open. Good morning. Thank you for taking my question and, congratulations on the data here. Could you just speak to the underlying characteristics for patients who experience blood pressure increases and whether there would be a chance a monitoring protocol would be necessary during treatment? Just curious what percentage of patients escalated to the highest dose. Thank you. Thanks, Salveen. This is Steve. Let me just comment briefly on the blood pressure readings that we saw. Let me reiterate just to begin with that in this study, like in EMERGENT-1, we took blood pressure readings at every visit two hours post-dose, which is around the Cmax for the drug. When we look at mean blood pressure readings across every visit from the very first visit to the last visit, the readings in the KarXT group and the placebo group are very similar, within one or 2 millimeters of mercury of each other. Moreover, those blood pressure readings are in a normotensive range for this group. In other words, they're not high. Said another way, by the way, very similar results from our phase II study. Remember, we've done a fair number of phase I studies with this KarXT formulation. We don't see any effect of KarXT on blood pressure. In a study like this, when you're taking blood pressure readings, and as you know, blood pressure can be a bit variable from time to time in each of us. You will record some high readings and some low readings relative to what we might define as normotensive. In this case, we did see some of that. But these blood pressure readings from baseline to endpoint were normal. None were deemed significant by the clinicians sufficient to stop dosing or change the protocol in any way, shape, or form. We, by the way, saw some readings that were on the lower side too, as you would in any kind of study like this. We continue to believe there is no real effect of KarXT on blood pressure in these studies. I just wanna also remind people that these individuals in these studies in schizophrenia tend to be heavy. They tend to be you know, fairly obese in some cases, but heavy due to previous treatment with standard of care antipsychotics at this point, about half of them, by the way, while not hypertensive coming into the study, have a history of hypertension. We don't view this as a signal whatsoever and don't feel any monitoring is required at this point. Andrew, you may want to comment a bit as well. Well, just add to that quickly, Steve, that during the study there was no additional monitoring that was put in place in any of the subjects who had a report of a treatment-emergent adverse effect of increased blood pressure. I think that also speaks to you know the response on the part of clinicians and what would be the lack of any monitoring requirements that would be needed going forward. I would also add you know the data is very consistent with what we've seen in our past studies of KarXT that includes normal volunteers, healthy elderly volunteers, as well as the EMERGENT-1 study, where we actually reported a slight decrease in blood pressure from baseline to endpoint on KarXT. As well as the long-term, large scale phase II study in Alzheimer's disease previously conducted with xanomeline, where blood pressure at endpoint was lower than it was at baseline as well. I did wanna address quickly the second part of Salveen, your question. In the study, you know, 80% of patients in the KarXT group escalated to the highest doses compared to 90% in placebo. About 10% less on drug. That's very similar to what we saw in EMERGENT-1, where six percent higher rate of escalation on placebo. Again, I think speaking very positively to the impressions of tolerability in this study on the part of the clinicians, given that that dose escalation was meant to occur only in patients who did not have any tolerability considerations. Thank you. The next question is from Paul Matteis with Stifel. Your line is open. Hey, good morning. Thanks for taking my questions and congratulations on the data. I was wondering if you could just expand a little bit on some of the adverse event rates of the different cholinergic side effects like nausea, vomiting, and constipation, and whether or not they were consistent with the phase II, any higher as you went to a broader population. Just one quick regulatory question, maybe for Steve. Can you just comment on your confidence that for your phase III program, there's no need to find the lowest effective dose? And if there's any discussion you've had with the agency about that this sort of titration based approach is enough because it is, I think, relatively unique to some of the other psych drug programs. Thanks so much. Andrew, you want to take first and possibly the second, and then I'll provide some commentary. Yeah. Happy to speak, maybe to the second question first. I think, you know, our development program, the full EMERGENT program, really reflects our feedback and alignment with the FDA based on our end of phase II meeting that we had prior to initiation of the phase III program. You know, again, I think it reflects those conversations. I think we feel confident in the plan we've put in place going forward, and I think especially given, you know, the robustness of the results that we see here, we think there's sufficient information to evaluate, you know, the risk-benefit of KarXT in these studies. You know, I do think there are, you know, a lot of development decisions involved in designing studies. I do think that some of the approaches we've taken can differ at a high level from some others, but I remind people that flexible dose studies like we run here have been a part of development programs in the past used as registrational studies. I think that also gives us confidence in our approach. You know, one of the main reasons why we've taken that approach is because we believe it does reflect the clinical practice of how antipsychotic medicines are actually used. They are titrated largely based on tolerability and real-world practice. It's consistent with how many other products are currently labeled. We believe really gives us the best opportunity to, you know, clearly demonstrate the benefits of KarXT over placebo, which I think we've seen very clearly in both the EMERGENT-1 and EMERGENT-2 studies. With respect to adverse effect rates, you know, sort of commensurate with this top-line data release. We haven't given additional detail on specific rates at this point. You know, that is a plan for release of information at future medical congresses, consistent with typical practice. You know, I would remind people, you know, we are able to state here that the tolerability profile and safety profile is substantially consistent with what we've seen in our historical studies of KarXT. We continue to see, you know, cholinergic adverse effects that are characterized as mild to moderate. We continue to see those appear to be mostly transient in nature as well. I don't know, Steve, if you'd like to add anything to that. Well, I would just underscore the mild to moderate transient patients dosed right through them, and stayed on the drug. This is, you know, again, something that we learned from our EMERGENT-1, our phase II study, and as you say, they're substantially consistent with that. We will provide more data on it, but, you know, again, just to kind of summarize on the discontinuation rate just briefly, you know, for treatment-emergent adverse events, it was only 7% on KarXT and 6% on placebo. For an antipsychotic drug, that's pretty extraordinary. Thanks. Congrats again. The next question is from Yatin Suneja with Guggenheim Partners. Your line is open. Hey, guys. Thank you for taking my question, and let me add my congratulations on good results. Two questions from me. First is, could you maybe put in context the onset of action? How does that compare with standard of care? Maybe comment also on why it takes a negative symptom score to separate a little bit later than the positive. Then the second part or the second question is on the cognition side. Our understanding is that you probably need a longer study to establish a cognition benefit. Could you just talk about that? Is five weeks enough to show the cognition benefit and the role M1 plays there currently? Yeah. Yatin, I think this is a very good set of questions. Let me comment, and then I'll let Andrew comment. First of all, this was a five week study. So you know, again, those lines are divergent either at even at five weeks between active drug and placebo. So if you compare our study with a six week study, I think the effect size is gonna be much larger. The rapidity of response is really quite significant. Two weeks is the first time point we measure. Remember, 80% of the subjects in this trial took a week to get on their optimum dose based on the titration and the flexible dosing. So that's really rapid and, in my view, much, much more rapid than, again, the standards of care that we use today. I think, you know, overall, the efficacy data couldn't have been much better, frankly, for a phase III study. I think in consideration of the, you know, five week versus other studies that are six weeks and longer, that effect size and that delta of almost 10 points between placebo and active drug is really quite extraordinary. I think this drug works really quickly, as we've seen in virtually every study that we've run with it. With respect to cognition, as you recall from EMERGENT-1, our phase II study, when we stratified by cognitive impairment at baseline, we saw a pretty nice effect. Obviously, we pre-specified this in that in this study, we haven't analyzed the data yet, so we can't give you the data. It may actually take a little longer to fully set in. On the other hand, we did see a nice effect even at five weeks and in the early small study in schizophrenia done back at Lilly with xanomeline alone, we also saw cognitive improvement. We think there's a really good chance this drug has pro-cognitive benefits to patients, which of course would be huge for this patient population. Andrew, do you wanna comment at all? Yeah, I think you covered most of the points, Steve. I would just, you know, add quickly, as you said, you know, typically if you're going to run a study dedicated to looking at negative or cognitive symptoms, you'd have, you know, a 12- or 26-week duration. You know, I think the ability to see some difference from placebo is reporting here on negative symptoms in EMERGENT-2, as well as negative symptoms and then some cognitive benefits as well in EMERGENT-1. I think, you know, to us really highlights the potential for this drug and this pharmacology to have benefits beyond positive symptoms, which, you know, negative and cognitive symptoms are currently not served. There are no approved treatments for those symptom domains. You know, this top line data really reinforces our excitement about the potential of KarXT to treat negative symptoms. Just one more quick one, if I may. I understand this was a monotherapy. Can you comment on the adjunctive use? Any learning from this study on how the adjunctive might play out in the real-life setting? Thank you. Well, this was a monotherapy trial, and we do have the ARISE trial underway, which is adjunctive, and we think there's a good chance that we're gonna see benefits, additional benefits, some augmentation or synergy given this novel mechanism of action. We do think that's going to be very important given that the functional outcomes in patients, even when positive symptoms are managed, are not great in this population. We remain excited, optimistic, enthusiastic about the adjunctive or combination therapy, but stay tuned. We also think it's a huge medical and commercial opportunity. Again, as a reminder, please limit yourself to one question. The next question is from Chris Howerton with Jefferies. Your line is open. Hi. Thank you so much. I really appreciate you taking the questions and a huge congratulations from me. One question that I would have would be, you know, what learnings, if any, can you take from the schizophrenia population moving forward into the Alzheimer's disease? Obviously, safety being one of the key considerations. You know, what have you learned there and how will you incorporate that, if at all, in that patient population? I don't know if this is a question or just a clarification, but, you know, how could you describe the high rate of, I guess to me, the Asian patient population experienced in this trial? Is that representative or are any comments about the demographics there? Thank you. Let me start, and then Andrew can chime in. You know, in terms of the demographics of the population, let me start with that question first. They're similar in virtually all of these schizophrenia trials. This was very similar to our phase II study, EMERGENT-1, and they reflect really the sites where these trials are done at least in the U.S., predominantly an African American population, heavily weighted towards males in the study. This is very typical. Obviously, in EMERGENT-3, where we did have enrollment in Ukraine before the invasion, the demographics of that trial should be somewhat different. With respect to the Alzheimer's population, the two takeaways from, frankly, this study and the earlier study we did in Alzheimer's dementia-related psychosis at Lilly is that this drug is likely to work. It has very, very powerful antipsychotic effects. For us, we learned from our phase I-B healthy elderly study that the doses required to achieve therapeutic blood levels or exposures comparable to what we see in the psychosis trials in schizophrenia are going to be lower. The oral doses are going to be lower, and the ratios of the two drugs are going to be somewhat different. In the ADEPT trials, the Alzheimer's dementia-related psychosis trials, we've made adjustments for that as well as we have on the titration schedule. As we've said in the past, we're optimistic that we can achieve therapeutic blood levels and oral doses that result in those therapeutic blood levels with good tolerability in that patient population. Given everything we've seen, you know, from our phase II and phase III studies with xanomeline and trospium and KarXT, we're optimistic we're going to see efficacy, good efficacy. Andrew, I don't know if you want to comment. No, I think you captured it largely, Steve. You know, I think this study result just really further reinforces what we saw in EMERGENT-1. When you put that in combination with historical data in Alzheimer's patients as well as our healthy elderly volunteer data, I think it further increases, you know, our excitement, you know, and further commitment to evaluating KarXT in that patient population. Yeah. Just to refresh everybody's memory, in the earlier study, the Bodick et al. study at Lilly, we saw a nice rapid reduction in psychotic symptoms and behavioral symptoms in patients with Alzheimer's that had those symptoms at baseline within a couple of weeks, very similar to what we see here in the schizophrenia trials. We also saw a reduction in the emergence or prevention of those symptoms in patients during the course of the six months versus placebo. Highly statistically significant in that trial. Really, it's a question of making sure we get good tolerability in the elderly patient population that has Alzheimer's disease. Given the phase I-B results, and frankly, everything we've learned about this drug in phase I and phase II, we're optimistic we can achieve those therapeutic levels. Okay, excellent. Thanks so much. The next question is from Neena Bitritto-Garg. Your line is open. Hey, guys. Thanks for taking my question and congrats on the data. I was just wondering if you'd talk a little bit about some of the serious adverse events and specifically the patients who had suicidal ideation. Can you provide any more information on whether those patients historically had any previous suicidal ideation or anything like that? Any thoughts on maybe what caused the suicidal ideation? Thanks. Andrew, do you want to comment? Yeah, I can offer a little comment there, Steve. You know, I think with respect to suicidal ideation, unfortunately, suicidal ideation is, you know, a common occurrence in schizophrenia, in patients with schizophrenia. You know, the patients that are enrolled in a study like EMERGENT-2 or EMERGENT-1 are experiencing, you know, an acute exacerbation of their symptoms represented by that total PANSS score, a baseline of almost 100. You know, I think when we look across historical studies, again, it's not an infrequent occurrence to see this type of adverse effect. You know, when we look at specifically the studies of KarXT and xanomeline, there doesn't appear to be any consistent pattern of suicidal ideation. From our perspective, you know, we don't assign at this point significance to that observation of two events on KarXT in this study. It's always difficult to interpret data with small numbers. But given that it's not an unexpected finding sort of from a background perspective in this patient population, it's not something that we're particularly concerned about at this time. Perfect. Thank you. The next question is from Laura Chico with Wedbush. Your line is open. Good morning, everyone. Thank you for taking the question. I guess I have just one with respect to who would be the most logical candidate to use KarXT at launch, and I guess I'm thinking about also not only treatment history but site of care. Are there any limitations that we should be thinking about with respect to site of care? Thank you. Well, this is Steve. Thanks for that question, Laura. I've been giving this a lot of thought lately. I think that this drug will be used in almost everybody across the board. By that, I mean, when patients are started on therapy and given a choice, do I start them on something like KarXT or an atypical, it just as a clinician doesn't make much sense to put somebody on a drug that is poorly tolerated that will likely cause them to gain weight and get metabolic syndrome that has a high risk of, you know, tardive dyskinesia, EPS liability, all of those things versus something that doesn't. I just, you know, again, as a clinician or I guess a former clinician, if you have to make a choice, it seems to me that choice is pretty easy. I also think there's a lot of patients out there today, and I get calls like this all the time, or emails, who have been on an antipsychotic drug but have gained a lot of weight. You know, the more effective drugs, the Zyprexas, the Risperdal, the Seroquels of the world, the Clozarils of the world, cause you know, in a very substantial percentage of patients, you know, significant weight gain. I think those patients will wanna switch and get on this drug. With respect to adjunctive therapy, let's say you're on a drug that might be referred to as antipsychotic light with maybe less weight gain, but still you're symptomatic. I think the addition of this drug used adjunctively in that patient population is gonna be quite substantial as well. You know, my view is that I could see, you know, clinicians using and prescribing this drug just across the board, and I think every category of patient out there. Remember, the churn here is enormous. You know, 75% of patients that are started on antipsychotic drugs are not on that drug 18 months later. I don't care what line you are, you'll eventually get to KarXT. Andrew, I don't know if you want to comment. No. I'd add one thing to that, Steve, which is maybe a reference just to you know the idea that EMERGENT-1 and EMERGENT-2 are studies that are conducted in an inpatient setting. You know, that's really reflective of the fact that these are placebo-controlled studies in patients who are unfortunately quite ill and is consistent with how you know phase III and phase II registrational studies have been conducted for really the past several decades in schizophrenia. I think that data is representative. I wouldn't interpret the inpatient nature of these studies as reflective of any you know motivation or restriction to specifically use KarXT in that setting if we're able to make it into the hands of patients. Thanks very much, guys. Congratulations. The next question is from Jessica Fye with J.P. Morgan. Your line is open. Hey, guys. Good morning. Congrats on the data, and thanks for taking my questions. It sounds like it is, but can you confirm that accumulating sufficient safety data is the only leading factor for submission? And can you also talk about how enrollment is going in the safety trials and whether or not the Street should expect to see those safety data prior to filing? Hey, Andrew, why don't you comment on the questions? Jessica, good to hear from you. Yeah, absolutely. You know, I think from a timing perspective, you know, continuing to collect long-term safety data is really the gating factor from a submission perspective. You know, I wouldn't offer specific comments towards, you know, enrollment at this point in time. Obviously, the fact that we're, you know, offering guidance towards a submission in the middle of next year suggests that we're quite far along in collecting long-term safety data. You know, I would offer one additional comment in that, you know, there are a lot of different aspects that go into an NDA submission, preclinical data, CMC being, you know, two big pieces of that as well. You know, I do think we don't spend a lot of time speaking about those things, but that's all wrapped up in that, you know, guidance towards the middle of next year as well, as we think all of those things are on track. You know, to specifically reinforce, we do not believe that we need any additional efficacy data beyond EMERGENT-1 and EMERGENT -2. -2. Obviously, we have EMERGENT-3 reading out in the first quarter of 2023, but not a study that, you know, we need to be successful from an efficacy perspective in order to support the submission. I just want to underscore something Andrew said. When we gave the guidance, we did it very thoughtfully. There's a lot of work. Safety, long-term safety in the open label extension is very important, but there's a lot of work that's gone on and going on behind the scenes on virtually everything needed for that NDA submission. The guidance, you know, was chosen very thoughtfully. Got it. That last part of the question was just, should the Street expect to see that long-term safety data before you file? Yeah, we haven't set any expectations. Boy, I haven't thought about that one. Andrew, what do you think? Yeah, we haven't set any expectations at this juncture about particular safety updates, so have to stay tuned on that one. Thank you. The next question is from Jason Butler with JMP Securities. Your line is open. Hi. Thanks for taking the question. Congrats on the data. Just a quick follow-up on the last question there. Can you make any comment about the retention rate you're seeing in the open label extension study? Just beyond Alzheimer's disease, how do you think about prioritizing other indications? For example, running a trial specifically for negative symptoms in schizophrenia or expanding something like bipolar disorder. Thank you. Yeah. Just to jump in there, you know, at this point, again, we haven't provided any specific updates on the long-term safety studies. I think, you know, we continue to be really encouraged by the safety and tolerability profile of KarXT. I think that speaks well in terms of our own expectations in terms of what we'll see from a long-term safety perspective. As you may know, it's actually the long-term safety considerations that are some of the most problematic with existing standard of care. As you know, Steve has mentioned them a little bit earlier on this call with respect to weight gain, metabolic dysfunction, you know, hyperprolactinemia, development of motor symptoms that can become irreversible. These are a lot of side effects that continue to build up over time, which, you know, really appears to be in stark contrast to what we see with KarXT, where we do have adverse effects, tend to be cholinergic or anticholinergic in nature, but they tend to be transient and resolve quickly. I think, you know, we're optimistic that as we continue to collect long-term data, it'll really highlight the potentially significant safety advantages of KarXT. We're quite excited about at this point. Yeah. Just on the first part of your question, I think what we have here is a treatment, a holistic treatment for schizophrenia, not just an antipsychotic drug that treats positive symptoms. We're gonna be, I believe, heavily focused on negative and cognitive symptoms. Those are arguably among the most disabling symptoms. Looking for really functional, really significant functional benefits in patients with schizophrenia. This I think is the game changer, potential of KarXT. Okay, great. I would add just to that quickly, Steve. You know, you talked about the idea of additional indications and, you know, I think it's certainly something that we think quite a bit about. I think there are a lot of potential opportunities for us. You know, what we're doing is introducing really a completely new class of medicine. You know, that's been the goal all along. I think that's what we've taken a significant step forward toward today. I do think there are lots of opportunities to explore the impacts of this muscarinic pharmacology. You know, I think negative and cognitive symptoms you've already spoken about, but I think there are a number of opportunities as well, and we'll really evaluate. Yeah the scientific basis, you know, and what really makes sense to pursue in the short term. Yeah. Bipolar disorder, particularly bipolar mania, is certainly on our list. Obviously, Alzheimer's dementia-related psychosis is a very high priority for us. There's nothing approved as yet, and we think we have something that's gonna really work here. Thanks for that. Thanks for taking the questions, and congrats again on the results. The next question is from Jason Gerberry with Bank of America. Your line is open. Hey, good morning, and thanks for taking my questions, guys. Was wondering if you could just maybe put today's results in in just some broader commercial context. I know that with a lot of the more recent atypical launches in schizophrenia, they've been in the $200 million-$500 million range. Clearly, you offer a lot more from a value proposition than tried and true older, I guess atypicals. You know, just curious, do you think you need the combo adjunct data for KarXT to be used in combination with atypicals? As we look ahead to other muscarinic agonists coming into the competitive space. You know, the QD versus BID dosing is a topic, but how important do you think the sort of first mover advantage will be for you guys as the first muscarinic approved? Thanks. Boy, we could spend a while on that. Let me just start that, you know, again, even though, you know, everything that's been launched of recent vintage is essentially a D2 receptor antagonist/partial agonist antagonist with more or less the same labels, if you will, of everything else that's been in this field, including all the generics. You know, many of them have done pretty well, which I think shows you there's a lot of churn in this space, and people are looking for treatments that might work, even if they are very similar. My own view on this, if you look at something that's very innovative, that has the target product profile of something like what we're talking about, robust efficacy right at the top in terms of the Cohen's, the effect size of everything else that's out there, a possibility of affecting, and we'll need to demonstrate this for the label, obviously, negative and cognitive symptoms. No weight gain, no sedation, no somnolence, no extrapyramidal side effects. You're not blocking dopamine receptors. You probably don't have a risk of tardive dyskinesia. Again, something we have to show. I think this becomes, you know, a new standard of care. I think there's a real significant medical and potentially commercial upside for something like this. I don't see BID dosing here being a problem, particularly with that kind of product profile. I think people are gonna wanna be on this drug. I don't know if I can add much more than that. Andrew, Troy, do you wanna make some comments? Yeah. Yeah, Steve. I think maybe just to highlight a point that we were saying, frankly, leading into the data, and there was a lot of anticipation about what the PANSS difference to placebo would be. We made the point that, you know, five, six, seven point difference would be great because of the different mechanism, and obviously we exceeded that with the score, the results that we saw in the trial. I think you combine that with the tolerability and safety profile that we've seen so differentiated from the standard of care. To your adjunctive question, unfortunately right now doctors don't have a choice. They're adding D2s onto D2s. The introduction of a new mechanism is gonna give them another, I guess, an opportunity to treat these patients. We all in all couldn't be more happy with the results that we saw and think that this probably pushes us to the you know higher end of what we would have expected from the results and then commercial opportunity. Great. Congrats, guys. The next question is from Jay Olson with Oppenheimer. Your line is open. Oh, hey, congrats on these results, and thank you for taking the questions. Based on the favorable trajectories for the PANSS total score and positive and negative subscales at week five, do you believe a longer treatment duration could lead to even greater efficacy benefits? Maybe one administrative point, just any color on when and where we could expect to see the data on cognition recovery. Thank you. This is Steve. The answer to your first question is simple: Yes, yes and yes. I think these data are gonna get better and better over the ensuing, call it three, four, five, six weeks. Those lines are still separating. As I indicated earlier, five weeks is a pretty short trial. It's adequate. It's what people do in this space. But remember, many of these patients, in fact, 80% didn't get to their optimal dose until the start of week two, after week one. I think that, to me, indicates that this effect size is all the more extraordinary, and we're gonna see even better efficacy as things progress. It'll take us time to analyze the cognition data, and we plan to present that at some medical meetings, you know, in the not too distant future. Until we get heavy into the analysis. We literally just received this data a few days ago. We're trying to get the top-line data out. It'll take us some time to fully look at the cognition data for sure. Great. Thank you very much. The next question is from Myles Minter with William Blair. Your line is open. Hey, everyone. Congrats on the data. Super impressive. My question's on the regulatory front. Are you planning to meet with the FDA to discuss this data prior to a pre-NDA meeting where you'd have the open label safety data? More coming from the fact that you did the end of phase II for EMERGENT-1, and the FDA is like, "Okay, no blood pressure, no heart rate monitoring studies required here." I'm wondering whether you wanna meet and get the same sort of clarification after we have this EMERGENT data set. Thanks. I think with respect. In terms of regulatory interactions, obviously as typical of any sponsor, we regularly meet and discuss with the FDA. It's typically prudent to go through a pre-NDA meeting process. You know, beyond that, we haven't set any specific expectations in terms of regulatory interactions. I think obviously we're quite excited about this data and looking forward to sharing it obviously today, but also in future discussions with regulators, but no specific guidance at this point. Gotcha. Quick, quick follow-up just on the 81% of patients that did up titrate to that maximal KarXT dose. Is that data from patients that up titrated and maintained that dose throughout the study, or that's inclusive of patients that tried the up titration and then maybe stepped back down again after trying it? Thanks. Yeah, I think similar to how we released the information for EMERGENT-1, that data represents the number of patients who made the optional escalation. You know, there is a small number of subjects, I think, consistent with EMERGENT-1, that would step back down to the lower dose. I don't have that specific number as part of the top line released, but you know, similar to what we saw last time where I think we had 4% that went back down to the lower dose. Beautiful. Thanks, Andrew Miller, and congrats. The next question is from Vamil Divan with Mizuho. Your line is open. Morning, guys. Congrats on the great data. I guess my question is, the EMERGENT-3 top line data is expected to read out in 1Q 2023. But you're filing in mid-2023. Do you think the FDA may want to also see the EMERGENT-3 data? And also, what is your ex-US strategy at this point? Thanks. Yeah, maybe I'll take the first part of that, and Steve can comment or Troy. Yeah. I can comment on the second part of that. You know, I think with respect to EMERGENT-3, obviously, you know, in addition to the efficacy data that will be part of EMERGENT-3, there's also safety data. You know, our submission we'd want to submit all of the existing safety data that's available at that point in time as part of the submission. You know, I think with respect to efficacy, again, I think we have, you know, we believe we have everything we need at this point in time to support the submission. Obviously, any new data that's available would still be a part of that. I wouldn't place any specific requirement on what we see from EMERGENT-3 to support the submission itself. You know, as it relates to ex-U.S. and consistent with what we've said previously, you know, our focus is moving the program forward and launching it in the U.S. We'll continue to identify partners, as we did with Zai for China, who have the capabilities and frankly, the leadership in market to really make sure this is available to patients. All right. Thank you. Our final question today is from Brian Abrahams with RBC Capital Markets. Your line is open. Hi, it's Leon in for Brian. Thanks for squeezing us in in the end, and congratulations on the great data. So I guess, you know, just curious sort of on what your latest thoughts are on building out any commercial infrastructure and what positions you might wanna target, how many reps you might need, and when you might wanna start outlays for that given the strong data. I guess sort of related to that, you know, is there anything you'd wanna see on the label to help with that? You know, would you like to see both negative and the positive symptoms called out, given the strong data that you've seen? Yeah. Great questions. I'm not sure we should comment any further on the regulatory strategy. Obviously, the better the label, the better the opportunity commercially. Just to say that given these very, very encouraging phase III data, obviously we're gonna ramp up our commercial effort. We began that last year when we recruited Charmaine Lykins-Hollingsworth as our Chief Commercial Officer. We built a superb marketing group and have been doing a lot of work with KOLs and payers and a whole variety of important stakeholders. Now is the time to be thinking about, you know, a sales force and how we're gonna ramp that up. We're, you know, focused on doing this ourselves in the US. We will partner outside the US, but we're very excited to move that forward right now. That concludes the question and answer session. I'll now turn it over to Steve Paul, Chief Executive Officer, President, and Chairman of the Board, for any closing remarks. Okay. Just a brief summary. First, thanks to everyone for your attention and your terrific questions. As you can tell, we are absolutely thrilled by these phase III data on KarXT, which we believe confirms the robust efficacy of this potential new medicine and across all 3 major symptom domains of schizophrenia. Without, importantly, without the troublesome side effects of the current standards of care, there's really no akathisia, no EPS, no sedation, insomnia to speak of. We're just absolutely thrilled. Overall, the tolerability was quite good as these drugs go. Certainly we believe much better than the current standards of care. We look forward to sharing more data with you from EMERGENT-2 at upcoming medical meetings, and we really appreciate your attention this morning. Thanks so much. Have a great day. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.