All right, I think we're gonna get started here. It's great, we got a packed room. It's my pleasure to be hosting this panel with Andrew Miller, founder, Chief Operating Officer of Karuna Therapeutics. I'm gonna just ask Andrew to just give a very brief snapshot of where Karuna is at with the NDA submission, various ongoing trials with KarXT, and then we can get into Q&A. So thank you, Andrew. Yeah, absolutely. Great to be here. So in terms of just overall picture of where we are, at Karuna right now, obviously, most recently submitted our NDA for the treatment of schizophrenia in adults with the KarXT at the end of September. So we're in sort of the 60-day filing review period. Our anticipation is we would get our acceptance or the, the filing would be accepted here towards the end of November. Obviously, as everyone knows, day 60 will pass. If we get a refuse to file action, we would hear immediately. But assuming acceptance, FDA would have some discretion up to day 74 before providing us a formal written communication. And obviously, once we hear formally from them, we'll be out, informing others, what the result of that was. But obviously looking forward to that as another step closer to getting KarXT into the hands of patients living with schizophrenia. KarXT represents what we believe is a new mechanism and novel class of medicine in comparison to existing antipsychotics. KarXT focuses on the pharmacology of both the M1 and M4 muscarinic receptors in comparison to the dopamine and serotonin-based pharmacology of all current treatments. In addition to the NDA in schizophrenia, we have a number of ongoing Phase III programs, which have six ongoing Phase III studies right now. That includes continued treatment in the long-term safety extension studies that form the basis of long-term safety for the NDA. It also includes the ARISE program, which is our adjunctive treatment in schizophrenia program. So an opportunity for us, I think, again, to demonstrate the uniqueness and novelty of KarXT by potentially using it in conjunction with current standard of care. And then we also have the ADEPT program, which is our Phase III program in Alzheimer's. It's three studies as part of that, two efficacy and safety focus studies, and then also a long-term extension. So those are all currently enrolling. In addition, we're continuing to build up a pipeline of innovative products focused on neuroscience and neuropsychiatry. We recently, at our Q3 earnings release, indicated we were gonna be initiating a Phase Ib, in patients with major depressive disorder with our, TRPC4/5 program, here in the first half of 2024. And couldn't be more excited about continuing to press forward across all of those activities, but obviously, our focus remains on supporting what will hopefully be the NDA review, and the preparation for a launch in the second half of next year. Great. As it relates to the NDA, we've talked about this, you've set the expectation for not getting priority review, which I think to some folks who've followed the drug for a long time is, like, in a way, a surprise, given the unmet need in schizophrenia. It's a new mechanism. Why, why is that your expectation? And then, you know, from our seat, right, people sometimes read into priority review or lack thereof as it relates to sort of FDA, how much time do they think they need or are there other questions they're vetting? Are there any tea leaves to read on that decision? Yeah, I mean, I think from our perspective, obviously, the most important thing is we get accepted for review, which we do anticipate. Uh-huh. Our base case scenario is a standard review, and I don't particularly read any tea leaves into that from a regulatory perspective because the expedited review programs aren't necessarily focused on new class of medicine. They do obviously have some relationship to unmet need, but when you look at procedurally how those expedited reviews are granted, they typically rely on one of two things. So one is some demonstration of superior efficacy, but that tends to mean a head-to-head comparison or pivotal studies that are done in patients who have not had an adequate response to current standard of care. That is very atypical, I would say, in psychiatry. And in fact, the Psychopharmacology Division of the FDA, which we deal with, has only granted one priority review under the entire expedited program. and we don't have head-to-head data as part of our Phase III program, so we don't anticipate, despite, you know, in our view, what is obviously a very robust, promising, and potentially broad efficacy profile of KarXT, the study designs themselves don't really support that expedited review. Now there's also the opportunity on safety and long-term safety, and as we all know, there are some pretty substantial long-term side effects associated with current standard of care. But there's a little more gray area there. We don't have a- In terms of differentiation, you mean? Yeah. Well, I think it's not—we don't have a Phase III pivotal study that, again, compared directly to standard of care or demonstrated statistical superiority, you know, from- Right ... a safety perspective. So it's just a little bit more ambiguous how, you know, those metrics will be applied to it. And again, I think we're also just speaking from the precedent of a division which historically has just not granted a lot of priority reviews. Yep. Yep. Okay, makes sense. In the meantime, you have this blood pressure study coming up. Do you wanna just kind of walk through the different scenarios of that data as it relates to what are or are not the implications if you statistically rule out your goal and you've reiterated a ton of confidence into these data and that it's gonna be benign, and this is just gonna kind of come and go. What underlies that? Yeah, I mean, I think, you know, just to level set a little bit, the ambulatory blood pressure monitoring study. The eight-week study in patients with schizophrenia follows the same dosing paradigm as our pivotal EMERGENT one, two, and three, actually, four and five studies. And what we observed across those the programs, the EMERGENT one, two, and three studies was a very small increase in blood pressure from baseline endpoint. It's less than 1 mm Hg on the systolic side, which is the primary endpoint for the ABPM study. The idea being you want to statistically reject the hypothesis that you have a more than three millimeter increase, so the 95% confidence rule has to be under that. So, you know, we have a lot of confidence in that because all of our data with clinical vital sign assessments so far suggests that we would be successful in this study. And it's also an open label program, and I think as we get closer to the final data readout here pretty shortly, likely this month, that's also given us just confidence that we're going to be successful. From an outcomes perspective, I don't think this study is really about approvability, it's really about labeling. We talked a little bit about that last night at dinner, but, you know, the downside risk would be if the primary endpoint were not successful, that you could get a meaningful warning and precaution related to blood pressure. That data would likely go directly in the label. You know, there are precedent products that have box warnings for meaningful blood pressure increases. You know, I think the scenario that we're going to end up in is obviously being successful, I believe, on the primary endpoint in ABPM. It doesn't mean that there's not going to be still some labeling language related to, Blood pressure and heart rate. Blood pressure or heart rate. Yeah. But that's actually quite common across CNS. Do you think there's going to be, like, a defined monitoring interval, or just a more vague, "Hey, provider, you should check this out sometimes? Yeah, I mean, obviously, I don't want to speculate too much with an NDA that's going to be hopefully under review here, and everything is subject, obviously, to discussion with the agency. I do think there are precedent products when you look out there at antidepressants, the stimulant-based ADHD medicines, et cetera, where a general warning of, you know, use precaution or monitor blood pressure and heart rate during treatment. Mm-hmm. That's been the outcome that I think a lot of other products have ended up. I think in general, again, across CNS, given the magnitude of what we've seen, and I think the magnitude of what we'll see in the ABPM study, I don't think it'll generate a lot of concern. Okay. Okay. All right, so as we gear up for next year, you're prepping to launch KarXT. I think one thing about your launch strategy that sticks out relative to some of the other biotech companies is how big your sales force is going to be at launch, right? When I just compare it, I know it's different markets, but, like, to Neurocrine, Acadia, Sage, even ITCI, to a degree. What's the thought process there, and what kind of level of investment are you planning over the next couple of years for this drug? Yeah, I mean, I think, first and foremost, from a level of investment perspective, you know, we want to make an investment in the launch that's commensurate with our expectations for what we think KarXT can be. And obviously, I can't speak to the specifics of why other companies have done exactly what they've done, but I think the perspective that we take, and I think if, you know, Bill were here sitting next to you as well, what he would tell you is we're approaching the launch like any major company would approach that launch. We're not going to dip our toes in the water. We're not going to hire 100 reps and then hire 100 more if it goes well. We believe in the product, and we're going to make the investment sort of commensurate with that. When you talk about a sales force of 300-400 field representatives, that's really focused on targeting 30,000-35,000 prescribers, both psychiatrists as well as a variety of different nurse practitioners and advanced practitioners that are common prescribers of antipsychotic medicines for patients living with schizophrenia. I think that sales force is really focused on that number of call points. I think it's reasonable. It's within our grasp. Obviously, we've done, I think, a nice job of managing the financial resources of the company as well, and you know, that's in part because we want to be able to make a launch investment commensurate with our expectations. That preparation is well underway. We largely have the commercial leadership already inside of the company. Obviously, from a sales force perspective, we'll put the sales leadership in place. We already have our head of sales. We'll put sort of the account director level people in place the first half of next year and then hire the reps in a sort of phased-up continuing way, which is pretty typical. And I think we have confidence that we know how to do that and we can execute on it. Makes sense. We, we talked about this, you know... I guess I'm going to stop referencing that we talked about this yesterday. I just feel, I almost feel bad asking you the same questions over and over. We had a dinner with some people last night. Anyways, on the comp analog side, you guys have talked a lot about why some of these third-generation atypical antipsychotics, like Caplyta, Vraylar, Rexulti, are not the right comps because in schizophrenia, they're the thirteenth, fourteenth, fifteenth D2 blocker, and they really were more mood disorder products. So I get that. On the converse, what actually are the good launch analogs to KarXT? Yeah, I mean, I think there's a couple points I would make, and just to emphasize one thing, Paul, you already said it. I do think when you look at Rexulti, Vraylar, Caplyta, the products that have launched over the last, say, five-seven years, they do tend to be products that end up focused on the mood disorder side. So when you think about where current atypical antipsychotics are used, there's about 70-75 million scripts a year in the U.S. About 30-35 million of that is on the major depressive disorder and depressed phase of bipolar side. The rest is in schizophrenia, Alzheimer's, pediatric indications like autism, bipolar mania. And so when we think about KarXT and what we've demonstrated so far, we have, I think, in our clinical studies, demonstrated a very robust efficacy signal that, again, without head-to-head comparison, but based on historical comparisons, really puts us much more in line with the more effective antipsychotics. In fact, the numbers are actually slightly above that. That's really what is the key driver of utilization in schizophrenia. When you look at the antipsychotics and where they're used on the schizophrenia side, the vast majority of utilization right now is risperidone, olanzapine, quetiapine, and aripiprazole, which were launched between 1992 and 2002. So the older medicines, they tend to be more effective. They also tend to have more side effect and safety considerations than some of the newer agents, but their profile of less efficacy, but better tolerability, tends to be more, I think, applicable and more interesting on the mood disorder side. So when we look at KarXT, I would say there really hasn't been a launch in the last 10-15 years focused on schizophrenia with a product that really has a target product profile that I think is, is particularly interesting. So does that mean no good analogs? I think when you look at antipsychotics, it's hard to define an analog- Yeah. inside of that class. Okay. Now, I think you can go and look at examples of other areas in neuroscience where you see a class shift happening, which is what we think will happen with the sort of muscarinic agonist field. Obviously, starting with KarXT, I would look at something like triptans to CGRPs as something where there's perhaps mechanistically unique aspects of that. I don't know that on paper they actually have such a substantially superior profile, but it's a new option in an area where you have patients who- Right ... tend to individually respond or not respond to certain medicines, cycle through different medicines, you know. So I think those types of class shift opportunities in neuroscience are sort of where we look at as what we think is possible. There's a launch, and then there's obviously a much longer game here. You can look at something like SNRIs supplanting SSRIs. You can look at atypical antipsychotics being used in depression as a second- and third-line treatment. Mm-hmm. So these examples where eventually you could see a class effect of, say, 20%-40% of the market being utilization of muscarinic agonist space antipsychotics, obviously, starting with KarXT. So I think from our perspective, obviously, we're, you know, give or take about a year from an anticipated launch. As we get closer to that, I think you'll obviously see us start to set much more clear expectations in terms of what a launch trajectory would look like. The only thing I would say towards that is when you look across neuroscience products, you would... I think in many cases, you'll see 3%-10% of peak sales be represented in year one, right? So I think these products have a lot of opportunity to grow after year one. They often bring on different indications, which obviously is part of our strategy as well. But I think we're, you know, very optimistic about what we'll see, but we just haven't set any specific expectations at this point. Okay, fair enough. Do you want to talk about your adjunctive study that's going to read out next year? Mechanistically, doesn't seem like there's any reason why it shouldn't work. But when we think about the two questions there, they're really, one, kind of powering and patient selection on the efficacy side- Mm-hmm. - and then, two, on the tolerability side, do you run into issues with just a much higher dropout rate because you're dealing with side effects from, from two drugs, right, in the, in the same patient? How do you kind of get comfortable with these risks, and how do you guys think about the probability of that study working? I mean, I think there's... Obviously, any study, there's always key considerations and risks that you're trying to mitigate. I do think from a scientific basis perspective, you know, personally, I believe strongly that muscarinic agonist mechanism is gonna be able to be used in conjunction with current dopamine and serotonin-based treatments. Part of that is because we have the preclinical data to support sort of synergistic or additive benefit in preclinical models of psychosis, but also, frankly, just because when you look around at neuroscience and more broadly, you have a complex heterogeneous disorder. You have a largely imperfect, and certainly not sufficient clinical benefit associated with current treatments. There's an opportunity to add more, and I think when you have a novel approach to doing that, you generally see success. From a clinical study perspective, obviously there are a couple of important considerations that are, you know, maybe a little more unique to the ARISE program, the adjunctive program. Obviously, one is you have to make sure that patients are actually taking their background medicine prior to entrance into the study. If you're initiating both drugs at day zero, that's gonna, you know, introduce a, an outsized placebo response into that study. So we have some control metrics for that. We actually take blood and actually analyze it for background antipsychotics before admission into the study. And I think separate of that, you know, we would expect the symptom severity at baseline to be lower than what we've seen across the sort of acute psychosis monotherapy program represented by EMERGENT. So there's just less dynamic range, which is an important- Mm. Consideration in psychiatry with, you know, what are, in the end, interview-based assessments that have some variability from day to day. So we've been more conservative from a powering perspective, statistical powering perspective. Because of that, we're powered to see about half of the benefit that we saw in the monotherapy programs. It's not necessarily our expectation, but from a statistical assumptions perspective, we thought it was appropriate to be conservative. On the safety and tolerability side, I think it is a very important outcome from the ARISE study, but again, I think we don't have side effect overlap with the existing product. So I do think that patients will be experiencing some of the side effects of existing background medicines during the ARISE study, whether that be weight gain, metabolic dysfunction, sedation, somnolence, or other factors. But I don't think we're going to add to that. You don't think... You're not—that's not a big concern for you. I mean, I think it's not, it's not what keeps me up at night with respect to the- Okay. the ARISE program. Yeah. Okay. It's interesting if you look at adjunctive trials in bipolar and major depressive disorder and even like epilepsy—different mechanisms tend to have synergistic benefit. I think in bipolar and MDD, those studies tend to actually have a higher probability of success. Maybe you have a more homogeneous population, less, like, variability. Do you make anything of that? I guess, are there any precedent studies in the adjunctive schizophrenia space we can look to? Yeah, I mean, I think—I, I do think from a mood disorder perspective, you know, placebo response considerations tend to be larger than they are in, in schizophrenia. But when you have an adjunctive treatment, by definition, you have patients who are perhaps more stable, have already sort of had an inadequate response to one course of therapy. And so it's actually a common strategy in mood disorders to recruit patients who have had treatment during their current episode as a way to, in, in effect, remove some level of placebo response from the study. I think in schizophrenia, there's just less data to support that that would, that would carry over, and, and part of that is because we don't—we effectively have one class of medicines. So there have been adjunctive studies of all of probably all of the atypical antipsychotics at this point, but never been able to replicate a clear benefit in that setting because of that pharmacological overlap. Now, there are precedents then that provide information about what you could expect from a placebo response perspective in those types of studies. It's actually not that different than what you see in the monotherapy programs, but you're starting from a lower baseline. Mm-hmm. It is an important consideration. Okay. Okay. Let's talk about Alzheimer's psychosis. You have said that from an efficacy perspective, you're pretty confident the efficacy can translate. The converse, right, is how will safety tolerability translate, and you went through work to try to get to the right dose, and you arrived at TID versus BID, which seems like it's a side effect-based strategy. What are your thoughts there? And I guess, as we think about the elderly, how much more sensitive is that population to side effects, at least from the present or atypicals? Yeah, I mean, I do think in general, the elderly, as well as I would say, pediatrics on the other side of things, can be more sensitive to effects of medicines. I think what we've been able to nicely do as part of our program is we did a Phase I study in healthy elderly volunteers. We did it as a dose exploration study, really to try to find the right ratio and balance of xanomeline and trospium. But the idea was have volunteers come in and then just titrate the drug to whatever the effectively maximum tolerated dose would be in those patients. And what we saw was we had the vast majority of subjects ending up on 150-200 milligrams of xanomeline, which we think is in the effective range. When you look at the blood levels in those patients, you see blood levels that are almost identical to what we've seen in the successful schizophrenia program. So the idea that we've taken xanomeline, a molecule which previously demonstrated efficacy, and now taking that and said, by adding trospium, we can make it, I would say, generally well-tolerated at therapeutic doses. That's kind of what gives us confidence going forward in- Mm. in the Phase III Alzheimer's program. And in the end, you know, I think we have flexible dosing built into the ADEPT program, just like we have in the EMERGENT program. So that should allow us to, on an individual subject basis, find whatever the right dose for that subject is. So, I think it's a challenging global program to execute. Yeah. We have a large number of countries, a large number of sites. You know, we're managing that, but I think if we successfully execute that program, I think we're in a great position to replicate the efficacy data that already exists. In an indication where right now there are currently no approved treatments for psychosis or hallucinations and delusions in the elderly. The cynical interpretation with you guys going with TID is you must have not liked what you saw on the tolerability side of BID. Is that unfair? Well, I mean, as part of that Phase I program, our focus all along was on TID dose administration. Okay. Didn't you have some BID cohorts at the beginning, though? Not, not as part of that Phase I program. So you know, I think in the end, from a dosing frequency perspective, I think we have a couple considerations. One is you're going into a patient population experiencing psychosis already, and in the background of dementia. They're often on a large number of existing medications, both prescription as well as OTC, in a variety of products. They're often in a caregiver setting. Actually, it's a requirement to enroll in our studies that you have a caregiver to provide input. And so I think our view was looking at the overall program, looking at an area with no approved products, that the right thing for us to do at first was put ourselves in the best position to get in the hands of patients, and I think that's what TID gave us that option to do. We have an ongoing formulation development program. We have one currently in Phase I development. We have a number of other projects that we hope to enter the clinic here in the near future that I think are possibilities to reduce that dosing frequency. But I think if we're able to establish clear efficacy and safety in this population, and understand what that pharmacokinetic profile looks like- Mm-hmm. The next step of introducing a sort of next-generation KarXT formulation is already something that we've started on. So I think you've got it to 2025 for those readouts. You just made a side comment that maybe I'm overinterpreting, but I think you said it's a global program that is very challenging to execute. Mm-hmm. Should I be reading anything between there, or like, how are things going relative to your expectations? Yeah, and I, I wouldn't change anything about what I said. I do think it's a challenging program to execute, but I also think we've given ourselves more time- Right already than we did for the EMERGENT programs, right? That's baked in. Right. So we recruited a more- I have to ask, hey, there's been, you know, psych CNS, right? A lot of trial timelines have been revisited. Yeah. Well, I mean, Look, I think any study, it's always the day-to-day and week-to-week management strategy, and there's always assumptions that are built into it. You know, for our schizophrenia program, EMERGENT one, two, and three, those studies recruited over the course of about 12-18 months. You know, we've built in meaningfully more time from an Alzheimer's perspective, and part of that is because when you're launching, you know- over 50 sites across a bunch of different countries, you can't do that all simultaneously the way you can if you're starting 20 sites in the U.S. So all of that sort of already built into- Okay. how we're thinking about that. So you have a randomized withdrawal study and an acute study. From a regulatory perspective, any kind of learnings from what happened with pimavanserin? Yeah, with pimavanserin, I think we take a couple things away from that. It's always obviously important to look at sort of what others have done and what you can learn from it. In the end, that program, you know, they submitted and had an NDA reviewed on the basis of one relapse prevention study in a basket diagnosis study across dementia-related psychosis, Alzheimer's, Parkinson's, Lewy body dementia, vascular dementia, and frontotemporal dementia. I think in the end, there were a bunch of biometrics concerns about differential response across different forms of dementia. Part of our takeaway from that is why our program is singularly focused on Alzheimer's. There's no subgroups to analyze, there's no differential response to look at. But also, I think relapse prevention was demonstrated as a design that, you know, the agency was willing to consider a potential approval based on one successful study. Now, I think an acute study is an equally important sort of, I would say, equally important clinical setting- Mm-hmm. and type of study to look at. We're running both. I think that gives us the best chance to walk away with the positive data that we would need to submit for approval. Makes sense. Do you think that you have a real path here to differentiate on labeling with the box warning? I mean, I think it's a possibility. And what you're referring to, for people who aren't familiar, is all existing dopamine and serotonin-based antipsychotics have a box warning for increased mortality in the elderly. That's based on effectively doubling the risk of mortality in 12-week studies when you look across all of the agents. The exact rationale, pharmacological basis for that, I think it's hard to say exactly what that is at this point. I think there are a lot of interesting considerations out there around aspiration. Obviously, agents are associated with QT prolongation in general across atypicals. There's a lot of considerations there. I do think, given the unique pharmacology, there's an opportunity for us to not be associated with those effects. Now, what it exactly takes to not have that in your label, that's a whole different conversation that obviously we'll want to have with the agency at the right time. But you need to have sort of the data to really inform that. We do have in ADEPT-3, a 52-week safety extension study as part of our program, so we'll be collecting- Mm-hmm. -a substantial amount of safety data in a lot of patients. Even ADEPT-1, which is the randomized withdrawal study, is a 38-week protocol. Mm-hmm. you know, the data that suggests this, the need for this box warning for existing antipsychotics is really based on 12-week placebo-controlled studies. Have I told you that randomized withdrawal studies are my favorite types of studies? You probably have told me that in the past. Look, I think there's a lot of reasons why those studies you're starting to see them run more often. You know, pre- And they... It's hard for them to fail. They are, they are generally more successful, which is what we're sort of in the business of doing, is being able to demonstrate success, right? And they historically have been a very common post-market commitment in schizophrenia, in mood disorders, and other psychiatric indications. And I think people have really accelerated those in as part of Phase III programs. Yeah. Because they are, they're more resistant to some of the placebo effect considerations that we see across the sort of neuropsych development. Hey, the last thing, I know we have a clock that's gonna be at 15 seconds by the time I finish this question. But, where are you in next-gen formulations, KarXT once a day and a potential LAI, and when might we learn more? Yeah. So we have a Phase I program ongoing. The focus of that is really about that TID to BID transition in the elderly. And then we have a number of preclinical programs focused on two things. So one is, potentially a QD product that would be applicable to schizophrenia. And then we also have preclinical program developing a long-acting injectable formulation. Are those close, or are they, like, just ideas right now? No, I think they're definitely substantially more than ideas. I think hopefully we'll be able to set some clear expectations for 2024 about when we expect those to enter human testing. Okay, great. Thank you, Andrew. Yeah. Good stuff. Thanks, everybody.