All right, we're going to go ahead and get started. Welcome everyone to the Acadia Fireside Chat at the 44th Annual Healthcare Conference, TD Cowen. I'm covering analyst Ritu Baral, and with us from Acadia today we have Steve Davis, President and CEO, as well as Mark Schneyer, EVP CFO. Thanks, guys, for being here. Let's just launch into DAYBUE. This has been the preponderance of questions over the last six months and the launch of that drug. Really, you know, meteoric launch now settling into a more linear growth pattern, a linear growth and sales pattern. You provided full year guidance of $370 million to $420 million. Can you talk about the metrics used to inform both ends of that guidance? Yeah, let me, let me start at a high level and then, then I'll ask Mark to add some additional color. So, I mean, the three key metrics that inform our forecast, both short-term and long-term, are new patient starts, persistency, and then compliance to dose. So I think we have a pretty good read on compliance to dose now. That feels like it's, you know, well dialed in, 75% to 80%. In any particular quarter, conversion, you know, the time it takes and the rate at which you convert prescriptions to new patient starts can impact revenues. That's not as much of a driver of longer-term value. And then, new patient starts is really just a function of how rapidly we're moving through the prevalent population. 6,000-9,000 prevalent population in the United States, 5,000 patients diagnosed. As we move through that, and the pace at which we move through it, of course, has a direct impact, again, on a timeline, on a, you know, quarter-to-quarter basis. And then finally, persistence, you know, impacts, again, quarter-to-quarter. And you want to think about persistence from 2 perspectives. One is longer-term, how many patients will remain on drugs long-term? And we've recently described on our quarterly earnings call that of all the patients who started on DAYBUE, in our clinical trials, 40% remain on therapy today. All of them have been on for over 2 years, some of them well over 3 years. And that, and since we've converted to commercial drug, we've had, now this is not going to be true forever, but as of today, we've had 0 discontinuations from that group. So that tells us there's a sizable population that is an enduring population that will be on the drug for a very long time, and it's very sticky. Our clinical trial experience, through our clinical trial experience, we could also measure in clinical trials up to about 9 months what the persistency rates are. So in the real world, we've been measuring ourselves against that, and we've consistently continued to operate about 10 percentage points above where we were at similar points in time, 3 months, 4 months, 5 months, 6 months, and we just reported 7 months recently. So the persistence picture is continued to be very consistent and very attractive improvement of our clinical trial experience. Here too, in any individual quarter, you can see numerical differences. That does fluctuate some in terms of the number of discontinuations you have in a particular quarter. And so that can also impact revenues on a short-term basis. Mark, any additional color you want to add to that? Yeah, so I think what we've said really at the midpoint of our guidance is kind of on all these three metrics, right? We'll have a new patient start, you know, from February onwards, and we can get to presumably the question on seasonality, but from kind of February onwards, consistent with, you know, what we achieved in the fourth quarter. Persistency continues, as Steve mentioned, to be, you know, 10 percentage points above comparisons to our clinical trial experience with some estimation of how you link, right? Because we don't, we don't have the linkage between kind of the commercial setting and the long-term setting. But thinking about a long-term persistency rate, you know, in the range of 50% and compliance that continues to be in the, you know, 75% to 80%. And then when we look at the totality of the range, you know, things can change variability quarter to quarter, and metrics could evolve over time as you have more patient experience, plus or minus. So kind of the totality of our range is a whole variety of scenarios that flex those key assumptions that get us from the midpoint down to the lower end and up to the higher end. So let's talk about that, the Q1 guidance that was $76 million to $80 million due to seasonality trends. Now, you know, framed in perspective of $370 million to $420 million, that does represent a down quarter. I think one of the surprises is that it is a young population. We're used to, like, the Medicare donut hole and, you know, Q1 being down, but this is a Medicaid population, younger population. And it's the sort of thing where we usually see, like, seasonality from less clinic visits over the holidays, like Thanksgiving, New Year's, Christmas. Parents are running around like crazy, like the clinic visits, shoving kids into clinic are not, is not necessarily the biggest priority. Why is that seasonality coming in January for this population? So, just to recap, what we saw in January was a meaningful decline in new patient prescriptions. not re-auths? No, not re-auth, not re-authorizations. No, but just new patient prescriptions. And then to a lesser extent, we also saw a slowdown in refill rates and in conversions. Let me start with the second part of that, first, because I think that's the most straightforward. I would describe that to what we typically see in our industry. You know, the first quarter is many times kind of a weak quarter, and it has to do with patients or, in this case, families re-enrolling in insurance plans, and they need to get up and running again and usually see refills and conversions for new patients starting therapy slow down some. So we saw some of that. On the new patient prescription side, we anticipated that there would be some slowdown in January, but it was more pronounced than we expected. You know, every drug launch is a little bit different, and particularly when you're launching into the first drug in a new patient population. In rare disease, they tend to have more differences, more things that are unique to that population or particular to that population. So, so in this case, a lot of the Rett centers just had many fewer Rett, what they call Rett clinic days. These are days that are designated. Back up for a second, these neurologists typically treat a lot of other things besides Rett, particularly. Pediatric neurologists. Yeah, yeah. Particular pediatric neurologists. And so many times they'll have a day where they say, "Okay, today I'm just dedicating it to Rett patients." And the Centers of Excellence do that on at least a monthly basis, sometimes more frequently than that, but they have just a Rett clinic day. In January, about a third of the COEs didn't have any Rett clinic days, 0. That's very unusual. Not necessarily so unusual in January, but unusual for them on, in, you know, normally throughout the year. And then there were also about a 25% of them that had far fewer Rett clinics, they had about 50% of the Rett clinic days that they normally do. Some of that was weather related with some severe weather in the middle part of the country, so they just reduced the Rett clinic days. There was severe weather every year, so you might imagine that could happen. It just might be a different part of the country next year. They didn't reschedule or open up new days? No, no, they just. That's not how it works? No, no. I mean, the patients that would have been coming in for a Rett clinic day, yes, they did get rescheduled, but you know, it's they, they. They didn't open up new days or something? No, no, they didn't. No, the total number for those COEs was less. It's a similar dynamic outside of COEs. And I think one of the things, you know, that's unique about Rett is the these Rett clinic days and Rett patient visits, of course, are very much scheduled around the families and their availability and when it works for them. And the families are distributed across the U.S., but the treating, many times they have to fly to see their physician. And, or they're, or it's a long trip. And so January just historically has been a month where people are recovering from the holidays, they're planning other things, they've got other kids starting school, there's a lot of things going on. So we expect we'll see this kind of reduced number of clinic visits in January probably. So you're looking at February and March right now, and those look back to December? Yeah, almost back, almost back. So look, look back. December was the same as like October or November? Trending there. So not quite there yet, but definitely look, you know, the same thing again in February. February-March trending there? Okay, got it. One of the largest concerns, again, tolerability, discontinuation rates appear to have increased according to our quarterly tracking surveys. And you say that you have a good handle on persistence at this point. But some of our physicians noted they don't find out that their parent, their patients have stopped treatment or the parents and patients haven't stopped treatment until the next clinic visit, it's like six months apart. So have you, have you seen any new trends from your hub, essentially? And are those restarts that we were hearing about last year still happening? Okay, a little bit of that background. If I don't hit everything, just remind me. So we do have restarts. So some patients. You're still having restarts? Yeah, yeah, yeah. Some families discontinue. Many times when they do, they say it's just not the right time. I'd like to, I'd like to start again. You know, we have had some of those. As a percentage of the overall population, not a, not a big percentage yet, but we certainly have had, you know, a reasonable number of them. They usually restart at a lower dose. Many times if they discontinued and they restart, they, they might not have titrated, and so they'll titrate. And so, and so far, again, they're, you know, not big numbers to draw a lot of statistical. There, there were patients who never titrated. I mean, it just seemed like anybody, anybody who started at a Center of Excellence would have titrated. So it'd be like community. Generally more likely to titrate. But no, particularly with the surge that we had, you know, the surge will pay dividends in a number of ways. It essentially we just leapfrogged into year two. So you typically see with rare disease drugs, it's kind of linear progression. And ours is the same. So we just jumped up here and went forward. So one of the benefits of that is you get to a critical mass of understanding and experience with the drug in the medical community and in the caregiver community much faster. A downside is you have all these patients that started where you didn't have the benefit of those learnings. And so we, you know, as we go forward, we anticipate that, and we're seeing this already. And we've incorporated titration into our messaging. That's not the label, so we don't promote to it. But we certainly do call out to physicians, you know, doctor, many of your colleagues find it helpful to titrate. If you'd like more information about that, I can refer you to medical affairs, you know, etc. And so it's an important element that if you don't titrate, you're more likely to discontinue. And so it's a key element of our messaging and involvement with the medical community this year is to try to get that information in there. Is there a suggested titration schedule that you're putting forward, or are there going to be guidelines published by the societies with something more concrete? We do not. Again, it's not in our label, so we don't promote to it. And honestly, even if it really has to be almost a case-by-case assessment in terms of what the doctor feels is, you know, the right titration schedule. And many times they will adjust it even for the family and the patient based upon their assessment of the situation. And so, there will be additional data that will be published in the medical community, not by us, but that will, you know, help illustrate some of the titration approaches. Maybe just to come back to your question, maybe your survey on the physicians, right? It's, it's possible answer, right? So our, you know, the data that we track and, and we've shared with all of you, our persistency has been consistent, if not strengthening over time, not decreasing, no, not weakening over time. And one of the things just from maybe the way you, you, you phrase the question to the physicians or when they see their patients, right? If you haven't seen your patient for six months, that patient may have discontinued, you know, four or five months ago, and you're just catching that up on your kind of semiannual visit. Whereas for us, kind of the, you know, as we track our patients and how they use DAYBUE, you know, if you've stopped using the drug, either because you've declared that you're stopped using it or you're, you know, 60 days past your last refill date, we then count you as discontinued. So there just may be an information lag there. But as far as what we're seeing from the business, you know, persistency is consistent, if not strengthening, not weakening. Can you? Maybe just to add one other important points there. A physician might not know for six months, but almost all the time we know, right? Because we've got FAMs, family access managers that are in touch with these families on average about every two weeks. So we learn. And of course, we reflect that in our discontinuations. And then as Mark is alluding to, in addition, any patient that's more than 60 days past a scheduled refill, we count as a discontinuation. That's kind of an industry standard. We know that they don't all discontinue. We do have some of them that continue, but that's the metric that we use. So I feel like our real-time assessment of discontinuations is pretty spot on. What percentage of those discontinuations try restarts? Is that part of your marketing message? Yeah, you know, I appreciate the question. We haven't discussed that. We don't have enough yet to really be able to draw any firm conclusions from what. Restarts? On restarts, yeah. What you're saying after a patient discontinues and they restart. So it's a meaningful number that have, but it's not a large number at this point. You know, we're only, you know, 10 months into the launch. So, you know, I don't want to give you the impression that it's all discontinuations. It's not. I mean, there's some patients that don't respond to therapy. There's some patients for whom the drug is not appropriate. But when patients discontinue, we do frequently hear families say, "I'd like to try again. Please check back with me in, you know, whatever timeframe." And so, and so, of course, you know, we're, I mean, every patient and every family is very important to us. So we, we're very vigilant about trying to remain in touch with them. And if they are interested in restarting, helping them get restarted. Payers, lots of chatter. So I have had a lot of conversations with clients about whether the January dip was related to payers increasing pushback, more difficult reauthorizations, or people just giving up when they have to do paperwork because they feel how they feel about the drug. And any thoughts on evolving payer feedback, especially on reauthorizations? Yeah, we haven't seen that. So the reauthorization process, I would, you know, it's, you know, with every drug, you have to go through that periodically, and we do. And I would say, I would describe that the way we describe interactions with the payer generally, they, they get it. You know, there's no drug approved. It's a really highly debilitating disorder. Reauths every six months, do they have to provide attestation of benefit or clinical charts or anything? It really varies from plan to plan. Of course, we're very involved in helping physicians be positioned to know what payers are expecting and, you know, to the extent we can be helpful in flagging that for them, we do that. But I would say our overall perspective is on both authorizations and reauthorizations. I think the payer community gets it and we're, you know, pleased with the recognition they've given that this is an important therapy. So we're going to move on now to 204. Well, first, let's just touch on negative symptoms. That data still do? Yes. We'll have it by the end of the quarter. You looked at. You don't have it? You said you don't have it right now. I don't have it, no. And we knew we wouldn't have it by today. So I can say that. What are your expectations for the data? Do you expect this trial to be similar to the first? Then, you know, what are your expectations around taking NUPLAZID with its price and the current sales force into that indication? Yeah. So I'll start with, you know, our expectations for the data. We just really don't know what the data will be because, you know, in our industry, you never really know. In neuropsychiatry, you know, you have a placebo response that you have to power through. So there's just a certain baseline level of uncertainty with opening of data on any phase 3 program. Having said that, I mean, I really love the investment that we're making here. We have something very unusual in this space, a positive pivotal study. This study is almost a carbon copy of that. The principal difference is this study is being run at only the 34 milligram dose. That's the same dose we're approved at in Parkinson's disease psychosis. It's the top dose we can go to with this drug. In the previous study, the FDA likes to see a little bit of dose exploration. So we did that. The overall study results were positive, statistically significant. But when we looked at just the 34-milligram dose, the only dose that we're testing this time, the results were much more robust. So we had an effect size of 0.34 there. So, you know, with that, I mean, that's kind of where all the parameters are that we think about with the probability of success of this drug. It's a tough area. There've been a lot of failures. A lot of people tried. We have something kind of unusual, a positive pivotal study. Now we've run a second version of that that if anything, the probability of success could be higher. Got it. And then commercial. Yeah, you were talking about price. So what I've said is I wouldn't assume that we'd make any pricing concessions here. It's a. Or any adjustments to the Sales force? Oh, sales force, yes. Yeah, we'll have Yeah, we'll have to expand the sales force. Yeah. Yeah. So that would be a meaningful expansion of the sales force. PDP is treated almost exclusively by neurologists, some geriatric psychiatrists that work mostly in long-term care. Negative symptoms schizophrenia, that's almost entirely psychiatrists, some primary care physicians. And so, and a few neurologists. So it's a pretty different call point. They're similar and sufficiently similar that we would cover both with one sales force, but it's a lot more physicians to call on. So we'll need to, we would need to recut our territories, make them smaller, and then add reps. Would that impact profitability? Well, I don't, I think, I think where we stand in PDP, I think we're on, you know, just really solid footing there. So I, you know, anytime you make adjustments in your sales force, there's some transition, frictional transition period where you have some reps that are now, or some doctors now be called on by different reps. So I mean, there's, it's always that potential, but I, I wouldn't expect a significant impact on that. Oh, I just mean OpEx, like amount of spending. Yep. Sorry. Yeah. I mean, we'd certainly, our guidance for this year doesn't include, you know, expenses for negative symptoms of schizophrenia. So we'll adjust that, with positive data and expectation of following a launch. I mean, just because where we are in the calendar, you know, that those expenses to support launch would really start towards the end of this year as opposed to starting tomorrow. So I think that we'll talk with the street about, you know, in due course. And I think if you think about profitability, I mean, we're, you know, our PDP franchises, our financial objective on that is to maximize the profitability of that franchise. That franchise generates over $300 million of cash flow on an annual basis on a fully burdened, cost basis. Obviously, we're launching a new indication. We're going to invest to maximize the value of that indication. And so kind of the metrics change a little bit, but, but overall in the context of maximizing the value of the brand as opposed to necessarily, you know, we look at, you know, negative symptoms slightly different than PDP, but with more of a long-to-medium term profitability metric as opposed to current, which would remain for PDP. Got it. So let's move on to 204 for ADP. This is your next generation 5-HT2A antagonist, not an inverse agonist this time, an antagonist. Sorry. Blocker. ACP-204. There's ACP-204 developing for Alzheimer's disease psychosis. Can you walk us through the seamless phase 2/3 design and, and how the two parts differ? Yeah. So let me start with the second part of the question first. So we're running a seamless phase two. Phase two leads seamlessly into phase three. When a site enrolls their last patient in phase two, they'll just keep enrolling. The next patient goes into one of two phase threes. Those three studies, one phase two and two phase threes, are, will be almost identical. They're all sized and designed to be considered pivotal studies. And the objective in doing it that way. Even the phase 2. Yeah, even the phase 2. Yeah, yeah, yeah. And the objective in doing it that way is to try to have 3 bites at the apple, so to speak, to try to get 2 positive studies. We all know in neuropsychiatry, you've got high placebo response. You hear the phrase a lot. Many times the drug works, but the study didn't. You see a lot of approved antipsychotics, antidepressants that have failed studies, failed pivotal studies in their clinical development program. So it's just a prudent step to try to overcome the odds by powering your phase 2 study and designing it so it can also be considered a pivotal study. In this case, we have sufficient data to tip the scales in favor of running this seamless design. In neuropsychiatry, you test drugs in animals. You can't talk to them and, you know, ask, find out how they feel. So you measure in behavioral models to try to use as a surrogate. And you get a view of what your dose might be. You do allometric scaling based on the size of the animal and, you know, metabolic rate to get to what you would expect in humans. And when you get to humans, you can look at receptor occupancy, do a radioligand, PET study to see, okay, at what plasma dose of my drug or what dose of my drug do I get to full receptor occupancy? So we've done all that with 204. The advantage that we have with 204 is we did all that with Tim Aventurin too. So step by step, we've been able to put, here's what we saw with Tim Aventurin. Here's what we see with 204. They're, they're sufficiently closely related chemically and biochemically to make that extrapolation. So from a dosing perspective, we feel like we know a lot more about 204 and what would be the right dose than you normally would. Because sometimes the animal model is not entirely predictive. Their drug might be metabolized differently in humans, etc. But we have a lot of data to support that. So it made sense to us to do this study. We will have a phase 2 readout. When we have it, we will have already started enrolling patients in phase 3. If everything lines up, we will just continue enrolling and we will have saved about a year in development. If for some reason we said we need to make a change to continue going forward in phase 3, then we would just stop the phase 3 studies that we started. Those patients would go into our safety database. And then we would start a new study or studies. And we'd be in no different, no, the same position we would have been as if we had not run a seamless study. Of course, the only difference is we would have spent some money to enroll some of those patients, but again, they'll go into our safety database. So it's not a, not a, not, not a sunk cost. Can you talk about the powering of the phase 2 portion and what effect size you're expecting to see there on that primary endpoint? Yeah. So we typically don't get into precise powering assumptions that we make, but I would say given that we're designed it and sized it to be a pivotal study, all three of the studies would be what you are powered in the way that you would want to power them to, where you're to actually get a compelling result. You know, it's not, in other words, not just an exploratory phase 2 study to try to get a read on things. Got it. And that endpoint, that primary endpoint, is that FDA, do you have that in writing, that that is the accepted FDA endpoint, or is there a precedent for that endpoint? Well, you know, we often hear, you know, when we and sponsors in our industry talk about FDA, you know, and I know it's frustrating for you because you're kind of getting it secondhand, but you know, what you hear, the phrase you hear, and I don't know if you've heard it a million times too, is it'll be a review issue. So that's always the case. The primary endpoint. Yeah. I mean, that would be no matter what. That's the best you'll ever get out of FDA on a lot of the key things that we would like to get. I mean, unless you have guidance and they have written guidance. There's no written guidance right now for ADP. No, no. But it's a well-validated endpoint. Of course, we, you know, have had discussions with FDA, you know, meeting with them before we started this study. We laid out the protocol, we laid everything out. And I would just say that's, as we knew it would be, that's under the category of it, you know, it'll be a review issue. Why not? They need to see the data. They need to see the data. And we do too, honestly. So they're basically saying to, if they felt like that's not going to work then, they will tell you that. They did not. Why not do a randomized withdrawal study like, like? Takes longer. So that's the principal reason. The other is, parallel design studies, we feel like are given a more robust package for approval. I'm not saying you couldn't get an approval, with one of your pivotal studies being randomized withdrawal. But it's a stronger package from an FDA perspective. And randomized withdrawal studies, although there's a lot of advantage to them, they do take quite a bit longer to run than a parallel design study. Now, I'm not saying that when we get the phase 2 data, if we felt like, well, we want to run, we want to add to the 2 parallel design studies that we're doing a randomized withdrawal study, I'm not saying we wouldn't do that, or possibly run one of the studies as randomized withdrawal in lieu, you know, you know, we'll have the flexibility. We can do those kinds of things. Ultimately, if this drug is approved for ADP, we will have to run a randomized withdrawal study. It's typically a post-approval commitment that you make to demonstrate durability of the study. I mean, the placebo controls trials won't tell you as much on durability. How important is durability, durability of response to FDA at this point? Yeah. So So good news is we have 20 or thereabout approved antipsychotics. They're, I think without exception, they were all approved on 6 or 8 weeks of dosing. The FDA's, you know, has a long track record now saying, look, if you have shown this effect in 6-8 weeks of dosing with an antipsychotic, that's enough for approval. That was the case with PDP. They say, and then they almost invariably say, however, you need to do something to show durability of effect. That usually is done with a randomized withdrawal study. Got it. After the fact, after the approval. After the fact. Got it. All right. We are at time. However, I'm going to take an extra 45 seconds and ask you to just give us an overview of 101 for Prader-Willi, especially timelines for data, and that, and that phase 3 trial that you're starting up. Yeah. So Prader-Willi, we really like that program. We just started enrolling patient populations, physician, I'm sorry, caregiver population, I should say, pretty enthusiastic. We're off to a really good start on enrolling. Here too, once we have more enrollment data, we'll kind of, you know, narrow the aperture some, but usually, you know, you should expect about two years this kind of study, but we're, you know, again, it's a, it's a great investment for us. Great. Well, thank you, Steve. Thank you, Mark. Thank you. Thank you to everyone for joining us. Thank you.