Welcome to the Fireside Chat with Karuna. I'm Yigal Nochomovitz. I'm one of the biotech analysts at Citi. It's my pleasure to have with me Andrew Miller, who's one of the founders and the COO of the company. Welcome, Andrew. Thank you so much for taking the time. Yeah, great. It's great to be here, and thanks for having us. So maybe well, let's just start out with, you know, just a quick two, two minute overview of the company. What are the programs? What are some of the key, the key timelines? And then we can dig into KarXT mechanism, and some of the, the details. Yeah, absolutely. So, at Karuna, we're focused on delivering new therapeutics for the treatment of neuropsychiatric conditions, with a focus initially on schizophrenia as well as Alzheimer's disease. Our lead product is KarXT. It represents a completely new class of medicine for treating schizophrenia. It's a muscarinic agonist, as opposed to the dopamine and serotonin pharmacology of all existing antipsychotic medicines. Along with that new pharmacology comes a differentiated, and I think, advantageous clinical profile, headlined by robust efficacy that we've seen across our complete phase III program, as well as long-term safety that's free of the problematic side effects of existing dopamine and serotonin-based therapies, including motor impairment and motor symptoms, sedation, somnolence, as well as metabolic effects, weight gain, glucose intolerance, dyslipidemia, and other considerations. So I think we have the opportunity to offer a compelling, new treatment, new class of medicine. We're quite excited about the medical impact that we can have in schizophrenia, an area which is really underserved, and I think underappreciated from a therapeutics perspective, and have, right now, seven ongoing phase III studies. Some in schizophrenia, some in adjunctive treatment of schizophrenia, given the unique mechanism of KarXT, as well as three ongoing phase III studies in Alzheimer's disease, where we're looking to potentially become the first therapeutic approved for the treatment of the psychosis associated with dementia, specifically Alzheimer's disease. So quite excited about that. A lot of activity ongoing. Of course, the, the most near-term milestone is our anticipated NDA submission later this quarter, which obviously is coming to a close quite quickly, so that's very imminently at hand. which is really, you know, I think, an important moment for us from a company perspective and really representative of the transition we're making from an R&D company to a fully integrated biotech company. You've seen not just our preparation for that from a staffing perspective, but I think we're in a good position from a financial perspective to make the necessary investments, to successfully launch KarXT in the second half of next year. So let's just go through the basics of xanomeline and trospium, what KarXT. Why the two drugs? How do they work together? The ratios, just the MOA, the thinking behind that combo. Absolutely. So, sort of the genesis of KarXT and the company Karuna is really about, again, how do we introduce a novel therapeutic? And so xanomeline, as the efficacy component of KarXT, is actually a molecule that was originally tested by Eli Lilly, being developed as a pro-cognitive treatment for Alzheimer's disease. That resulted in a large-scale, six month, phase II, double-blind, placebo-controlled study, looking at ADAS-Cog and co-primary functional outcome measures, where there was the observation of a pro-cognitive effect in that population. But there were two other important observations. One of those was a meaningful burden of what you would describe as muscarinic or cholinergic side effects, particularly GI upset, nausea, vomiting, excessive salivation, and sweating. That was really limiting from a development perspective, led to significant discontinuation rate in that study. And then the other important observation, which was a serendipitous observation of a robust antipsychotic effect in that population, both looking at treatment of existing psychosis, and showing advantages over placebo, but also showing that the rate of onset of new symptoms with the progression of the disease in that study was also significantly lower, with xanomeline treatment in comparison to placebo. So with that discovery, that publication, you know, I'd say generally the field set out to say: How do we take advantage of the efficacy of xanomeline, but figure out a way to navigate around the side effect considerations? We've successfully done that by co-administering with trospium chloride. It is a marketed, approved generic drug for the treatment of overactive bladder, but most importantly, for us, it is a muscarinic antagonist, that doesn't cross the blood-brain barrier. And so it acts to counter the side effects of xanomeline at peripheral muscarinic receptors, but leave the efficacy profile unchanged. We've now demonstrated that through a whole series of completed clinical trials, from phase I, showing a fundamental improvement in adverse effect rates, all the way to our completed three, EMERGENT-1, EMERGENT- 2, and EMERGENT- 3, successful pivotal registrational studies showing clinically meaningful benefits in patients with schizophrenia. The ratios are not. It's a little bit interesting, the ratios of those two in the co-formulation. You wanna just quickly mention? Yeah. So one of the clinical studies, actually, our second clinical study we completed, was really what I would describe as a dose optimization study, looking at tolerability as the primary outcome, where we studied different doses and dose ratios of both xanomeline and trospium to really determine what that optimal balance point was. And so that was what we used for dose selection, for the doses we're gonna be seeking approval for, and we used across the, the program in schizophrenia and patients with schizophrenia. We've also done a similar study in healthy elderly volunteers, that led to the dose selection for the ongoing phase III program in Alzheimer's, which are different than what we're using in schizophrenia. In particular, we've substantially changed the ratio of xanomeline and trospium from about four to five to one in schizophrenia to about 10 to one in Alzheimer's. Because of the sort of practical readouts we got from that study in terms of where the right balance point was for the sort of agonist-antagonist effects. Okay, so let's talk about the regulatory. You mentioned the NDA filing coming up soon. So, what's left to do? What else is left on the table as far as getting that filed? Yeah, I mean, obviously, at this point, we're very close. The end of September is not too far away. So, at this point, it's really about QC. Obviously, an NDA is a pretty substantial document, and so it's really about dotting I's and crossing T's, getting that all published and hyperlinked in the appropriate sort of eCTD format for FDA. That's all ongoing. So it's really a little bit of blocking and tackling left at this point. It's not waiting for interpretations, it's not waiting for data or anything like that, so it really is imminent at this point. Why don't we just review what are the key clinical studies that are, that are encompassed in the, in the NDA EMERGENT-1, EMERGENT- 2, EMERGENT- 3, but not EMERGENT- 4, EMERGENT- 5? Yeah, I can comment on that. So I think the primary basis of review will be the full EMERGENT program. So that is EMERGENT-1, EMERGENT-2, and EMERGENT-3, but also EMERGENT-4 and EMERGENT-5, which are 52-week long-term safety studies. Those studies are not yet complete, but as is traditional, well, we have a data cut-off date, where all data collected prior to the date, regardless of study, is put together, analyzed for efficacy as well as safety. That supports the NDA submission and review. At the Day 120 safety update, there's a further data cut, about 120 days after the original, that will provide updates on that. So as we sit right now, we're already sufficiently clear of the ICH guidelines for the amount of data, safety data, both unique exposures, six month exposures, and one year exposures to support the NDA review. That will all go in at the Day 120 safety update. And what's the thinking in terms of the review clock, the standard versus priority? Do you have a view there or just a- Yeah, I mean, I think our expectation, and I think we've been communicating this for some period of time, the base case assumption is a standard review. That's based on really looking at and reviewing the procedural aspects for the expedited review programs under FDA guidance. We work through the Psychopharmacology Division, historically has not substantially granted priority review, and part of that is because of the nature of psychiatric medicines and studies, where priority review is typically granted, and often the case in oncology or rare diseases, on the basis of a clear superiority to current standard of care in the form of either a head-to-head study, or taking patients who fail to respond or don't have an adequate response to current standard of care and showing they respond to your treatment. In psychiatry, typically, first-pass studies that support NDAs are really about superiority to placebo, which is what our studies are about. Now, because of this conserved study format, design, and endpoints, we can do historical comparisons using meta-analysis and other standard techniques that suggest the efficacy associated with KarXT may be, in fact, superior to current standard of care. But from a regulatory perspective, that's usually needs to be reflected in a direct head-to-head comparison, which isn't part of our development program. That's part of why we believe our base case assumption is standard review. There is the opportunity on the basis of superior safety to be granted priority review. That is more of a gray area. It's not a statistical endpoint, a primary endpoint in a study, so there's more uncertainty about that. You know, that's why our base case assumption is a standard review. If we were to get priority review, we will be ready to launch the product at the PDUFA date. What about an advisory panel? Is that in the cards or not likely? I mean, I think our view on advisory committee, we think it's not the likely outcome. More likely, we won't have an outcome. We've already started our preparation process to the extent we do have an advisory committee. Typically, those advisory committees answer questions like clinical meaningfulness, et cetera, because of the nature of our development program, because the studies and endpoints are well validated. I don't expect a lot of discussion about that, and for the most recent antipsychotic drug approvals over the last five years, there typically has not been an advisory committee as part of that. But there are certainly things that could be discussed, and we'll be ready for them. Okay, and then concurrently, which just, I believe, completed enrollment last quarter, is this ambulatory blood pressure monitoring phase Ib. Just remind everyone the study design and what was the trigger for running that phase I, you know, sort of late in the process, as so close to the NDA. Sure. So with respect to the ABPM study from a design perspective, very consistent with sort of FDA guidance and how these studies are conducted across multiple different therapeutic areas. It's an eight week open label study in patients with schizophrenia, use the same dosing that we use in our pivotal trials. The primary endpoint is being able to statistically reject the hypothesis that KarXT is associated with a 3 mm Hg or greater increase in systolic blood pressure. If that were to be the case, then you get into a conversation about increased cardiovascular risk and warnings and precautions in labeling, et cetera. I think as we sit here today, you know, our EMERGENT-1, EMERGENT-2, and EMERGENT-3 data and all of our clinical studies previously completed all have standard clinical vital sign assessments. Those are not indicative of showing a 3 mm or greater increase in systolic blood pressure. You know, I think with the ABPM study, the study is complete from a data collection perspective. Last patient, last visit has already occurred. So we're in the process of, you know, cleaning and analyzing all of that data. We'll We'll have top line here in the fourth quarter. Our expectation based on that study and all of our historical data is that we will be successful on the primary endpoint in terms of rejecting that systolic blood pressure increase hypothesis. Is there some belief that xanomeline or trospium is a contributor to the increase in the blood pressure? Yeah, I think the consideration is really more around xanomeline. I think part of the trigger for us doing the study is, quite frankly, some of the data with other programs in the space, and that there may be some substantial blood pressure increases associated there. We felt like, given our position where we felt like we had a clear demonstration of benefit coming out of the EMERGENT-2 study just over a year ago, that the most appropriate course of action was to be proactive in generating the most definitive data we could about the cardiovascular effects of KarXT. I think ABPM studies are becoming more common. There's more focus on it from a regulatory perspective. The way that I look at it is, it's not dissimilar to a thorough QT study. We conducted a thorough QT study with KarXT, despite the fact that all of our clinical ECG assessments don't indicate any sort of QT prolongation, and the QT study confirmed that. But we were requested by FDA specifically to conduct that study because antipsychotics that are currently marketed as a class have QT prolongation. So we look at that as a proactive step. It wasn't something that was requested from us. But when you have a product that we believe has the potential medical impact of KarXT, we don't want to leave any stone unturned about what potential barriers that would be, and I think having the most definitive data set coming out of an ABPM study is going to help serve that purpose. Will that go in the NDA as well, or how will that be handled? Yeah, it'll go into the Day 120 safety update, consistent with our pre-NDA meeting that we had with the FDA in second quarter. Part of that, that meeting is a very procedural meeting. Here's exactly what we have, here's when it's going to be submitted, here's what the analysis is going to be, and got alignment generally with the agency across the entire submission strategy, but specifically being able to submit that Phase Ib safety data as part of the Day 120 safety update. Obviously, as we sit here today, we have not made the submission, so the Day 120 safety update is a January timeframe from where we are right now. And as I just mentioned, we'll have the ABPM data, study's already complete from a data collection perspective. We'll have that data fourth quarter, in time to go in as part of that Day 120 safety update. Okay. As you said, you're likely to reject this hypothesis around the 3-millimeter increase. If you didn't reject it, how would that be handled in the label language in terms of a safety comment or? Yeah, I think in general, the consensus in the field would be if you don't hit that endpoint and your 95% confidence interval goes above three, typically, it'll result in some sort of warning. Typically, for a effect of that magnitude, it could result in a black box warning. Mm-hmm. But it's not fundamentally an approvability consideration at that type of magnitude. Again, I think we're very confident that that data we have from the study is going to reject that hypothesis, and so we don't anticipate, like, a warning of that level being associated with the outcome of the ABPM study. Okay, let's talk about the adjunctive treatment you mentioned at the beginning, the ARISE trial. I think that's reading out in the second half of next year. Correct. So just to help-- first of all, just define what-- when you say adjunctive, what, what is the adjunctive treatment, and, and how is this different from the primary program for the EMERGENT program? Yeah. I mean, at a high level, the studies are actually... I'd say two differences. One is, obviously, as an adjunctive setting, we mean by that is patients are required to be on background atypical antipsychotic treatment. Unlike the primary studies, the EMERGENT-1, EMERGENT- 2, and EMERGENT- 3 program, where that was KarXT versus placebo without any background antipsychotic treatment. One of the implications of that is, given that they are maintained on background care, that they have some degree of response, but an inadequate response to, is we do expect baseline symptom severity to be slightly lower as part of the ARISE program. EMERGENT-1, EMERGENT- 2, and EMERGENT- 3, across those studies, the average baseline total PANSS, which is the primary endpoint, was in the mid to upper 90s. We would expect it to be probably in the low to mid-80s as part of the ARISE program. So with lower symptom severity at baseline, there's a little bit less dynamic range to see a statistical advantage over placebo. And so in response to that, the ARISE study is slightly larger, target enrollment of up to 400, as opposed to 250 for EMERGENT-2 and EMERGENT-3. But again, the treatment paradigm is very much the same. The top doses of KarXT are the same. We use the same flexible dosing paradigm. The primary endpoint is total PANSS change versus placebo, exactly the same as it is in EMERGENT-1, EMERGENT -2, and EMERGENT -3. -3. So we're fundamentally looking for the exact same type of symptomatic benefits. We can see an effect that's less than half of what we saw in the EMERGENT program, still be clinically meaningful, still be statistically significant. But it's a study that has the... I, I think, the upside of potentially emphasizing the unique aspects of KarXT. We see current antipsychotics being used adjunctively on top of each other, despite they have-- the fact that they have the same underlying pharmacology and basic science rationale. They don't have data to support that. They don't have labeling and indication to support that. But about 30% of patients with schizophrenia are currently being treated with two dopamine-based antipsychotics. This is an opportunity with really a new class, the first new class of antipsychotic, to demonstrate potentially additive benefits by using two different pharmacologies, frankly, like we do in many, many therapeutic areas. We just don't do it in schizophrenia because we don't have different classes of medicine to use. So I think it's an opportunity for us to further demonstrate the uniqueness of KarXT from a pharmacology perspective, as well as from a clinical profile perspective. And how do the patient populations compare in terms of time, time since diagnosis for EMERGENT versus ARISE? Yeah, I would say overall, our expectations that'll be quite similar. In the EMERGENT program, the average age across the studies is, in individual studies, ranges from low to upper 40s. That's sort of our expectation with ARISE as well, and part of that just has to do with the treatment course of patients living with schizophrenia. They tend to switch medications often. They tend to discontinue medications due to lack of efficacy and have a relapse event or buildup of long-term side effects. And clinically, the course of action is sometimes to switch, it's sometimes to add something on. And so, you know, fundamentally, that background care difference, I don't think will translate into substantial sort of demographic or other differences between the population in ARISE versus EMERGENT. As far as the dosing paradigm in the two programs, are they similar or they're different? Very similar. I'd say, in ARISE, there's two differences. So one is, given the outpatient nature of the study and the stability of patients, we actually titrate, KarXT slightly slower in ARISE. And part of that is because we believe, based on this muscarinic mechanism, the fact that the still relatively low rates of adverse effects we see in our studies tolerate with time, that by introducing the drug a little more slowly, we actually may see even further improvements in tolerability. And we're treating patients who are not acutely ill, as they are in an EMERGENT program, and have some more stability in an outpatient setting. There's relatively little downside to that, and in fact, the way that existing antipsychotics are used, they tend to be titrated over the course of weeks to months. So that's one difference. There's one additional titration step there. But when you look at the top doses that are part of that study and the flexible dose paradigm, they're exactly the same as they are in the EMERGENT program. So the top doses are 100/20 xanomeline and trospium BID, just like they are—and 125/30, just like they are in EMERGENT. The ratio, that's always 5 to 1, even in the titration, or it's a little bit, it varies a little bit? Yeah, so from a titration perspective, the 50/20 for two days and then 75/20 for five days. Okay. It has the same sort of loading dose of trospium, and that's in part to make sure that you're hitting steady state trospium levels as you escalate the dose of xanomeline. So that's been the historical way that we've done that. We do that a little differently in the Alzheimer's program. We actually fix that ratio because the titration happens over a longer period of time. So it's a little difference between how we approach those, but fundamentally, in the ARISE study, it's very similar to the titration in the EMERGENT program. Okay. And you touched on this before in terms of people cycling on and off therapies and discontinuing. Majority of schizophrenia patients, apparently, I'm looking at some data here, discontinue after 18 months. So how, how would KarXT potentially address that structural feature of the schizophrenia treatment landscape and, and keep people on therapy for longer? Yeah. Well, I mean, I think the first clue to that is really looking at the studies that you're referencing. Why do people discontinue? Of course, in clinical trials, there's always some level of just no longer wanting to participate or being able to participate in the study. But the main reasons for discontinuation in long-term schizophrenia studies are lack of efficacy or intolerability and buildup of long-term side effects. When you look at the different medicines that are available, if you take something like olanzapine, generally regarded as the most effective, widely used antipsychotic, the rate of discontinuation due to lack of efficacy is lower, and the rate of discontinuation due to side effects is higher, because associated with that more robust efficacy signal is also a more substantial side effect profile—motor symptoms, sedative effects, metabolic and weight gain, and others. If you look at something like aripiprazole, another commonly used medicine in schizophrenia, that's flipped. It's less efficacious, it's better tolerated, and when you look for reasons for discontinuation, there's more on the lack of efficacy side than there is on the tolerability and safety side. You have to figure out how to fundamentally solve those two issues. Right now, you're forced to trade off more efficacy or less side effects. I think KarXT has a real opportunity to offer, frankly, both of those. From an efficacy perspective, again, in the absence of head-to-head comparison, but in the context of historical comparisons, our study results are indicative of an efficacy signal on an effect size basis that's larger than what's been observed with current treatments, including olanzapine, risperidone, and what are considered the most effective treatments. The flip side to that being, we also see adverse event-related discontinuations in the EMERGENT program that are, you know, essentially the same as placebo, maybe 1% above placebo. We're not seeing buildup of weight gain, metabolic dysfunction, or motor symptoms over time. When you look at the actual reasons that are causing discontinuations for patients in schizophrenia in these studies, I think our data suggests we could be superior on both of those metrics. That's why we're excited about the impact of what we have. Let's shift gears and talk about the Alzheimer's disease psychosis program called ADEPT. So provide an overview, if you could, just on the trial design and the endpoints, and then, most importantly, you know, why would KarXT work in this setting? Or what are the features of Alzheimer's disease psychosis that's common to schizophrenia that would allow KarXT to work in both cases? Yeah, there's sort of a lot wrapped up in there. I'll try to get to most of those points. But, you know, fundamentally, the standard of care right now in treating the psychosis associated with Alzheimer's disease is atypical antipsychotics, the same medicines that are used to treat schizophrenia, despite the fact that none of them are indicated for that. And part of the reason none of them are indicated for that is because it's very challenging to get patients up to therapeutic doses. They also have a black box warning for increased mortality, actually double the rate of cerebrovascular-related deaths in elderly patients when administering atypical antipsychotics. And so when we look at the fundamental risk-benefit profile of current standard of care, it's the same as schizophrenia from a treatments perspective, but the risk-benefit is actually inferior. And so I think there's a clear need for what could be new treatments there. Now, I referenced a little bit at the beginning, the historical story of how xanomeline and KarXT was developed. There was a serendipitous discovery of an antipsychotic benefit in exactly these patients, patients with Alzheimer's disease. In the study that was originally conducted, there I sort of divide the patients into two groups. One was patients who had psychosis symptoms at baseline, hallucinations, delusions, and the other was the group of patients who didn't. And when you look at the effect of xanomeline in those patients, patients with symptoms, you saw a clear reduction, dose-dependent, robust, statistically significant versus placebo in those patients. If you looked at the patients who did not have those symptoms at baseline, but you follow the course of illness over the six month duration of the study, patients on xanomeline developed or had an onset of psychiatric symptoms at a significantly lower rate than those on placebo. Those two subgroups and two paradigms, sort of prevention of onset of symptoms or recurrence of symptoms or treatment of active symptoms, that's the paradigm for ADEPT-1 and ADEPT-2. The program overall, ADEPT, has three studies. ADEPT-3, 52-week long-term safety extension. ADEPT-1 and 2: ADEPT-1 is a relapse prevention study, taking symptoms, psychiatric symptoms, particularly hallucinations, illusions, 12 weeks of open-label therapy, taking the patients who have a response, and we have clearly defined response criteria, and then randomizing them to continue on either KarXT or placebo and looking for relapse events. How do you prevent the recurrence or onset of symptoms? ADEPT-2 is very similar to EMERGENT-1, EMERGENT- 2, and EMERGENT- 3, taking symptomatic patients with hallucinations and illusions and comparing over 14 weeks, KarXT versus placebo in its ability to reduce those symptoms. So it's really kind of two different ways at getting at the same potential therapeutic benefit, both of those paradigms, sort of randomized withdrawal or relapse prevention and acute therapy. We use both of those types of studies in schizophrenia. We use them in mood disorders as well, so they're well-established clinical paradigms that are familiar from a regulatory perspective. I'd say in general, relapse prevention tends to be a little bit more, more resistant to placebo effects, which is always a consideration in, in psychiatric drug development. So, but I think between those two studies, we're really set up for success in demonstrating a clinically meaningful and statistically significant benefit in patients with Alzheimer's. What are the timelines for these three trials you just mentioned? They're just starting now, and are these registrational trials, or what's the timeframe? Yeah, the ADEPT program is designed to expand the label of KarXT for the treatment of psychosis associated with Alzheimer's disease. ADEPT-1 started in the second half of last year. ADEPT-2 just started here this quarter. Those are both expected to have top-line data available in 2025. ADEPT-3 would trail that, given that it's a 52-week safety study. Again, similar to EMERGENT-4 and EMERGENT- 5, it would be supportive for a potential review of expanded labeling, but not necessarily necessary to complete that study prior to making a regulatory submission. Just give us a quick overview of the market dynamics or the size of the market for schizophrenia and Alzheimer's disease psychosis. What are the relative scales there? Yeah, I mean, I think from an overall patient population, actually somewhat similar in terms of, the addressable patients who are unfortunately have, psychiatric symptoms or, or specifically psychosis. In schizophrenia, right now in the U.S., there's about 15 million scripts for antipsychotics written a year for patients with schizophrenia. In Alzheimer's, number's a little bit lower than that, but the overall patient population in the U.S., talking about as many as 6 million patients with Alzheimer's, up to 50% of those will have, psychosis as part of that course of illness. So you're talking about 3 million patients who are experiencing those symptoms in the U.S. who would be potentially eligible for, for treatment. Many of them are being treated right now with atypical antipsychotics, again, despite the fact that that's not a labeled indication, and there's actually a specific contraindication for use in that population. Now, you've also demonstrated some data with a pro-cognitive benefit, in some of the other analyses you've done. How is that going to work its way into the label or the marketing pitch, and how does it differentiate relative to the standard of care? Yeah, and again, a couple aspects of that. You know, in terms of what we've seen, as I mentioned, the original hypothesis for xanomeline's development was as a pro-cognitive treatment for Alzheimer's, and there was an observation of benefits on ADAS-Cog as part of the original program. In every single double-blind, placebo-controlled study that's been conducted with xanomeline or KarXT, there's been a cognitive assessment, and we've seen a benefit of treatment over placebo, including in our EMERGENT- 1, EMERGENT- 2, and EMERGENT- 3 programs. We actually just presented at scientific conferences starting late spring, some of that data from EMERGENT- 2 and EMERGENT- 3. So we see a cognitive benefit tied to that M1 pharmacology. That was the original hypothesis for development. Now, in terms of how that makes its way into labeling or data, and peer-reviewed publications, that can be discussed. We would not anticipate anything around cognition being in the initial label, given that is an exploratory endpoint across the program. It's not part of the primary hierarchy of endpoints. But it is data we've already published. We do expect to be indicated broadly for the treatment of schizophrenia in adults, without respect to specific symptom domains or treatment settings. And so we do think the ability to get that data out there and talk about the fundamental hypothesis of KarXT and the pro-cognitive benefits we've seen across the program, will be helpful to us. We also have ongoing cognitive data collection from all of the studies that I just mentioned. And we also are contemplating a dedicated future cognition study in schizophrenia, where we look specifically at the primary outcome measure being related to cognitive function, as well as potentially social and social performance and functional outcome measures as well. So that's something to look for more details from us here in the next couple of quarters. Well, can you just expand on the nature of the cognitive benefit? Was it a trend? Was it statistically significant? What was the finding? Yeah. I think if, if maybe to speak specifically to the EMERGENT program, I think is probably the most relevant, and this data that we've collected and presented and published. When you look at patients who enter the EMERGENT program, whether EMERGENT-1 or EMERGENT-2 and EMERGENT- 3, who have cognitive impairment at baseline. That's not the entire population, because that wasn't the primary outcome measure, it wasn't a key inclusion/exclusion criteria. We have a computerized test battery that's been, a computerized test battery was used in each of those studies. About 40-45% of patients at enrollment would score one standard deviation below the mean of normal age-matched controls at baseline, which is a common literature definition of cognitive impairment. When you look at that subgroup of 40%-45% of the patients, you see a statistically significant benefit across that cognitive battery, which focuses on the areas of known deficit in schizophrenia or known disruption. So executive function, working, and learning memory, and attentive domain. So we see a substantial benefit. Actually, the effect size across EMERGENT-1, EMERGENT-2, and EMERGENT-3 is about 0.5 from a Cohen's d perspective. That's actually slightly larger than the average effect on psychosis that you see with existing antipsychotic treatments. So something that would be clinically meaningful, something that we've observed statistically, even in a subgroup of only 40% or 45% of patients that have enrolled. When we think about future work, we would do a study and focus on patients who would meet that impairment criteria at baseline, and effectively look to see the exact same type of benefit we've already seen across the EMERGENT program. Beyond schizophrenia and ADP, what are you thinking in terms of where you would take KarXT next? You obviously... We'll talk about IP later, but you have a very long IP runway, so you could do a lot of things. Yeah, one, and I think, you know, in psychiatric illnesses, there's unfortunately, a conservation of particular symptom domains and behavioral disruptions that carries and cuts across a number of different diagnosis and disorders. When you look at how existing antipsychotics are used, there's about 70-75 million scripts a year in the U.S. About 30-35 million of those are for depression as part of major depressive disorder or, bipolar disorder, and the balance, about 40 million, are focused on psychosis or related behavioral disruptions. Schizophrenia, which we've already spoken about and are developing for, the psychosis associated with dementia, in particular Alzheimer's disease, and then there's also, a few different indications. So mania-associated bipolar disorder. The symptoms of mania, if you look at a mania rating scale, substantially overlapping with, schizophrenia in terms of disorganized thought and delusions. And then you can look at irritability and behavioral disruptions in autism. There are two approved treatments for that, two different atypical antipsychotics, risperidone and aripiprazole. Similar to my comment that I made about the elderly earlier with respect to risk-benefit, the risk-benefit in pediatric populations of existing treatments is even poorer than it is in patients with schizophrenia. So when we think about, in the short term, additional indications and development work for KarXT, it focuses on expanding the potential benefits of KarXT to that larger bucket of patients with psychosis or behavioral disruptions. So autism, I think, is certainly a part of that. We think there's the potential for a real benefit there, and the improvements or advantages we see on the safety and tolerability side could be even more meaningful in a pediatric population. So that's something that's certainly on our mind. Bipolar mania, I think, is also an opportunity for us. I think that the broader mood disorder space on the treating the depressed phase of bipolar illness, as well as depression and MDD, is, is less, less of a focus for us. I think mechanistically, what we've demonstrated so far is really about antipsychotic and pro-cognitive effects, as opposed to antidepressant effects. That may be somewhere we go eventually, but I think it's lower on the priority list for us. I mean, the pro-cognitive effects are interesting, and it makes me think of, of mentioned pediatric, of Angelman syndrome. Is that, is that an area that you would consider, or that's too far afield? I think initially our, you know, the efforts that we're contemplating in pediatric populations focuses more on the demonstrated antipsychotic benefits than it does the pro-cognitive effects. I think those are still things that we can do, and I think will do eventually, but in the short term, you know, our strongest data reflected in the primary endpoint of our existing completed studies is about that antipsychotic effect. So we think about, you know, indications in areas where we can go and demonstrate a clear benefit. That's sort of from a probability of technical success perspective, what makes the most sense. Now, just like in schizophrenia and in Alzheimer's, we have the ability to collect cognitive data as part of our studies, even if it's not the primary focus, even if it's not what the inclusion/exclusion criteria were set up for, we can potentially observe those benefits. So that would also be relevant to things like autism. So let's shift and talk about the commercial prep. Where do things stand there with hiring a sales force, market, you know, market access, medical liaisons, all, all, all the pieces of the puzzle for launching this drug in the United States? Sure. And there's certainly a lot of pieces to that puzzle, but I think where we sit today, you know, 12 months in, in advance of anticipated launch, I think we're doing all the right things, and we have all the right people in place. So what does that represent? You know, right now, for the next year, in a pre-approval situation, our medical affairs group is our primary conduit to speaking with researchers and healthcare providers, and we have an active field force already of MSLs out there. We have a medical affairs group that focuses on that field force, as well as the scientific and medical communication, so we have a robust function there. It will continue to grow for the remainder of this year, but it's very active already. On the more commercial side, you know, sales force, that's really a mid-next year target in terms of building out those, those reps. When you think about... We have a head of sales in place, we have a head of market access in place, we have a head of market analytics, we have a head of commercial operations. So when you think about those key- Right ... leadership, key leadership positions of those key functions, that's all in place. We have the, the leadership, and we're going to continue to build out those functions over time. And again, I think we're in the middle of sort of finalising and scoping out what a sales force would look like. But I think in broad strokes, we have 30-35,000 healthcare providers that are the primary script writers for antipsychotic drugs. So that's our, our target. With that magnitude of target, we're talking about something that's a 300-350 representative field force. You know, that represents, I think, a meaningful investment commensurate with what we believe the potential of the product is. We have the expertise in place from a leadership perspective to do that, and we have the financial resources to make that investment. What's been the feedback from the academics and the community practitioners in the psychiatry world regarding KarXT? Yeah, I mean, I think it's been really overwhelmingly positive, and I think when you think about the history of this development effort and us from a company perspective, clearly, longer term, we've had much more interaction with the clinical research community and the KOL community than we have been, sort of the more general prescribing community. But I think the enthusiasm from a KOL and research community has really escalated substantially in the last year. And part of that is really because of the EMERGENT-2 data readout last August, providing another definitive demonstration of KarXT's efficacy and sort of putting us on the clock for when is this drug going to be available. And so the questions that we get are really more about, "When is this going to be available and how do I use it?" rather than, "Does this work and how does it work?" And I think that reflects the anticipation of the community about KarXT being available. And I think our messaging and interactions continue to go further, out into the community to more of the sort of the general prescribing community. And I think we see a real interest in something that's new, something that isn't a dopamine pharmacology, that isn't just another product, which is some minor increment on what's currently available. That's what the field has really been waiting for and anticipating, and I think that's hopefully what we're going to be able to provide them. Another detail we want to touch on is EMERGENT-4 and EMERGENT- 5, as well as ARISE, are outpatient studies, whereas 1, 2, and 3, EMERGENT-1, EMERGENT-2, EMERGENT-3, were inpatient. So how does that extend the value proposition in, in terms of, you know, broadening the, the pitch for, for KarXT, and what are you learning from the outpatient studies? Yeah, a couple of comments towards that. EMERGENT- 1, EMERGENT- 2, and EMERGENT- 3 were inpatient. That is the traditional paradigm to evaluate the potential benefits in an acute psychosis population. The reason they're done inpatient actually has nothing to do with KarXT. It's because we have patients who are acutely ill, and in our studies, 50% of them are on placebo. So from providing 24-hour observation and care perspective, that is the paradigm in which those studies are typically done. It's not something that is looked at as having an effect on the benefits or side effects that were observed in those studies. So it is an expansion for us to go into the outpatient setting, but that's really not about further detailing or supplementing anything we saw in the inpatient nature of EMERGENT- 1, EMERGENT- 2, and EMERGENT- 3. It's just because you have stable patients. Many of those studies are open label. You don't need to have that inpatient nature of the study. So they're important studies for us, but I don't think the treatment setting is something that's being looked at as a, a primary difference. It's more just about, you do a 52-week safety study that's open label. Obviously, you're not gonna have patients maintained in a dedicated 24-hour facility for the duration of that study. Okay, let's touch on some other topics. You did a deal with Goldfinch earlier this year, where you got a TRPC4/5 drug for mood and anxiety. Tell us about that, and how would you develop that asset? Maybe just one overarching comment before we get into the details of that program, but I think that transaction is really representative of the growing pipeline of opportunities that we are developing at Karuna. And I think our goal, obviously, is first and foremost, right now, focus and priority is on KarXT and that launch and the indications we've been speaking about. But longer term, I think we have the real opportunity to launch a portfolio of innovative products, of which I think this licensing transaction earlier this year for the TRPC4/5 channel inhibitor represents one of those opportunities. It's a molecule that's already been in more than 100 humans. It's been in studies as long as 48 weeks. It was originally developed for renal disease, but that's a target that we've been interested in. We've been able to go and take that compound and demonstrate CNS activity in the appropriate preclinical models of mood and anxiety. You'll be hearing from us here in the short term about how we're gonna return to the clinic with that molecule and think about the development efforts for mood and anxiety. I think for a company like us, who's really focused on neuropsychiatry, there are many similarities in the need and market opportunity that exists in mood and anxiety disorders, as there is in schizophrenia. There's a need for new treatments, particularly ones that act through alternative pathways in comparison to existing treatments. There are multiple classes of treatments available for depression, but there does continue to be a substantial need there. The anxiety space is, in many ways, more similar to schizophrenia, in that we effectively have-... benzodiazepines, and we've had them for 30, 40, 50 years. There's been relatively little innovation there. We think a TRPC4/5 channel blocker has the opportunity to have anxiolytic effects without the sedative or abuse potential effects of, of current treatments. So we're quite, quite excited about some of the changes that that could introduce into the treatment paradigm for those disorders, not dissimilar to how we think about KarXT and schizophrenia. Two final questions: What's the ex-U.S. strategy? We actually cover Zai Lab, so we know what's happening in China, but what about other territories? I think our strategy with respect to ex-U.S. is very similar to what it is in China. We're not gonna develop the infrastructure to commercialize KarXT outside of the U.S. on our own. We'll do that through strategic partners. You know, we're always talking to partners, always have interest, but I think fundamentally, we're looking for, you know, someone who has the development, regulatory, and commercial expertise outside of the U.S. That's really, you know, I think fundamentally about the less about the regulatory part and more about the commercial healthcare, health technology assessment, reimbursing and pricing dynamics outside of the U.S., and understanding how best to navigate that, something we wanna do with a partner. Last question on IP, just give us the-- what's the... I mean, I have here 2039, 2040 for the, for the IP. That's on the innovation of the ratio of the two components, or is there any claims on the chemical matter as well, or that's- it's not, it's not set up that way? Yeah. We kind of have a whole portfolio of both issued as well as pending intellectual property around KarXT. I think there's kind of two fundamental buckets there of existing issued patents. One of those gets more at what you're speaking about it. It's not the chemical structure of xanomeline and trospium, but it's a pharmaceutical composition that contains those agents, or the method of use of using those agents together. That is the fundamental innovation of KarXT. You know, xanomeline is not a product that's available in any form for any indication in any territory, so an ANDA filing has to come in on the full combination. And we have claims around the use of xanomeline, trospium or any pharmaceutical composition containing those two. That's a foundational and fundamental barrier to entry for an ANDA filing. That IP goes through 2034, and then we have IP through 2039, which captures all of our early development work around KarXT. One of the silver linings of developing a combination therapy, particularly one which contains one product which has never been approved or marketed before, is that there's work to be done and there's discoveries to be made, and we've captured those in the form of those patents related to not just the formulation that we have, but matching the pharmacokinetic parameters, regardless of what that formulation is. Taking the dissolution profile needed to get that pharmacokinetic profile, as well as impurities and other challenges that we faced from a drug product perspective, we now all have, and we have a series of issued patent claims around that, that places someone with a choice. They can either, you know, develop a formulation of KarXT that's bioequivalent and infringes upon our IP, or they can develop a formulation which is not bioequivalent and doesn't infringe on our IP. So I think that's the position we're putting people in with that, and of course, if you're not bioequivalent, it's very challenging to make an NDA or an ANDA submission that will be successful. So we feel in a very good place there. I think we're cognizant of the fact that, you know, without... When people hear formulation IP, and pharmacokinetic IP or impurity IP, they naturally have some skepticism towards that. In the context of what we've done from a development program and the complexities around this, and the fact that anything has to be about the combination, we feel very good, and I think the people who spend the time to look at the details of our IP position all come back with a similar, similar view. All right. Well, we'll have to leave it there. Thank you very much, Andrew. Good discussion, and good luck with the NDA filing in the next few, few weeks. Great. Thank you very much.