I'm gonna go ahead and get started. One for joining for the ACADIA Pharmaceuticals Fireside Chat here at the TD Health Care Conference. I'm covering analyst, Rawl, and joining from ACADIA's side, CEO, Catherine Owen Adams, Sanjeev Pathak, SVP and Head of Clinical Development, and CFO, Mark Schneyer. Thank you guys for joining us. Appreciate you being here and Let's start with cash. I'm sorry, not cash, revenues. Revenues good. Yeah. good. Yeah. Let's start with the cash you are generating through. Okay. Your product revenues. That's good. I'm looking at this $1.7 billion, and sorry, and clearly need more coffee. You've set a very strong outlook here with projecting $1.7 billion in net sales by 2028. Could you walk us through the key modeled growth drivers? Yeah Behind this guidance, especially as it breaks up between your two current products and, I would say your key investor focus in your pipeline, which is remlifanserin. I'm gonna keep calling it 204. That's okay. 204. That's okay. And how that factors in. Sure. The guidance for 2028 is split between NUPLAZID and DAYBUE. NUPLAZID at $1 billion and DAYBUE at $700 million. The NUPLAZID guidance for 2026 is, at its midpoint, is about a 12% growth, and that would assume a similar growth rate in 2027. The confidence in the NUPLAZID change in trajectory comes from us seeing a back half acceleration in MBRXs in 2025. We just reported fourth quarter growth of 18% in MBRXs. That's been driven by a really focused approach on marketing strategy, which is direct consumer campaigns, raising the awareness of hallucinations and delusions, coupled with a new field force strategy, which is broadening our ability to get to key clinicians. We're going from about 7,000 targets to 11,000. We've upped our field force by about 30%. They're now in place in Q1, and that we expect their impact to be driven by the back half of this year. The NUPLAZID confidence is based on current growth rates and incremental growth that we believe we're gonna see from our expanded field force. That's the NUPLAZID. Mm-hmm Strategy. DAYBUE, we're guiding for about 20% growth this year. We are seeing that growth come from two main areas. The first is the U.S., and that is incremental growth from the community setting. We're currently penetrated about 27%. We see that increasing to the early 30s by the end of this year, and that's on the back of an expanded field force that happened last year. We also see growth potential with the launch of DAYBUE STIX, which is a new formulation of DAYBUE, which allows the families to choose a product that's potentially lower volume, which is important for a lot of our girls that the current volumes can be difficult, as well as the flexibility of it having less carbohydrate, decreased Red Dye 40, all sorts of other things that add into the formulation being attractive for a proportion of our patients, and our named patient programs outside the U.S. The growth is coming from inside the U.S. with STIX and the penetration in the community and outside the U.S. with the named patient sales programs, which are beginning to drive traction now and really account for some growth in this year as well. Very quick follow-up on the expanded NUPLAZID force. Yeah. The extra 30%, are they doing anything different? Are they targeting a different set of providers? Yeah Or, sort of patient. Yeah Retail versus long-term care? How should we think about any changes to what was done before? Yeah. The target, as I mentioned, has gone from 7,000 physicians to 11,000. Mm-hmm It's 4,000 new physicians. Those new physicians are a mix of neurologists who we haven't called on before, but also PCPs. We're seeing more of our patients. [crosstalk]. More PCPs. Yeah. More PCPs. Yeah. We're seeing more of our patients now coming in through the P.C.P. route. Mm-hmm. That's also good because they tend to see the patients earlier in their psychosis. Yeah Journey. Once they get to a neurologist or a psychiatrist, they are pretty far down the track. Again, the NUPLAZID data now supporting earlier use in the patient's psychosis journey, that's those two things come together. It's a breadth and depth strategy we do. Mm-hmm. We're able to reach more and reach them more often, and so territories are smaller, et cetera. 40% of our scripts last year came from new writers. We're hoping to stimulate those new writers to continue to grow. Mm-hmm As we move into 2026. Let's move to 204 now. This is your next generation 5-HT2A inverse agonist. You got it. NUPLAZID. de-risking there, but new IP. Yes, new IP. New IP. Not arguing with that. No. Top line phase II data are expected August to October. Yes. It's a narrowed timeframe. Yes. Can you remind us of that study design, and the... Well, and how it differs from HARMONY, and then we'll get into the primary impact? Yeah. I'm gonna let Sanjeev take that question. Yeah. Sure. Good question. Now let me begin with the HARMONY's pimavanserin study because that informs our remlifanserin program. The HARMONY NUPLAZID study was in dementia-related psychosis. A population that included several dementia subtypes, which were not powered for. Mm-hmm. It was a randomized withdrawal double-blind study. Mm-hmm. Which asks the question that if patients were benefiting from pimavanserin, does it make sense to continue pimavanserin or switch to placebo? The primary endpoint was relapse. NUPLAZID of course beat placebo. The relapse criterion included a scale called SAPS H+D, which stands for - Mm-hmm Scale for the assessment of positive symptoms. Our remlifanserin phase II program and seamless phase II/phase III program is informed with these data in hand. Mm-hmm. Here, the patient population is different. It is Alzheimer's disease psychosis. Yeah. We confirm the diagnosis not only based on biomarkers, but clinical criteria as well as psychotic symptoms. The study is global and phase II initially, and with randomized double-blind placebo controlled parallel group design. Once patients are randomized, they get assigned to either a high dose, which is 60 milligrams or low dose, which is 30 milligrams or placebo, and they're treated for six weeks, and the primary endpoint is SAPS H+D at week six. We hope to enroll around 300 patients. That's that 60-milligram dose versus placebo, that primary analysis? Yes. As well as 30 milligrams versus [crosstalk] placebo. Oh, it's a blended? No. Wait. Okay. Yeah. Do both of them have to hit 60 versus placebo and 30, or how is that calculated? No. Okay. Well, if one hits, we will declare success. Only one of them. Is there any alpha hit for adjustment of the two doses? No. We start with the top dose. Si-sixty? Yeah. Okay. Got it. For starters, I believe in HARMONY it was 50% of patients were ADP patients in that original... Like, can you talk to us about what sort of the subpopulation of ADP patients showed within HARMONY? Yeah. Approximately 190 patients were randomized. Mm-hmm Once they had improved on pimavanserin. Mm-hmm. Around 127 or so is my recollection. Mm-hmm Had ADP. Mm-hmm. Okay. even more than 50%. Yeah. And is it that subpopulation of ADP patients that has informed sort of further development? The data that [crosstalk] The powering studies. Yeah. studies. Yeah. We are relying on, is not only the randomized withdrawal study, we also had a phase II- Yeah Parallel group study that was [crosstalk]. The U.K. study. Plus additional data. Mm-hmm Across the program that informs our remlifanserin program. Got it. That SAPS HD, what is the clinical meaningfulness of its? H+D stand for hallucinations and delusions, correct? Yeah. What does that primary endpoint tell us, and is that something that has precedent with FDA? Okay. You're asking about whether the primary endpoint has precedent. Mm-hmm. Perhaps you. Mm-hmm Wanna know, whether it's a good fit for purpose et cetera. Yes. Okay. Typically when we pick up a primary endpoint for a clinical trial, what we want is a endpoint that measures the symptoms that we are trying to address in the patient population, and SAPS-H+D does do that. We of course, it was part of the package of the NUPLAZID submissions. Mm-hmm. Now, the second element is that, we want a scale that is sensitive to change and moves with effective treatment, and SAPS-H+D has demonstrated that with our NUPLAZID database. Mm-hmm. The third, we want generally prior data- Mm-hmm To inform our study design, powerings, sample size, et cetera. Therefore, we picked up SAPS-H+D. Mm-hmm. I do wanna clarify, there's nothing approved for Alzheimer's disease psychosis yet. Mm-hmm. There is no established precedent. Mm-hmm. The scales meet all the criteria that we would require. How similar is it to the endpoint that NUPLAZID was approved on? The NUPLAZID A different indication. Right. To be clear. Yeah. I'm just trying to get- Yes A sense of FDA alignment on the endpoint. Yes And how this endpoint answers the same question in a regulator's mind that the NUPLAZID endpoint answers that. Yeah. Yeah. The SAPS. Mm-hmm H+D- Mm-hmm Comes from an older scale called the SAPS. Mm-hmm. Scale for Assessment of. Mm-hmm Positive symptoms, and it has 20 items. Mm-hmm. SAPS-PD is a subset of the SAPS H+D. It has- Okay... only nine items. We in our PDP program with pimavanserin or NUPLAZID, we had the SAPS-PD as the primary endpoint. Mm-hmm. We also had the SAPS H+D. Mm-hmm. There's tremendous overlap. Mm-hmm. It just SAPS-H+D has many more items. I see. Okay. That's very helpful. I think in our discussions with Liz, she mentioned that the phase II is powered for a 0.4 effect size. Right. A total at week six. Mm-hmm. Well, first of all, are you going to be releasing any additional data with the top line? Any additional endpoints? Any additional. I guess you're asking what's gonna be in the press release. Mm-hmm. In terms of the press release, you know, you can, we will have an indication of the primary endpoint. Mm-hmm An indication of the safety and tolerability. Beyond that, right now I'm not gonna sort of. Mm-hmm Very specific about what's in there, but there will certainly be an indication of the primary endpoint within the press release. Beyond that, you know, whether we give you all of the sub-analyses or the baselines, TBD. Mm-hmm We will definitely be obviously talking to that. Are there any concerns around phase III, trial equipoise, given the automatic sort of feed in from the phase II s? Yeah To the phase IIIs ongoing? How do they differ in design from the phase IIs? I think as you guys have mentioned, when you ended phase II development, you automatically at those sites started feeding into phase III. How does it impact the, I guess, equipoise of the two trials, if different? We have no equipoise concerns. Okay. If you think about it is a traditional phase II design and traditional phase III design. They are just accelerated. Mm-hmm. No concerns at all. I, you perhaps asked the question, if I heard you correctly, is phase III different from phase II? In the design, yeah. Yeah, yeah. Yeah. No, phase III currently is similar. It just has a bigger sample size. Now, we as phase II reads out, we will optimize the phase III design. Mm-hmm For success. Definitely. How do you statistically define then phase II success? I mean, like, if you see a stat sig 0.4 effect size, like, that sounds like an obvious win. What's sort of the boundaries, I guess, what are the boundaries that still would be successful to you, in the sense that it gives you proof of concept, it gives you an effect size, it gives you a way to optimize the phase IIIs? Do you know what I mean? Like, is it a P value or a particular effect size or some aspect of the data that gives you? What does that data look like? Yeah To maximize phase III success? Yeah, what we would want is to see results that align with our target product profile. Mm-hmm. What we would want is efficacy in the context of convenient dosing, once daily dosing, with or without food, no meaningful drug-drug interaction- Mm-hmm With medicines commonly prescribed in this age group. Safety and tolerability similar to pimavanserin, no cognitive deteriorating side effects, no motor side effects. In that context, statistical significance and improvement in hallucinations and delusions. We'll of course look at secondary endpoints of 30% or 50% improvement, also look at CGI-I. I do wanna underscore that there is nothing approved... Mm-hmm For this patient population. off-label treatments are deemed generally ineffective. I myself have prescribed first-hand, these medicines for patients and in, certainly in my hands it did not work. Having a efficacy signal in the context of the favorable safety tolerability as well as convenience should help us move into phase III, and then, we'll optimize. Mm-hmm Powering accordingly based on the data. Catherine, hypothetical question. If the data shows, say, a 0.3, 0.35 effect size with like a P value just out of bounds, would you see that as a success? Would you see that as the trial giving ACADIA what it needs to get 204 approvable? Not, I mean, not immediately, like with the data in hand, but to chart a path through phase III. I think it's in the context of the whole data package, right? Okay I think it's, you cannot just look at the P value on its own and make. Mm-hmm An extrapolation to a decision. It has to be the whole view of the data. You know, I think we feel that we can make a good decision on this trial. It's a, it's a well-powered trial. Mm-hmm. There's two doses. We will be able to make good solid decisions about moving into phase III. Mm-hmm. If it's very closely statistically significant and everything else, then yeah. Yeah I see a path forward. Mm-hmm. Yeah. If it is very statistically significant with the effect size you're going for, could this function as a pivotal study? You know, I think with the FDA's current, external communications [crosstalk]. Situation Around, single trials and being, wanting to lean into faster, getting drugs to patients faster, we would be very interested in having conversations with the FDA. Mm-hmm In the context of a highly statistically significant trial, in the context of over 300 patients, about what our phase III could look like. Mm-hmm. We'd be very interested to see what we would work on together to put that into action. As yet, you know, I think it's difficult to postulate about what that could mean. Fair enough. you've got a phase II as well, the Lewy Body Dementia study. Right That will enroll both DLB, Lewy Body and PDP patients. PDDP, yes. PDDP. Yes. It's Parkinson's disease. Parkinson's disease... Dementia Dementia Psychosis, yeah. Psychosis. Yeah. Lots of acronyms. Biological rationale there in LBD and, if you could go over that primary endpoint in powering. Sure. Sure. Yeah. There's not just biological rationale, we have clinical science rationale as well. The biological rationale is that, first of all, the Lewy Body Dementia population is an, it's an umbrella term that includes two subpopulation, Parkinson's disease dementia and dementia with Lewy bodies. The only difference between these two population is how they present initially and what the underlying biology is. Both of them have misfolded alpha-synuclein proteins, and the proteins may, in, within these two populations start at different locations in the brain. By the time they present with dementia and psychosis, they look very similar from a biology perspective with all the higher, cognitive level, areas of the brain or areas of the brain involved at higher level cognitive processing, involved. What the alpha-synuclein pathology does is that disrupts the serotonin signaling and upregulates the 5-HT2A receptors. Therein comes the remlifanserin, which is, as you pointed out it to is a 5-HT2A inverse agonist. Clearly there's biological rationale for this investigational medicine for this population. Now we have the clinical science rationale as well coming from pimavanserin data. Pimavanserin was studied in the PDP. Mm-hmm Pivotal trial where. This is HARMONY again. No. This is the pivotal study. Oh, sorry. Yes For PDP that led to registration. Right, to the approval. Right. the approval. Right. Yeah. Where there were 50 patients with cognitive impairment at baseline, which helped us get the new NUPLAZID label with or without dementia. Mm-hmm. In that subpopulation, there was a large delta with statistical significance versus placebo. So... Then there is this second line of evidence comes from the HARMONY randomized withdrawal study, which had 46 patients with Lewy Body Dementia, and that includes PDD as well as DLB. Mm-hmm. In this, when patients were randomized to placebo, 55% relapsed. On pimavanserin, only one subject. Mm-hmm Or approximately 5% randomized. Two studies, two lines of evidence, clinical evidence, supporting this mechanism in the Lewy Body Dementia psychosis population. Got it. With that, I wanna move on to DAYBUE. Sure. The guidance, the $700 million in guidance, from DAYBUE in 2028 as part of the 2028 guidance. You mentioned the current penetration you said was about 27%. In the community setting. In the community going into the high 30s. What strategies are you implementing to achieve this, especially given that sort of wraparound support of tolerability could be more important in the community setting than in the KOL setting? The guidance for DAYBUE this year is $460 million-$490 million. We see that growth coming from two areas mainly. The first is continued new patients coming in from the community and continuation of that penetration into the community setting. Those patients are seen by neurologists. Each neurologist has one or two maybe patients. Our expanded field force can now get to more of those physicians. Mm-hmm. We're able to reach them, educate them, and start patients on DAYBUE. Because of the launch of STIX, we also believe we can unlock patients who have previously discontinued on DAYBUE due to the volume involved in the daily dosing and/or the taste and/or a combination of both. Is that a sort of... Does STIX have a particular appeal in the community setting or does it not matter? I think it appeals to everybody 'cause it's just easier. It's more transportable, it's more flexible, it doesn't need to be refrigerated, it has less. Taste Taste issues. Yes. Taste. Taste. They can reconstitute it with whatever liquid they like as long as it's not dairy. There's just more flexibility all around. Mm-hmm. The attractiveness for a new patient is they get the choice, for a current patient they can look at switching, and for a discontinued patient they can look to come back on. Mm-hmm. In terms of tolerability, we believe they're about the same. We don't believe right now we have enough information to say that they would be different. Mm-hmm Because they were approved on a bioequivalent study. Those that discontinued due to the formulation are the ones that we're looking to unlock to come back onto DAYBUE. There are also a group of naive patients who are starting on DAYBUE, who will start because of STIX, because they just did not want to either have Red Dye 40 or the high ketones or whatever reason. We think there's more patients now that will try DAYBUE because of the new formulation. Mm-hmm. We're estimating about 400 incremental additional patients that can be unlocked through the 2028 timeframe, which the launch of the new formulation. Got it. Europe and the CHMP, you had a negative trend vote. You don't have your formal decision. We have the formal opinion that was published on Friday. Oh, it was Friday. Okay. Yeah. Yeah. There will be a press release going out today just to support that. Got it. The formal opinion was published on Friday. Mm-hmm. It says what we expected it to- Mm-hmm Which the CHMP negative opinion. Mm-hmm Was based on the fact that they don't find the RSBQ or the CGI endpoints to be clinically meaningful. Mm-hmm Even though they are part of a randomized, statistically significant trial. Mm-hmm We are gonna be- The scales themselves or the delta [crosstalk] in the scales? They have an issue with the scales [crosstalk] themselves. The scales. Yeah. Okay. Yeah. Yeah. How would you address that? Is it a secondary endpoint? you said this, They find the CGI compelling either? They don't find it clinically meaningful. Okay. Now when you go back, are you going to... I guess, is the argument going to focus on the clinical meaningfulness? Yes Of the scales? The clinical meaningfulness of the scales in the light of the patients whose, where we see an effect for DAYBUE. Mm-hmm. As in, if a child goes from not being able to use her hands to being able to use her hands, that is clinically meaningful. Mm-hmm. In the context of being able to verbalize one word, to being able to verbalize four words. Mm-hmm That is clinically meaningful. Mm-hmm. It's that sort of relative meaningfulness that we're trying to sort of make more [crosstalk] Are you going back with, like, skills? I mean, this comes up with the gene therapies, right? The skills gained. Are you gonna go back with skills gained data? No, it's the same data but it's bringing it to life Right Possibly in a different way. The detail. Yeah. Yeah. The detail of skills gained within [crosstalk]. Yeah Just to make it idiot-proof. Not calling people idiots, but- We've already gone down that route. We've shown them the domains and the changes- Mm-hmm It's more that they don't... Is this a place where the EU Rett community can help? Yes Something that's they've been organized for? The upside of the timing now is that we have a number, quite a few patients now in the EU on DAYBUE. Mm-hmm Where we didn't when we put the package. Mm-hmm The CHMP. Now that we have the named patient program in Europe, we can actually activate patients who are on DAYBUE, as well as the advocacy community who have now got families on DAYBUE. Mm-hmm As well as key opinion leaders in the EU who have now treated with DAYBUE. Mm-hmm. That's the key difference in terms of the voices that we'll be able to bring to the reexamination process that we didn't have prior. Mm-hmm In the current examination process. What are the timelines for the reexamination process, and where do you fit in the patient voice? We have specific timelines for applying for reexamination, which we'll do in the next couple weeks. Mm-hmm. They then have a timeline for review and a timeline for decision. It's about 120 days from beginning to end. Mm-hmm As long as it all sort of flows as it should. We have the opportunity to bring in the patient voice at, in two places along that journey. The first is in the way we... Actually, three. The way we repackage the data, we can add patient voices in that sort of, if you like, repackaging- Mm-hmm Bring the patient voices to life at the SAG with this scientific advisory. Mm-hmm An oral explanation. Those patient voices can come in and articulate at those two specific points. Got it. I wanna move on to other pipeline programs, specifically 211. Mm-hmm. In depression. Can you speak to 211 and its potential differentiation from IV ketamine and SPRAVATO? It's an isoform, essentially, of ketamine for depression. It's a major metabolite of. Mm-hmm. I mean, metabolite. First of all, there's one thing to understand is that IV ketamine. Mm-hmm As well as SPRAVATO, are dissociative anesthetics. Mm-hmm. IV ketamine is approved for general anesthesia, so what it means is that at a certain dose, people get anesthetized, completely pass out. Mm-hmm. That limits their dose. The second is that IV, ketamine is given IV because oral bioavailability is poor. Mm-hmm. As well as SPRAVATO is given intranasal. Mm-hmm. ACP-211 does not have these attributes, so we have bigger dose range to deploy, and it's orally bioavailable. For key differentiation versus SPRAVATO, we are hoping to demonstrate much better patient experience, lower level of dissociation, and no psychotomimetic effects in the context of similar efficacy. Mm-hmm With SPRAVATO of this work. Can you review the phase II study design and when data is due? Yes, indeed, I can. The patient population that we will. Mm-hmm Would have major depressive disorder. Mm-hmm With inadequate response to antidepressants. We'll treat them- MDD, not the TRD population of SPRAVATO. There will be a subpopulation of TRD in there too. Okay. We'll treat them as monotherapy. Okay. This is a phase II, U.S.-only study. Mm-hmm. It would be a double-blind, randomized, placebo-controlled trial, and patients, once randomized, get assigned to either a high dose of 600 milligrams and low dose of 300 milligrams, or placebo. Mm-hmm And treated for four weeks. The primary endpoint is the standard depression scale called the MADRS scale. Mm-hmm. It would be at four weeks time point. Data is due? We are still in early days. Okay Yeah. We haven't quite tightened the timeline. Yeah We've just started recruiting, so. Yeah. Fair enough. Yeah. Great. We'll enroll around 150 patients. 150 patients. Great. With that, we are at time. Great. Thanks so much. Thank you, everyone, for joining us. Thank you.