ACADIA Pharmaceuticals Inc. Aktie

Good afternoon. Welcome back to Bank of America Healthcare Conference. I'm Tazeen Ahmad. I am one of bio analysts here at the bank. It's my pleasure to have our next presenting company, Acadia Pharmaceuticals. Sitting up here on stage are a couple of members from the team. Of course, Catherine Owen Adams, CEO of the company. Welcome, Catherine. And also, Liz Thompson, who is Head of Research and Development.

So we'll go into the specifics of a couple of [ catalysts ] that people have their eye on. But maybe, Catherine, start off by giving us an overview of the company. You brought in a new era [indiscernible]. And can you talk to us about changes that have happened to the company since the beginning of the year?

So I've been in the role now for over 8 months. And the initial focus for us is stabilize the commercial business and also look for new growth opportunities and bringing in [indiscernible] reassess the opportunity and have made some significant changes to [indiscernible] in terms of the [indiscernible]. And as a result of that, we were able to guide to $1.7 billion [indiscernible]. And then Liz, who came in about 3 months ahead of me, we've been working together [indiscernible] and looking at how we can invigorate the pipeline, both looking at how we can accelerate the [indiscernible], but also look at the whole pipeline and start to [indiscernible].

And then in terms of BD, we've definitely got a nice balance sheet, $851 million. And we have no debt. And so we've been looking actively at BD opportunities, and really in two areas. One is later stage that we can add to our commercial portfolio within the next couple of years. And we've been looking, as many other people are, in the areas of rare disease to try and sort of ensure that we can have something beyond DAYBUE and look to build on the great commercial infrastructure we have there.

And we're also looking slightly earlier in the pipeline to add to that. So we're looking at sort of preclinical. And then we have a really nice bolus of Phase II and Phase III products, which I'm sure we'll spend a lot of time on today, which are going to come to fruition in the next couple of years.

Okay. Great. So maybe let's talk about currently marketed products just for a couple of minutes. So for NUPLAZID, that's a maturing launch. It's been on the market now for some time. But you felt it important to continue to focus attention and time on this launch. You had a sales force increase in order to increase focus on areas that could increase demand. Can you talk to us about how that's been going and what early indications of upside you're seeing?

So the -- when I came into role, the peak sales, depending on the analyst, was $650 million to $700 million for NUPLAZID. As I said earlier, Tom and I looked at it again, and we felt we could really drive some incremental growth into that figure, and we've guided now to $1 billion in 2028. And the confidence behind that is based on the fact that we have a great brand that has a strong clinical profile, and we didn't feel that it had really been looked at in terms of its commercial opportunity through the lens that we wanted to see.

And so we have increased the field force by 30%. And the focus of that is to really get to about 4,000 to 5,000 new physicians. So we have been looking at the impact of our direct-to-consumer campaigns, and they've really raised the awareness of hallucinations and delusions amongst the caregiver population. And we've been seeing new types of prescribers for NUPLAZID beyond neurologists, and that's in sort of PCPs and NPPAs that are now treating more patients with Parkinson's disease.

So we've really almost doubled our sort of physician population that we're going after with the field force, as well as revamping our direct-to-consumer campaign, working with a new agency and signing Ryan Reynolds for the unbranded campaign, which has been incredibly impactful. We've had a fourfold increase in the awareness of hallucinations and delusions since we started working with Ryan. We have a new campaign coming out next week, which we're really excited about.

And so both of those two things together gives us confidence that we really have a lot of room to grow NUPLAZID in this market. We're roughly, depending on how you look at the market basket, about 20% to 25% share, and we think we have the ability to go way beyond that.

Okay. And as you think about the IP runway, so you did win some important cases on patent challenges. So how should the Street be modeling sales in terms of just strict IP expiry now?

So we have composition of matter out to October 2030 and MOU out to 2038. So we're looking at our runway to 2038. And the -- I guess, the biggest sort of inflection point for NUPLAZID over the next sort of 5 years or so will be the '29 to '31 time frame, where we will highly likely get IRA price reductions. And so we do qualify for the small company benefits. So we step into those price reductions over the first 2 years.

And then we do expect those price reductions to come to NUPLAZID. But even so, we still think there's a strong runway beyond that in terms of having NUPLAZID on the market. And so that's how we're looking at it in terms of out to 2038.

Okay. And then for DAYBUE in Rett syndrome, the launch has started off with a lot of enthusiasm and demand from the community and from physicians. Talk to us about sort of like the intermediate stage of the launch, what you saw, what tweaks you think were needed and what you're seeing as a result of making some changes?

Yes. So one of the initial tweaks was to increase the size of the field force. We didn't feel we were getting to enough of the community physicians. 65% of Rett patients are treated outside of centers of excellence, and we really didn't have enough reach and frequency on those physicians to get them. So we increased our field force initially.

And then we've also been evolving our patient support model to ensure that we're really thinking about the patient journey right from -- actually prior to the prescription starting to all the way through and beyond. And we've really increased our focus from our family support educators and our MSLs in terms of educating the physicians. And we've seen a nice stabilization in terms of those initial sort of first, I think, few quarters post the launch pump where we saw this sort of increase in dropouts on DAYBUE due to the GI side effects.

We've learned a lot through the process. We've got a white paper out now on how to titrate patients, looking at how you can increase patients over time. And we've got a very steady persistency rate now, which has actually increased a little bit since we first came on, which is 55% at 12 months. And we've just launched DAYBUE STIX. And so we've had a lot of community interest and physician interest in that, and we're really excited to see what incremental opportunities that now gives us to penetrate the market.

Yes. So maybe explain what DAYBUE STIX is for those who may not know.

Yes. So it's a powder for oral solution. It comes in a sachet, a little bit like a liquid IV that you get to add to your water. And it's much more flexible for our caregivers. So it doesn't have to be refrigerated. It's obviously a lot smaller in terms of the size. It could be importantly mixed with any liquid apart from dairy that the child prefers, so apple juice, lemonade, iced tea, whatever it might be. And importantly, also the volume that the caregiver can choose to mix it to is about half of the volume of the liquid. And we've also removed Red Dye 40 and maltitol.

So from an overall patient experience perspective, it's just got a lot more to offer the patient and the caregiver. And because of that, we're seeing 3 types of patients now coming back to DAYBUE. First of all is switch patients, patients that are currently on liquid who are looking to switch over. The second is new patients who would not start DAYBUE because of mainly the maltitol and Red Dye 40. A lot of these girls are on a keto diet, and the parents didn't want to start them. And then the final group is patients that have discontinued DAYBUE in the past who are now coming back to try DAYBUE STIX. And so those are the 3 groups we're now seeing who have a lot of strong interest in the oral solution.

Is there one of those groups that's more representative?

So in terms of the first quarter, we launched mainly in the centers of excellence because we wanted to get experience with physicians who understood how to use DAYBUE. We had 250 prescriptions for DAYBUE STIX, of which 30% were either new to DAYBUE or restarts on DAYBUE. And so the rest of them were switches, so 70-30. And then for the foreseeable 3 years, we've guided to about 450 incremental patients that we believe will come to DAYBUE as a result of the powder for oral solution. And so we're tracking slightly ahead of that right now, and we'll see how Q2 plays out.

Okay. So maybe let's just move to the pipeline. So ACP-204, remlifanserin. Liz, I'm sure this is now super near and dear to your heart with all the questions that you're getting. So just remind us, this is a study that's Phase II that we're expecting to see top line data for between August and October of this year. Just remind us of that study design, and then we'll go into a few more questions.

So briefly, just sort of set the stage of remlifanserin, ACP-204 is a cousin of pimavanserin. It was informed by a pretty vast amount of data on pimavanserin, both from a molecule perspective and from a program perspective. And so NUPLAZID is a good drug, does good things for people. It does have a QT prolongation signal. And so that can be important in and of itself in an elderly patient population, but it also limited our ability to dose range with pimavanserin.

That's important because we've seen some indication that there's an exposure response relationship for pimavanserin with efficacy in Alzheimer's disease from some of our many prior studies there. So here, with pimavanserin, we have the opportunity to look at higher exposures and see if we're able to get more efficacy. And also, we have a faster time to steady state, which could translate into quicker onset of efficacy.

We've also focused our Alzheimer's program. And so now I'll talk a little bit more about the study design aspects. One of the main learnings from our prior history in Alzheimer's was the importance from a regulatory perspective about having a study that is devoted entirely to the patient population you're looking to get indicated in. So in our Phase II and the follow-on Phase IIIs, we're requiring a clinical diagnosis of Alzheimer's, but we're then confirming that with biomarkers, which we think is going to be hopefully helpful from a technical perspective, but I think very important from an eventual regulatory perspective to be able to prove that we have the population that we want.

Our primary endpoint is at week 6. It's something called the SAPS-H+D, which focuses in on hallucinations and delusions. It is an instrument we have used in the past with pimavanserin. What other things are important to note. The 3-arm study, placebo-controlled. The lower dose that we're using of remlifanserin is roughly equivalent to the exposures you get with the currently marketed dose of NUPLAZID, and the higher dose that we're using is roughly twice that exposure. So it's going to give us the opportunity to see if we can get more efficacy out of higher exposures.

Okay. So a couple of things. Is 6 weeks enough time to detect if you're seeing efficacy?

So I will say, if we look back at the pimavanserin data set in Alzheimer's in the Phase II study, we did have a positive primary endpoint at week 6. That was part of what led us to choose this. And we've seen efficacy by week 6 in other aspects of the NUPLAZID program. Hopefully, with a faster time to steady state and potentially faster onset of efficacy, we will see more consistency of efficacy across that time frame, but we think week 6 gives this mechanism time to work.

Okay. And then as far as the doses that you've chosen, for the higher dose where you have double the exposure, is there any concern about safety profile that comes into play there?

Yes. I mean, you always have to think about the -- there's exposure response for efficacy, and oftentimes, there's exposure response for safety. What I can say is a couple of things. Overall, aside from the QT prolongation signal, the NUPLAZID safety database has been fairly reassuring, but of course, that's the exposure for the lower dose.

We've used remlifanserin in a variety of Phase I trials, and some of them have gone as high as 180 milligrams of dosing. But of course, that is in short term and limited numbers of patients, but seems to be generally supportable there. And as always, it's a blinded thing. So it's going to depend how things sort out. But at least at the blinded aggregate level, so far, the safety profile appears to be -- we're not seeing anything concerning in blinded data. We'll see how that sorts out eventually. But thus far, we think there are promising signs.

Anything on QT prolongation?

So we feel pretty good about the QT prolongation based on the Phase I work that we've done. So I feel pretty confident from that perspective.

Okay. Now what should we be expecting to see when you release that data later this year, level of data to expect in the press release, assuming it's on a press release? And what are you going to hold for, let's say, a medical meeting?

So I don't know exactly what we're going to hold for a medical meeting. What I can say is that we're currently anticipating that we would be sharing a comment on the primary endpoint at week 6 SAPS-H+D as well as general commentary on the safety profile. That's sort of the minimum set that you should expect. We may very well share additional information as needed to sort of contextualize what we're seeing. There's a number of aspects of the clinical data that we're looking at in terms of thinking about what a successful product could be and what we want to see.

Yes. Have you talked about what effect size you would think would be clinically meaningful?

Well, so what we've talked about is the effect size that we're currently powered for. And I will say that I think that something a little bit below that probably would also be clinically meaningful. But what we're powered for at this point is a 0.4 effect size or a moderate effect size, 80% power. So again, this is a Phase II. Our primary goal here is Phase III enabling. But we feel confident in the KOLs we worked with as we put the program together, felt that if we saw the level of data we're powering for, that would be a win.

Okay. So you get your data, you top line it. What would be the next steps, making arrangements to go talk to FDA? Or have you already had some preliminary discussions about what a Phase III would look like?

Yes. So we have a bit of an unusual situation here in that we have a master protocol that covers a Phase II and 2 Phase IIIs. It's operationally seamless. And so what that means is once we stop enrolling in the Phase II, we start enrolling in the Phase III. So I'm saying -- but it is statistically separate. So we're able to evaluate the Phase II and apply learnings to Phase III. The reason I'm saying this is we talked to FDA before we went into the Phase II, Phase III program.

We have the opportunity to learn from the Phase II and potentially make modifications to the Phase III. Depending on those modifications, we may want to go talk to FDA again to make sure those are still in line with thinking, but that's going to depend a little bit on the scope of what they are.

I'll say in general terms, the kinds of things I think about that we might consider modifying. Right now, we do have, I said, the placebo, 30 and 60 milligrams. If there were evidence that made us feel really good that one of those doses was the right one to take forward, we might well consider dropping one of those doses. That has a number of advantages, but one would be presumably speed.

There is the possibility that we may need to modify our estimates around effect size, and that could have sample size implications. And there could be things that we would think about from an endpoint perspective. We are looking at steps into H and D, but we are considering other endpoints as well.

Okay. So I guess, why choose to kind of have an outline already as opposed to wait to see this Phase II and then figure out what Phase III looks like?

Yes. So I think part of it was we felt good about many aspects of this. And so while I'm saying these are things we could do, that doesn't mean these are things that we definitely think we're going to have to do. So the intent was to have the benefit of the time savings of starting up that enrollment directly, but then the opportunity to make modifications if we need to.

Okay. And how are you thinking about the competitive landscape for ADP?

So I'll make a couple of comments and then hand it over. I mean, I think one thing is that this is a pretty -- this is a pretty substantial unmet need. There's a large amount of patients out there. I think that there are some other later-stage programs also looking at psychosis. There are some related but separate things that are looking at agitation. We think we have something that's mechanistically distinct in terms of those agents that are currently looking at the psychosis component actually overall. And so I think that if we have the kind of profile out of pimavanserin that we're hoping for, we think that could be a really powerful agent for patients.

Okay. You bring up a good point on agitation, and I wanted to talk about agitation versus psychosis. And do people use these terms interchangeably? And are AA drugs viewed by physicians as eligible to treat psychosis?

So they may use the terms interchangeably, but they are not interchangeable. Agitation can come from a number of different sources. It's a pretty complex phenomenon. It can be driven by pain. It can be driven by confusion. It can be driven by psychosis. It can be driven by just separate mechanic anxiety-related behaviors. And so by and large, the agents that are targeting agitation don't generally target the underlying driver of that agitation.

So I think that as I think about it, something that is effective in agitation may or may not be and frankly probably isn't effective in treating the underlying manifestations. On the flip side of the coin, as we look at psychosis, we -- I don't expect that we would be able to address agitation broadly. But I do think -- and we've got some data from NUPLAZID that suggests that in patients who have significant psychosis and associated with that, they also have significant agitation. In those patients when their psychosis got better, their agitation got better.

And so I think that we have a positive within the psychosis realm. I think we could treat the underlying and the resultant agitation potentially, but again, not agitation more broadly. And the agitation agents are, by and large, not going to positively impact psychosis. And some of them, based on mechanism, may actually have not helpful impacts on psychosis.

And I think just as a market as a whole, I think probably, people are very well aware, but there are 7 million patients with Alzheimer's in the U.S. and about 30% of those will have a psychosis episode during their diagnosis. So for us, there's a large market of patients who currently don't have an approved medication. Because of that, I think there's a lot of competitive focus on the space.

And that's great because patients need choice. And we all know that within just psychiatry generally, different MOAs, different patient types, there's co-prescribing and there's all sorts of ways to treat these patients. So just in terms of the competitive environment, of course, we expect competition, but there's a lot of patients, and we believe that we hold a specific space in terms of the type of patient that we can treat. We'll see with the data, what that looks like. But I feel confident that there's room for quite a few players in this space, and it will be better for patients to have those different choices.

Okay. Now several years ago, pimavanserin did do an umbrella study where ADP was looked at, and we've talked about this a few times. But just to put a bow on this conversation, if you will. The difference in what you're doing with 204, mechanistically, what gives you more confidence that it will have the desired effect that pima did not?

So I would say that for me, at least. It's a little bit less of a mechanistic question and more a little bit of the molecule parameters we talked about with the potential for greater efficacy, greater speed to efficacy, et cetera. But a lot is about the umbrella DRP trial wasn't powered for any of the individual subpopulations.

And I think that -- I'm not trying to condense all of the challenges in that indication down to that one thing, but I think that was a pretty substantial component. So the biggest thing that we're doing differently here is having a very Alzheimer's-specific program that then, again, goes that sort of extra mile with the biomarker confirmation.

Okay. But the flip side of the argument is that Lewy body did work even though it wasn't -- that umbrella study wasn't powered. So we feel particularly bullish on that study being positive in 2027, I believe, is the readout. So I wanted to get your thoughts about -- is that observation from pima the reason why you chose to do a Lewy body study for this asset as well?

Yes. So I was very -- the Lewy body study is the first program I started when I got to Acadia. I was very intrigued by the data. Small patient population, exactly, as you know, but pretty striking data. So I think that, that is a really exciting opportunity for remlifanserin. And I will note that it is also -- while it is a smaller patient population than Alzheimer's, it's about 1 million patients, but...

It's still quite large.

They're still quite large, and they are disproportionately impacted by psychosis. 50% to 75% of patients with Lewy body are going to have psychosis as part of their journey. And from a clinical development perspective, there's less going on there. So I think this is a really impactful constellation of something where I have some good data to believe in from a mechanism perspective as really substantial unmet medical need.

What do patients with Lewy body take now, if anything?

It is -- well, it is a lot of off-label...

[ Antipsychotics ].

Yes. Which, given that they do have motor impact, can be very problematic for them. The cognition impact can be really difficult. So yes, there aren't good options.

So in terms of sites that you use, what was the overlap in ADP sites versus Lewy body sites? And can you compare the pace with which these enrollments occurred?

So we haven't yet shared our expectations on when Lewy body is going to be done. So what I can say is we are looking at a somewhat smaller study for Lewy body, and part of that is because we're expecting a somewhat larger effect size. I anticipate that it will probably not take as long as the Alzheimer's program, but part of that may be sample size. There is some overlap in sites and some distinct sites that we're working with.

Okay. And is it the case that for studies where you're looking at these types of indications, the same concerns might pop up as for study sites for, let's say, schizophrenia, where there are -- there's concern about certain patients being enrolled in too many studies, for example?

I think that we see maybe not to the same extent those dynamics. But I think we are very cognizant of doing everything we can to ensure data quality, that the patients are appropriate patients. I think in the Alzheimer's trial, in particular, the fact that we're biomarker confirming these, we're pretty confident that these are the right people to have in here. So there can be some of that dynamic, but I don't think it's as significant as you see in some of these other spaces.

Okay. And in the few minutes we have, maybe let's talk about 211 in major depressive disorder.

Sure.

Yes. Yes.

Okay. So ACP-211 is our selectively deuterated R-norketamine. We are looking at this in major depressive disorder. It is in a Phase II trial right now. The sort of promise of this is ketamine-like efficacy with a different patient experience. We base our expectations of that on preclinical and early clinical data, preclinical data suggesting efficacy and absence of sedation. It's kind of hard to measure dissociation in preclinical studies. But in early Phase I, we have seen no sedation and only low levels of dissociation at the highest doses. And that's in healthy volunteers, which can be a little bit more sensitive to these things.

We designed our Phase II in part, of course, to look at efficacy, but also to try to help us rule out unacceptable levels of sedation and dissociation. And we are looking for the proof-of-concept readout in that in roughly midyear next year.

Okay. And on that, just because there are so many mechanisms that are being developed for MDD, how are you thinking about where this could fit in?

I mean, I think that you're right, there is a lot going at this. I think that this is widely understood, all the way up to the President's executive order around psychedelics, widely understood as a massive unmet medical need space with huge numbers of patients suffering. I think that a profile that is consistent with what we're hoping that 211 can be could be pretty impactful for patients. And I think that's true, again, to Catherine's point earlier about these are spaces where having a variety of mechanisms handy is a good thing for patients. I think that's going to be true here. And I think this profile is pretty compelling.

Yes. I think the oral nature of the product is an additional benefit to patients. And to the point that Liz just made, there's going to -- there's plenty of competition already, but the ketamine-like efficacy without the dissociation and the monitoring required of the total patient experience is something that we're really holding out hope that we can launch into this market.

I do want to ask you, I mean, there are companies that are leaning into psychedelics. And so how -- do you think that this is a type of disruptive treatment to go against the grain on traditional antidepressants? There's obviously a certain subset of patients that don't respond to any treatment so far. And do you think that allowing things like psychedelics could also in the longer term, also help products like what you're trying to develop and become a little bit more seamless in how FDA chooses to look at data?

I think psychedelics are obviously flavor of the moment a little bit right now, both with the administration and also the companies that are in that space. I think for us, there's room for many opportunities. And I don't want to talk specifically about whether I think psychedelics are good or bad, other than there's obviously a high unmet medical need.

What is kind of important about getting these products to patients is the schedule and the controlled nature of getting drugs to patients. And so psychedelics will be highly controlled no matter what happens. And so that's going to be a very specific channel in terms of commercialization. Having had quite a lot of experience with fentanyl from my durogesic days, it's a specific commercial execution opportunity that you have to really be very careful about, and it's a very -- you have to have high ethics and high monitoring of the whole supply chain to get these products to patients.

And so it's quite a complex area. And so I feel like the ketamine-like efficacy with the patient experience that we're aiming for is something that we can achieve both clinically through our clinical study, but also commercially. And I think those two things together are actually quite important. You need both to be successful.

Okay. And I guess last question, based on today's update, there looks like there's going to be staffing changes at the FDA again. And so does that impact any of your expected interactions with the agency near term?

Yes. I guess what I'd say is putting on my just biotech hat, I think that getting to a place where we've got a little bit more stability in the agency is going to be a good thing for all of us. Wearing just my Acadia hat, I will say that a good part of our portfolio has been we've had pretty consistent review teams sort of throughout. We've been -- most of our products, certainly, our later stage ones are in the psychiatric -- the division of psychiatry. And Tiffany has been a pretty consistent force throughout, and the review team has been pretty consistent. So thus far, not expecting an Acadia-specific impact, but it would be great to get to a little more stability.

Okay. With that, I'll say thank you for joining us here today, and thanks, everybody, for listening.

Ladies and gentlemen, thank you for standing by. My name is Krista, and I will be your conference operator today. At this time, I would like to welcome everyone to ACADIA Pharmaceuticals First Quarter 2026 Earnings Conference Call. [Operator Instructions]

I would now like to turn the conference over to Albert Kildani, Senior Vice President, Investor Relations and Corporate Development. Please go ahead.

Good afternoon, and thank you for joining us on today's call to discuss ACADIA's first quarter 2026 financial results. Joining me on the call today from ACADIA are Catherine Owen Adams, our Chief Executive Officer, who will provide some opening remarks; followed by Tom Garner, our Chief Commercial Officer, who will discuss our commercial brands, DAYBUE and NUPLAZID. Also joining us today are Elizabeth Thompson, Ph.D, Executive Vice President, Head of Research and Development, who will provide an update on our pipeline programs; and Mark Schneyer, our Chief Financial Officer, who will review the financial highlights. Catherine will then provide some closing remarks before we open up the call for your questions.

We are using supplemental slides, which are available on our website in the Events and Presentations section. On today's call, both GAAP and non-GAAP financial measures will be discussed, including non-GAAP NUPLAZID net sales and non-GAAP total revenues. The non-GAAP financial measures that are also referred to as adjusted financial measures pertain only to NUPLAZID sales in 2025 and their impact on total revenues.

All references to non-GAAP are reconciled with the most directly comparable GAAP financial measures in our earnings press release and slide presentation, which has been posted on the Investors page of the company's website. Before proceeding, I would like to remind you that during our call today, we will be making several forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, timing of events, future results and financial guidance are based on current information, assumptions and expectations that are inherently subject to change and involve several risks and uncertainties that may cause results to differ materially.

These factors and other risks associated with our business can be found in our filings made with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date, and we assume no obligation to update or revise these forward-looking statements as circumstances change, except as required by law. I'll now turn the call over to Catherine for opening remarks.

Thank you, Al. Good afternoon, everyone, and thank you for joining us today to discuss our first quarter 2026 results. ACADIA delivered a solid start to the year with total revenue of $268 million in the first quarter, representing 11% year-over-year growth on an adjusted basis. DAYBUE had an especially strong quarter with sales of $101 million, up an impressive 20%, our highest year-over-year growth since the third quarter of 2024, marking an excellent start to the year.

We are excited about the successful launch of DAYBUE STIX with strong feedback from both caregivers and health care providers. As announced last month, DAYBUE STIX is now broadly available across the United States, and we're seeing strong early uptake from both new and previously discontinued patients that gives us confidence in our growth outlook.

NUPLAZID sales were $167 million in the first quarter, up 6% year-over-year on an adjusted basis. The first quarter performance reflects that some patients were slower to refill than in prior years. We are pleased to report that these refill dynamics have since normalized. Importantly, we saw double-digit referral growth in the first quarter and robust demand growth at 8%, even prior to the expected impact of the recent sales force expansion.

I'm pleased to share that we are reaffirming our 2026 net sales guidance for both DAYBUE and NUPLAZID. Looking at our pipeline, we have several significant catalysts on the horizon. Most notably, we are approaching the highly anticipated Phase II readout for remlifanserin in Alzheimer's disease psychosis, which we continue to expect to share results from in the August to October time frame.

This represents a key inflection point for our company and could unlock substantial value given the significant unmet medical need in this indication. Additionally, the timing of our Phase III study in Japan for trofinetide has accelerated, and we now expect results in the September to November time frame of this year.

I want to remind everyone of the tremendous opportunity we have across our pipeline. We have 4 molecules targeting large markets with a combined full peak sales potential of $11 billion, with approximately $4 billion of that specifically attributable to remlifanserin across the ADP and Lewy body dementia psychosis indications. This underscores the transformative potential of our research and development efforts.

With that, I'll now turn the call over to Tom to provide a more detailed insight into our commercial performance.

Thank you, Catherine. Let me dive into the details of our first quarter performance. Starting with DAYBUE. I'm pleased to report another excellent quarter with revenue of $101 million, representing 20% year-over-year growth. This was another record quarter for unique patients receiving shipments, highlighting the continued momentum and durability of the DAYBUE franchise.

Growth was fueled by robust referral volumes driven by new patient starts, alongside meaningful reengagement of previously discontinued patients following the recent approval and launch of the new powder for oral solution formulation of trofinetide, DAYBUE STIX. During the first quarter, we launched DAYBUE STIX with a focus on centers of excellence to ensure optimal launch execution while gathering valuable real-world feedback.

We've been extremely pleased with both the initial uptake and positive experiences we've received from both caregivers and health care providers. Through Q1, we received DAYBUE STIX prescriptions for more than 250 individual patients, demonstrating strong early demand for the new formulation. Notably, nearly 30% of these patients were either treatment naive or restarting therapy, aligning with our expectations and further supporting DAYBUE's growth outlook.

In addition, we're also seeing strong interest from existing patients in switching to the STIX formulation. Collectively, this early experience demonstrates how DAYBUE STIX can help retain current patients, bring discontinued patients back into therapy and grow the treated patient population, aligning closely with our long-term growth strategy for DAYBUE.

From a patient and caregiver perspective, DAYBUE STIX offers meaningful advantages, including flexible dosing volume, potentially shorter dosing time, a preservative-free formulation, no requirement for refrigeration and enhanced portability. These attributes are resonating strongly with early feedback reinforcing the value of the new formulation, as you can see on this slide.

Caregiver response has been particularly positive with more than 80% of those who have tried STIX reporting high satisfaction, complemented by strong endorsement from health care providers across rep centers of excellence where the product was available through the first quarter. Following the focus launch, we announced in early April that DAYBUE STIX is now fully available in the U.S. We look forward to seeing the continued impact of this broader rollout for patients and caregivers.

Outside of the U.S., our global named patient supply programs continue to contribute meaningfully to our growth through the first quarter. The number of patients receiving product through our MPS programs continues to increase over time, providing important access to patients. The recent Delphi expert consensus reinforces DAYBUE's position as the standard of care for Rett syndrome, reflecting broad adoption across centers of excellence and accelerating uptake among clinicians treating Rett patients.

This important publication demonstrates that Rett syndrome experts agree that DAYBUE plays a crucial role in patient care, including the importance of initiating treatment early and dosing individualized to the patient's needs. The Delphi publication adds to the growing body of real-world experience supporting DAYBUE, complementing our robust clinical trial programs that support the meaningful impact that trofinetide can make for patients living with Rett syndrome.

Taken together, the successful launch of DAYBUE sticks, combined with sustained referral strength and durable patient persistence positions DAYBUE for continued growth through 2026 and beyond. Now turning to NUPLAZID, which delivered sales of $167 million in the first quarter, representing 6% growth year-over-year on an adjusted basis.

I'd like to walk through the dynamics behind the quarter and explain why our confidence in full year performance remains strong. Starting at the top of the funnel, physician referral growth was strong at approximately 11% year-over-year, even ahead of the anticipated impact of our sales force expansion, which was completed in the quarter.

This level of referral growth reflects continued physician confidence in NUPLAZID, driving strong underlying demand. However, as Catherine noted, first quarter performance was impacted by a temporary increase in patients taking longer than expected to refill their prescriptions. This dynamic emerged in January and extended into early February as refill timing lagged historical first quarter patterns. Importantly, these delays proved temporary.

Patients who are late to fill returned in the latter part of the quarter, and we have now returned to normal patterns. Despite the short-term timing impact, NUPLAZID delivered 8% year-over-year demand growth in the quarter, reinforcing our confidence in the full year outlook.

As a reminder, our commercial strategy is focused on driving earlier awareness and use of NUPLAZID in the Parkinson's disease psychosis journey through smart, disciplined execution. We're sharpening prescriber reach, improving call quality and maintaining tight segmentation while strengthening field and digital engagement in order to engage physicians earlier and convert strong referral momentum into improved pull-through.

Building on this foundation, we expect to realize the full impact of the recent 30% expansion of our customer-facing teams by late 2026 and into next year as we extend these capabilities across a broader target universe. In addition, we anticipate further benefits from our direct-to-consumer efforts. We've recently renewed our partnership with Ryan Reynolds for the unbranded Parkinson's campaign, reflecting its strong resonance with patients and caregivers, enabling us to introduce new content and creative to further raise awareness of Parkinson's disease psychosis. Since launching the campaign, awareness of hallucinations and delusions amongst the Parkinson's disease community has increased from 8% to over 30%, underscoring the campaign's significant impact.

We're complementing this with refreshed branding creative on nuplazid.com to engage patients earlier in their journey and clearly reinforce NUPLAZID as the only FDA-approved treatment for Parkinson's disease psychosis. I'd also like to highlight a significant milestone for NUPLAZID. This year marks the 10-year anniversary of its FDA approval.

Over the past decade, nearly 100,000 patients, along with their families and caregivers have benefited from this therapy. This milestone underscores both the durability of the NUPLAZID franchise and its meaningful impact on the Parkinson's disease community.

In summary, NUPLAZID remains firmly on track for another strong year with continued referral momentum, the scaling impact of our expanded sales force and ongoing market development supporting our path towards approximately $1 billion in annual sales by 2028. And with that, I'll now turn the call over to Liz to provide an update on our pipeline developments.

Thank you, Tom. Before turning to pipeline updates, I want to briefly address the retirement announcement we shared last week. For personal reasons, I've decided to retire by year-end. But while we seek the right next head of R&D, I remain fully engaged in driving our pipeline forward. We will ensure continuity through this transition, including supporting the upcoming Phase II readouts and early Phase III planning for remlifanserin.

With that context, I'll now walk through the key R&D progress for the quarter. I'm pleased to share updates on our pipeline, which continues to offer meaningful opportunity with real momentum building across multiple programs. Across our 8 disclosed programs, we continue to anticipate initiating 5 additional Phase II or Phase III studies by the end of 2027, demonstrating the breadth and depth of our development portfolio.

Most recently, we successfully initiated our first-in-human study of ACP-271 in healthy volunteers, and I'm pleased to report that the study is going well to date. We continue to advance enrollment across several key studies. Our Phase II study of ACP-211 in major depressive disorder is progressing as is our Phase II study of remlifanserin in Lewy body dementia psychosis. And of course, both of these programs represent significant opportunities to address substantial unmet medical needs.

Looking ahead, we currently anticipate reporting 4 Phase II or Phase III study readouts by the end of 2027. And of course, the closest to these is the top line results from our Phase II study of remlifanserin in Alzheimer's disease psychosis. The Alzheimer's study is still enrolling, and the enrollment dynamics continue to support our expectation for top line results in the August through October 2026 time frame.

As a reminder, throughout the study, we focused on ensuring our patient population has biomarker-confirmed Alzheimer's disease, which we think could be an important component of both technical and regulatory success. We're excited for this readout and what it could mean for the future of the company if successful. But most importantly, as a step towards relief for the patients and families affected by this challenging condition.

Turning to regulatory and international developments. The trofinetide reexamination process in Europe remains ongoing, and we continue to expect that process to conclude by late June. We remain focused on working closely with European regulators to address their questions and support the positive benefit-risk profile of trofinetide for patients with Rett syndrome.

In Japan, enrollment in our Phase III trial with trofinetide has been progressing exceptionally well, and I'm pleased to share that we now anticipate completing enrollment this quarter. This accelerated time line positions us for top line results in the September through November time frame this year, which represents an earlier completion than we previously anticipated. Now as a reminder, this is a small study that was designed with regulators to provide descriptive information on Japanese patients receiving trofinetide. We expect this study to provide the remaining new data needed for our Japanese filing package, which will rely largely on the LAVENDER trial to establish trofinetide's efficacy and safety with an expected regulatory submission in 2027. These pipeline developments underscore our commitment to advancing innovative treatments across neurological and rare diseases, and we look forward to sharing more updates as these programs continue to progress. And with that, I'll turn the call over to Mark.

Thank you, Liz. I'll now walk you through our first quarter 2026 financial results. Starting with our revenue performance. Total revenue for the quarter was $268 million, up 11% compared to adjusted total revenue in the first quarter of 2025. NUPLAZID generated $167 million of net product sales in the first quarter, representing 6% growth year-over-year on an adjusted basis.

As Tom discussed, we are very encouraged by the strong demand growth and referral growth in the quarter, which we saw even before the anticipated impact from the field force expansion that was completed in the quarter. The gross to net adjustment for NUPLAZID in the quarter was 22.1%.

As stated in our press release, NUPLAZID year-over-year growth metrics are derived by comparing our Q1 2026 GAAP NUPLAZID net sales to our Q1 2025 non-GAAP NUPLAZID adjusted net sales. DAYBUE delivered strong performance with $101 million in net sales, up 20% year-over-year. Our DAYBUE results reflect the robust momentum Tom described in both the U.S. market and through our international programs.

The gross to net adjustment for DAYBUE in the quarter was 25.8%. Turning to our operating expenses. Research and development expenses were $76.9 million compared to $78.3 million in the first quarter of 2025. Our SG&A expenses were $171 million compared to $126.4 million in the first quarter of 2025, reflecting our continued investments in our commercial franchises with increased marketing investments for NUPLAZID and the expanded field footprint for both NUPLAZID and DAYBUE, which both took place after the first quarter of 2025, which is an important consideration in any year-over-year comparison.

Our cash position remains exceptionally strong with $851 million at the end of the first quarter as compared to $820 million at the end of the fourth quarter. This increase reflects our positive operating cash flow generation and positions us well to execute on our strategic priorities. Moving to guidance. I'm pleased to reaffirm our full year 2026 guidance for net sales and expenses. In terms of quarterly progression, we expect total revenue to be back-end loaded as the year progresses with a greater sales contribution from both brands in the second half of the year, driven by the expected productivity ramp from our expanded NUPLAZID field force, coupled with broader availability and adoption of DAYBUE STIX. With that financial overview, I'll turn the call back to Catherine for her closing remarks.

Thank you, Mark. As we wrap up today's call, I want to highlight the key milestones and catalysts that make 2026 such an exciting and potentially transformative year for ACADIA. First and foremost, we're approaching our highly anticipated top line results for remlifanserin in Alzheimer's disease psychosis, which we expect to report in the August to October time frame. This represents the most significant near-term catalyst for our company with the potential to unlock tremendous value and address a massive unmet medical need affecting millions of patients and their families.

The ADP market represents a substantial opportunity with no currently approved therapies and successful results could position remlifanserin as a cornerstone therapy in this underserved patient population. We also anticipate top line results from our Japan Phase III trial with trofinetide later this year, which could establish an important new market for DAYBUE.

This accelerated time line reflects strong international engagement and our commitment to bringing innovative treatments to patients worldwide. Importantly, as we head into these upcoming data readouts, while Liz has announced her intention to retire at the end of the year, we are grateful that she will continue to lead R&D to provide continuity and leadership while we look to find a strong replacement.

Beyond these clinical and regulatory milestones, we have a strong commercial foundation. And we're pleased to reaffirm our 2026 financial guidance for total revenues of $1.22 billion to $1.28 billion. Furthermore, our cash balance of $851 million provides us with significant strategic flexibility, enabling us to pursue business development opportunities, including potential acquisitions, licenses and partnerships that could complement our existing portfolio and further accelerate our growth trajectory.

We remain actively engaged in evaluating opportunities that align with our strategic focus on neurological and rare disease with significant unmet need. Throughout all of these initiatives, we remain steadfast in our mission to turn scientific promise into meaningful innovation for underserved communities.

Every program in our pipeline, every commercial initiative we undertake and every strategic decision we make is guided by our commitment to bring life-changing treatments to patients and families who need them most. The combination of our strong commercial performance, robust pipeline and solid financial foundation positions ACADIA exceptionally well for both near-term catalysts and long-term sustainable growth. We're excited about the opportunities ahead and look forward to sharing our progress with you throughout the year. And with that, we're happy to take your questions. Operator?

[Operator Instructions] Your first question comes from Tessa Romero with JPMorgan.

So I wanted to ask a pipeline one here. So where are you more precisely in terms of enrollment of the Phase II RADIANT study of remlifanserin in Alzheimer's disease psychosis? And how confident are you in your time line from August to October of this year? When might you see the last patient in? And then second question is just how is enrollment going in your Phase II OMEA study in Lewy body dementia psychosis? And what is the right way to think about the potential time line to data there as well?

Thanks. I'm going to ask Liz to take us through the time lines for remlifanserin.

Sure. So Tess, thanks for the question. So first off, for the ADP program, we continue to feel very good about that August to October time frame. And the study is still enrolling, but we are getting to the last phases of enrollment. So we feel confident about that time line. That said, I'm not yet able to narrow that any further than what we have right now. As we look at Lewy body, I'm pleased with the enrollment progress that we have there. I don't think we've yet shared publicly what our expectations around the end are.

We want to get a ways into enrollment. So I do look forward to sharing more about that in the future. But so far, pleased and on track with what I was hoping for.

Your next question comes from the line of Ash Verma with UBS.

So maybe just on this upcoming Phase II study, I know you mentioned the biomarker-based selection for confirmation of the Alzheimer's patients as opposed to just looking at the clinical presentation. Can you help us explain a little bit why is that critical for clinical trial execution? And just in the real-world setting, I know patients are typically not diagnosed based on the clinical presentation and imaging -- sorry, they are diagnosed based on clinical presentation and imaging and not necessarily biomarker confirmation.

So how does that inform the applicability of the results to real world? And then secondly, just on ACP-204. So I mean, NUPLAZID has a black box warning for this increased mortality in elderly patients. Given that this is kind of a connection of that, would the molecule still put the black box warning if it comes to the market?

All right. Thanks, Ash. Some comprehensive questions to get to. So let's start at the top and go down.

There was a lot in there. I was madly writing down. So hopefully, I captured everything. So in terms of the biomarker basis, I think this has been a really interesting thing to watch in the Alzheimer's field with a number of years back, there was the idea of biomarkers being part of a clinical trial basis way of thinking about diagnosis.

And at this point, it actually is considered part of the diagnostic pathway for Alzheimer's. I fully anticipate by the time we would make it to FDA with our potential package for pimavanserin that there would be an expectation that Alzheimer's disease is a biologically confirmed disease. And so we've been -- we put this in place to try to future-proof the program that we have.

And I think that probably touches a little bit on your point about real world. I think that the real world is starting to move that way as well. So we think that this has an important component of regulatory success. I should note, it may also have a potential opportunity for improving technical success.

There is a possibility that this helps you be more confident that the patient population you have is truly Alzheimer's and that there's less heterogeneity in that patient population from a response perspective. So we think it's important on both aspects.

Finally, to your point about the black box warning, -- it's a really great question. There was an FDA workshop probably about 1.5 years ago at this point. And one of the discussion points was about the black box warning and for future agents, what kind of data might be necessary to help FDA make data-based decisions on individual agents.

So we attended that eagerly, learned from it and have taken into account feedback that we got both through there and through other discussions about the kind of information we need to collect to be able to let FDA make a specific decision on remlifanserin and whether it does or does not warrant such a box warning.

So right now, I don't know. But we know the data we need to collect, and we do think that there is good reason to think that this could be a path forward without a black box, but it's going to depend on the data at the end of the day.

Your next question comes from the line of Ritu Baral with TD Cowen.

I've got some more remlifanserin questions as well, extending from clinical into commercial. One, as we think about that Phase II data that's coming, what should our expectations around either effect size or delta on the SAPS-H+D? Is there an accepted minimal clinically important difference here?

And what frames success on a statistical level? And then as we look at our market model, just given the recent competitive approval an Alzheimer's agitation drug, how should we be thinking about differential diagnosis between the 2 indications, accurate diagnosis and sort of decision -- treatment decisions between the 2?

With all the interest in remlifanserin. So I'll ask Liz to kick that off and then maybe Liz and Tom can both talk to the market a little bit as well.

Yes, absolutely. So in general terms of what we should all be looking for and what defines Phase II success for us as we are walking into this readout, there are a few things that I'm looking for.

I mean the main thing really with any Phase II is what you're looking for is Phase III enabling data. You're looking for information that helps you know what to do in a Phase III, any modifications you may need to make, et cetera. Beyond that, I'll be looking for continued information that suggests that this -- that remlifanserin is delivering results that are consistent with our TPP.

We're not going to know all of those definitively coming out of Phase II, and there will be some things that we already feel pretty good about, but I'll be looking -- we want to make sure that we've got something that can be dosed once a day that can be done easily with respect to conmeds, with respect to food, anything that makes it easy for patients to take their drug.

We are, of course, looking for efficacy. We'll be pleased with an effect size that's in line of what we're powered for, which is a 0.4 or moderate effect size. We'd be pleased with safety that looks similar to the pimavanserin profile. And this part, of course, we definitely won't be able to definitively answer out of Phase II, but continued data that suggests that there's no deleterious impact on movement, on cognition, which from the overall pimavanserin data set, we do feel good about.

And hopefully, we'll get some directional sense there. To the question about MCID on, that's not a well-established one at this point. Part of what we would be doing for a dossier that would go into FDA eventually is establishing that MCID based in part on the Phase II data that we have.

We are, however, also looking at, in addition to just the delta, some responder levels those who have improved by at least 30%, those who have improved by at least 50%, which we think help contextualize the meaningfulness of those results. And then I think there was also a question about the recent approval in agitation.

I'll just briefly say we're always happy to see more options for patients. Alzheimer's disease is a complex disease with many manifestations that are really profoundly impactful for patients and their families. What I think is important to keep in mind is that we always did envision as we looked at our business opportunity for remlifanserin that there is a potential competition, particularly including agents that would be approved for agitation and that there are distinctions between agitation and psychosis.

Agitation is complex. There are a lot of things that can play into it. It can stem from pain. It can stem from cognitive challenges, and it can stem from psychosis. For remlifanserin, we are optimistic. There is some pimavanserin data suggesting that in those patients who have significant agitation and significant psychosis, if their psychosis improved, it did seem to suggest that their agitation improved as well.

So there may be an aspect of agitation, but I wouldn't expect that we would have impact on pain-induced agitation, et cetera. And sort of on the flip side, if you look at molecules that are effective in agitation, there's not necessarily a good reason to believe that they can be impactful on any of the things that are actually driving that agitation like psychosis.

I mean, actually, if you look at de -- goodness, if you look at various components, they actually can be associated with an increase in psychosis. So taken together, I think we think that there's ample room for multiple players in this space and that effective players in agitation are going to be meaningfully impactful for the opportunity we see with remlifanserin.

Your next question comes from the line of Yigal Nochomovitz with Citigroup.

This is Caroline DePaul on for Yigal. So switching gears to DAYBUE STIX, you disclosed that 30% of patients are either treatment-naive or returning after previously discontinuing the liquid formulation. Just wondering how this compares to your expectations for the launch? And do you still expect to capture 400 or over 400 incremental patients with STIX? And if so, what is the anticipated cadence for capturing those patients?

Perfect. Thanks for the question, Caroline. So let me provide some additional color on your question just regarding kind of our expectations and performance through the first quarter. So just as a reminder, our launch strategy was very focused on COEs through the first quarter.

So we've not yet gone broadly into the community. However, we have been very, very pleased with the initial uptake that we've seen. So the 250 patients that -- or the 250 prescriptions that we had, we actually shipped 220 of those in the quarter, which, again, I think just talks to the fact that we're able to get this drug into patients' hands quickly. In terms of how it's doing versus expectations, we would actually say that the ramp in terms of speed that we're seeing here is actually going quicker than we anticipated.

I mean I think the 450 that you referenced is what we had spoken about at -- we still think that, that holds true. And we had modeled that over a 3-year period, which would basically get us to sticks being the dominant SKU by the end of that time. I think we may end up in a situation where it goes slightly quicker than that.

But again, I think the 30% that we're seeing is broadly in line with our expectations. And we're encouraged by the fact that it's not only returning patients but naive patients as well, supplemented by the fact that we're also seeing significant interest from patients already receiving the liquid formulation. So I think taken together, it gives us real optimism for the future of baby more broadly and the role that sticks can really play in fueling that growth.

Your next question comes from the line of Brian Abrahams with RBC Capital Markets.

Maybe going back to remli. As we think about remli and what could generate success in the upcoming study, I guess, can you -- what exactly are the key differences on potency, saturation and receptor binding properties that you might expect from 60 milligrams of remli as compared to the marketed and current and previously tested dose of pimavanserin? Or should we think about this more as being just having a more homogenous population in a study design that leverages prior learnings and uses a more sensitive endpoint?

It's a great question, and I think we can think of it as potentially a little bit of both. What we do know from our prior pimavanserin work is that if you look over the exposure response range, there does seem to be a suggestion that at exposures that are higher than what you can get to with the currently marketed dose of pimavanserin, you are able to get greater efficacy.

So there is at least a good reason to think that we're able to push to higher exposures as we are with the 60-milligram dose, we may be able to get further up on that exposure response curve. That said, even if that doesn't play out exactly the way that we're expecting it to, I do think that having a study design that is really specifically focused in on the Alzheimer's population.

I think that's first and foremost, our learning from regulatory in times past is that they're going to need data that are specific to that population, which as I mentioned before on this call, we're going the extra step in biomarker confirming. That's going to be important. And we think that it's going to be -- we've done other modifications of things like trying to make sure that we have a slightly more severe baseline population in terms of their psychosis based on PI data that suggested you get better responses there as well as the fact that we're looking at endpoints that we think SAS-HD as well as other things that we have in our study like the that we think may be better suited to being able to distinguish differences than the NTI-NH that we used way back in the day in our Phase II trial. So I think it's a little bit of all of the above.

Your next question comes from the line of Tienzein Ahmad with Bank of America.

How are you thinking about the read-through from the Phase II study for Alzheimer's onto the Lewy body study itself? Going back to a few years ago when a similar study was done, FMA did seem to show a pretty strong signal there. So regardless of how it turns out for Phase II for Alzheimer's, how should we be thinking about the derisking for Lewy body for next year?

Love that question, and I love what's baked into it. I agree that while it's in small numbers of patients, I've always found the data in pimavanserin in Lewy body to be fairly striking. In the HARMONY study, just for people who are a little less familiar than you are, the withdrawal study, there were about 20 patients per arm with Lewy body. And of those who had their treatment withdrawn about 55% of them relapsed and those who continued on only about 5% did.

So striking while in a small number of patients. So that actually, to your point, regardless of how the ADP study turns out, and we do have high hopes for that based on all the things that I just talked through in the last few answers. But regardless, I think we remain very optimistic about the Lewy body study.

I think the one thing that could be a read-through would be something significant from a safety perspective. I'm not currently anticipating that. But obviously, we only know that when we get the data at the end of it. Thus far, though, we're optimistic about Alzheimer's. But regardless of that, I think we're very optimistic about Lewy body.

Can you talk a little bit about how we think the formulation of remli might suit the Lewy body patient as well in terms of the fragility in the dose set?

So we do think that, obviously, the Lewy body patient population, both of these patient populations, obviously, are complex and with significant needs. Lewy body, generally speaking, is, I think, accepted to be a little bit more frail, and we think it is even more important to have something that is very safe and something that is very easy to take, which again has been something we've really prioritized with remlifanserin.

We look forward to seeing you next week.

Your next question comes from the line of Marc Goodman with Leerink.

Yes. My question is on NUPLAZID. And if we had a delay in patients that you know are kind of getting on therapy, but they were delayed from January and part of February, why would we not have a great second quarter that kind of makes up for that low first quarter because your guidance is kind of all this back-end loaded discussion. So I think you understand the question.

Yes. So let me kind of address that initially. I think we are expecting a strong second quarter, Marc. The dynamics that Tom referred to are definitely showing that from the current sales force. When we talk about the back end of the year, it's really the impact of the additional expansion. But let me just hand it over to Tom to sort of talk you through those specifically.

Absolutely. So thanks for the question, Marc. So as a reminder, we executed the 30% expansion of our sales team in Q1. That team has been in the field for now around kind of 6 weeks by the time we got to the end of the quarter. So we're really not seeing the full quarter impact of the productivity ramp that we anticipate seeing.

You are correct. We saw a very nice increase in referral volumes, 11% year-over-year. We saw good demand growth. But we did have this issue just in terms of late returning patients through the quarter, which was kind of further impacted by the normal Q1 dynamics you would expect to see for Medicare population.

So moving forward, we anticipate that the productivity ramp will continue to impact us moving into the second quarter and beyond. We're continuing to push on the DTC efforts that I mentioned, both in terms of our unbranded, more Parkinson's and branded efforts. And in addition to that, all of the additional work that we're putting into place just around the expanded target universe that we're now going after. As a reminder, we've now increased to a target universe of just over 10,000 HCPs.

We believe that tackling that is going to lead to significant uptick for the brand more broadly because we still have plenty of share growth that we can continue to drive over the coming quarters. In terms of the question just guidance, I don't know if Marc wants to add.

The one thing I'd add -- thanks for that comment. Just from a financial perspective, it's more late to refill of existing patients, not new patients. So those patients that were late to refill essentially missed the script in the year. So it's kind of a lost revenue.

The good thing, though, is it's not a lost patient. Those patients have come back based upon our historical numbers and have refilled in the quarter. So it positions us strong going forward, but not necessarily just a rebound of recouping what was missed in January and early February.

Your next question comes from the line of Jack Allen with Baird.

Just 2 quick ones from us. On remli, in the ADP study, this is a placebo-controlled study, and the FDA has started to put out a lot of guidance around potentially allowing for filings on single trials. I just wanted to hear any thoughts you had on the potential to file on positive results in a placebo-controlled setting for remli. And then briefly on DAYBUE, it seems like you're making a lot of progress with the fixed formulation, and you have thrown out the $700 million kind of aspirational sales number for 2027 longer-term guidance there. I'm curious to what extent you factor in gene therapy in Rett into that longer-term guidance as well?

You want to take this offline?

Sure. So great question about the single trial. And obviously, we've had lots of discussions about this. What I'd say is, thus far, I think we're all still waiting for a guidance document around this to have a better understanding of the thought process.

It's not clear some of the things which I anticipate will likely still apply things like the size of the safety database. And those are the types of considerations that make it such that my current expectation is that our base case assumption, which is that we need our Phase II and we need Phase III is going to be what we're going to need at the end of the day.

I do want to note that, obviously, if we were to see really striking results in this trial, we certainly would go have a conversation with FDA to explore what possibilities exist. But right now, again, our base case assumption is that we are going to need more than the single study just purely based on the size of exposure that we would have.

Just a top line basis, I think we continue to be very confident in our $700 million guidance for 2028. We have, of course, thought about competitive dynamics through that period, including gene therapy. Tom, do you want to add anything else that the team has been thinking through?

Yes, absolutely. So again, very pleased with the initial progress that we've seen with sticks. Obviously, this is complementing what we've already been driving over the last year with liquid as well as we continue to expand into the community. I think it's worth reminding everyone that our penetration for DAYBUE across both COEs and community physicians is still in like the 40% mark.

So we still got significant headroom for growth for this brand, and we believe with sticks, we can capture both naive and restart patients who may have stopped. And as a reminder, we have around 1,000 patients who have tried DAYBUE, but are no longer continuing treatment. we believe that we're going to be able to reengage those, and we've already seen that through the first quarter.

As it relates to gene therapy, as we mentioned on the call, we've also been very pleased to see the Delphi consensus published, which clearly positions DAYBUE as standard of care for patients living with Rett syndrome. Our view is that I think it will be good news to have more treatments available for the Rett disease for the Rett syndrome population.

I think we have to wait and see what the data actually tells us as the gene therapies come to fore, and we're going to be interested to see how that plays out. But irrespective, we believe that DAYBUE will have a role to play across all of these patients moving forward, whether gene therapies exist or not. So again, as Catherine said, we feel really good about the $700 million that we stated by 2028.

Your next question comes from the line of Ami Fadia with Needham.

My question is on remlifanserin. With regards to the powering of the study, I think you mentioned that you're looking for a 0.4 point change. What is the minimum effect size that you need to see for the study to be statistically significant? And then as we also are expecting data from study, where they'll be looking at the endpoint of you give us the top line data readout, would you be providing NPIC data? And at what time point is that being measured?

Just trying to get a sense of how will we compare data across trials just to sort of understand the competitive profile for this product when the data read out?

Well, I always feel like I need to start with saying, you need to be careful in cross-study comparison. in this case. I think an important thing that I should note is that NPIC was an addition to our study after it had gotten started. It was actually one of the earlier things that I did in my tenure here. And accordingly, we don't -- we will not have NPIC data on all patients who are participating in the Alzheimer's study.

So we think that this is going to be important in the Phase II Alzheimer's study, sorry, I should be clear there. We think this is going to be important information, but I don't know that I would anticipate it would be, for example, part of a top line result. It is an exploratory endpoint with a subset of patients. In terms of powering expectations, so we are powered at 80% for an effect size of 0.4. So you can imagine there's a little bit of flex around that with scenarios that could still be statistically significant, but that's generally what we're looking for.

Your next question comes from the line of Sean Laaman with Morgan Stanley.

This is Katherine on for Sean. We had another one on DAYBUE STIX. As adoption scales, can you just provide some color if you expect any meaningful change in persistency versus the liquid formulation? Or is the primary benefit improved front-end initiation and reduce early friction? And then just as a quick follow-up. I think you mentioned about 1,000 patients have previously tried DAYBUE. Can you share more about your strategy to reengage these patients?

Absolutely. So let me take that for you, Katherine. So starting with persistency. What I would say is we are monitoring this very, very closely because as you would imagine, if we can improve persistency further over and above what we're seeing with liquid, obviously, that would be very advantageous for us.

Just as a reminder in terms of the latest data that we have, just regarding persistency with the liquid formulation, at 12 months, we are now north of 55% remaining on treatment through 12 months, and we're retaining about 50% of patients through 18 months. So persistency for liquid actually continues to improve over time. And the latest data that we have is that 74% of our active patients have actually been on treatment for 12 months or longer.

So we continue to be pleased with just the growing group of like persistence persistent patients who are continuing to see benefit with DAYBUE. STIX, to your question, we believe it can help in terms of initial friction. Obviously, there is some significant advantages that we believe exist that go beyond the liquid formulation. But as it stands at the moment, it's probably too early to be definitive as to how sticks will perform in the real world in comparison to liquid, but we will be sharing more detail in due course.

Do you want to talk to the 1,000 patients then how many of those we think might be up for grab?

Yes, absolutely. So as you think about the 450 patients that we spoke about earlier on in the year and you kind of break that down, we think that roughly 3/4 of those would be naive to treatment and the remaining quarter would be restarts. If you look at what we're seeing so far, through Q1, it's roughly a 50-50 split of that 30%.

So we're seeing both naive. We're also seeing returning patients. But as I mentioned on the call, we're also seeing significant interest from existing patients receiving the liquid formulation in switching to sticks. So taken together, that's where we are. And just to close this one, the momentum that we saw in Q1 actually has continued into Q2 as we've gone broader into the community. So again, excited to share more details in due course, but we're very pleased with the initial uptake of STIX.

I think Q2 will be a much more descriptive story about sticks and the types of patients we're seeing, but we look forward to sharing more then, Katherine.

Your next question comes from the line of Evan Siegerman with BMO.

Hoffman on for Evan. Asking about STIX again. I just wanted to see if there was any specific stocking for the stick formulation this quarter. And then also, I want to get a sense of how you can ensure patients proceed with refills for the stick formulation to kind of continue the strong momentum we've seen in this quarter. Appreciate it.

Perfect. Yes, happy to take that,. So first question in terms of stocking, what I would say is very similarly to what we see with liquid. we supply everything through a single specialty pharmacy, and it really is on a patient-by-patient basis.

So there is very limited stocking that we are anticipating or have seen. And then in terms of refills, as I mentioned, of the 250 prescriptions that we actually had in the quarter, over 220 were actually filled. So we're not seeing any issues as it relates to payers or formulary issues on the whole.

We're actually seeing it seems to be very smooth and in line with our expectations, which again is a nice proof point that the strategy that we've employed here in terms of a limited launch has worked well for us.

Your next question comes from the line of Rudy Lee with Wolfe Research.

Just a quick follow-up for LDP trial. So how will these 2 endpoints being measured in the ADP trial help inform the benefits in LDP, which is measuring a different endpoint of? And to what extent there components overlap?

I think it was a little bit difficult to hear some of that Rudy, but I think it was to do with the different measurements of endpoints in ADP and LBD and tau versus maybe the alpha-synuclein view of biomarkers. Okay.

Thank you. I missed a bit of it appreciate it. So first off, I guess, a couple of important things with respect to the biomarker considerations. There are a number of more established biomarkers at this point that are considered to support the Alzheimer's diagnosis.

And so we are actually requiring a biomarker confirmation for -- of the diagnosis for entry into Alzheimer's. The Lewy body field is in a much more exploratory phase. And so we are including an assessment of alpha-synuclein, but it's not a requirement to get into the trial.

It's a thing that we think is going to help inform us in terms of potential future trial design and also hopefully contributing to the science. In terms of the endpoint, there is a fair amount of overlap between the SAPS-HMD and the SAPS Lewy body.

They are both derived from the overall SAPS scale and are a similar but not exactly the same subset of attributes. The SAPS Lewy body, in particular, was based on those aspects that we saw in the PDP and the pimavanserin PDP trial that seem to be most impacted. So that was the driver beyond that, but a lot of overlap between those 2 endpoints.

Your next question comes from the line of David Huang with Deutsche Bank.

This is Sam on for David. Back to DAYBUE, is there anything else that you're able to share on the prescribing penetration dynamics in the quarter as it relates to the community setting versus centers of excellence?

And as a follow-up, noting that the S6 formulation was initially launched in centers of excellence. How should we be thinking about the impact of that formulation in terms of how you think it would resonate prescribing in the community through the rest of the year in the future?

Absolutely. So happy to take that question, Sam. So as you would imagine, given our strategy for DAYBUE 6 is really focused on COEs at launch, we did actually see a an increase in terms of the number of prescriptions or the overall volume of prescriptions that was coming from COEs in the quarter.

So I think we were at roughly 79% was coming from the community in the quarter. -- from the COE versus a lower number from the community. And I think that, again, that's just reflective of the fact that there's been this significant excitement amongst the community around sticks. As you think about kind of the penetration that we have, which again, we've spoken about in the past, we still have significant opportunity.

So our penetration within COEs, even with sticks is around 60%, our penetration in the community currently sits at around 28% before the launch of sticks. Of note, both of those have grown significantly over the last year. Most importantly, though, our penetration within the community, which, as a reminder, is about 65% of the overall available volume has grown by about 7% on an actual basis over the last year.

So again, I think a nice proof point that the strategy that we've employed to kind of focus on COEs, but expand our reach into the community and sticks is very much going to be a part of our strategic road map there is working for us, and that's what's giving us real confidence in the outlook for DAYBUE for this year and moving forward.

Your next question comes from the line of Yatin Suneja with Guggenheim.

Just a quick one on the reexamination process happening in Europe. Could you just talk about where you are? What do you expect to learn from the process there on trofinetide?

So the reexamination process, there are a few points along the way. There is the original intent to request reexamination. We did that very shortly upon receiving the original negative opinion. There's submission for -- there's assignment of new rapporteurs, which has occurred.

There is -- my voice is going today. There is submission of the ground for reexamination, which we have completed. We anticipate an upcoming SAG meeting, and then there may or may not be an oral examination meeting. So we are just past the submission of our ground for reexamination.

Your next question comes from the line of Paul Matteis with Stifel.

This is Julien on for Paul. Really quickly on BD, just curious if anything has changed and how you may be prioritizing external innovation versus internal, especially with the announcement disclosed last week elsewhere. Also just curious on -- do you plan on disclosing total number of shipments at all moving forward? I know it's something that you disclosed in 4Q. And I know you said there was a record number this year, but I just want a clarification on that.

I'll get the team a rest from answer and give Liz the rest and tackle both of those. So in terms of BD, as we've stated, we remain very active and focused on our BD strategy. As you pointed out, we do have a very rich internal pipeline and our late stage is certainly looking great in the next 2 years.

But obviously, we're managing this for the longer term, and we're really focused on kind of 2 areas really right now. One is later-stage assets that we could bolt on to our current commercial franchise, which Tom is leading with such great success.

And so we're looking there. But we're also looking at continuing to refresh our early-stage pipeline, which Liz and her team are managing. So those kind of our 2 main areas of focus right now. We have a lot of ability to flex with our balance sheet, and we know that it's a very competitive process.

We are actively involved in processes, and we continue to look for the right fit for Acadia. We're not under any particular pressure right now, but we are looking for strong fits for our business moving forward to drive that long-term value and growth for our shareholders, but also more importantly, the patients that we aim to serve.

In terms of the shipping, we did commit to kind of moving now towards financial dollar top line. We feel after 3 years of launch that sort of specific patient level metrics on shipping to DAYBUE is probably not the right way to assess the brand.

We will continue to give clarity like Tom has to say on the 6 dynamics, you can see that playing forward. But in terms of patients shipped, we're not going to be sharing that anymore, but it just does continue to grow, and we're very confident again in our full year forecast for both brands, and thank you for the question.

Ladies and gentlemen, that does conclude our question-and-answer session. And I would now like to turn the conference back over to Catherine Owen Adams for closing comments.

I just like to thank everybody for the great questions today and the team here for answering them and specifically Liz for all the great answers on remlifanserin. We're very excited about the next few quarters for ACADIA, both with our commercial brands, but also obviously, the top line results of remlifanserin. And we look forward to continuing to discussing with you and to our conferences in the next coming weeks. Thanks again for your interest in ACADIA today.

Ladies and gentlemen, this does conclude today's conference call. Thank you for your participation, and you may now disconnect.

Thank you for standing by. My name is JL, and I will be your conference operator today. At this time, I would like to welcome everyone to the ACADIA Pharmaceuticals Inc. Fourth Quarter Earnings Call. [Operator Instructions] I would now like to turn the conference over to Al Kildani, Senior Vice President of Investor Relations and Corporate Communications. You may begin.

Good afternoon, and thank you for joining us on today's call to discuss ACADIA's fourth quarter and full year 2025 financial results. Joining me on the call today from ACADIA are Catherine Owen Adams, our Chief Executive Officer, who will provide some opening remarks; followed by Tom Garner, our Chief Commercial Officer, who will discuss our commercial brands, DAYBUE and NUPLAZID. Also joining us today is Elizabeth Thompson, Ph.D, Executive Vice President, Head of Research and Development, who will provide an update on our pipeline programs; and Mark Schneyer, our Chief Financial Officer, who will review the financial highlights.

Catherine will then provide some closing thoughts before we open up the call to your questions. We are using supplemental slides, which are available on our website under the Events and Presentations section. On today's call, both GAAP and non-GAAP financial measures will be discussed, including non-GAAP NUPLAZID net sales and non-GAAP total revenues. The non-GAAP financial measures that are also referred to as adjusted financial measures are reconciled with the most directly comparable GAAP financial measures in our earnings press release and slide presentation, which has been posted on the Investors page of the company website.

Before proceeding, I would like to remind you that during our call today, we will be making several forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, timing of events, future results and financial guidance are based on current information, assumptions and expectations that are inherently subject to change and involve several risks and uncertainties that may cause results to differ materially.

These factors and other risks associated with our business can be found in our filings made with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date, and we assume no obligation to update or revise these forward-looking statements as circumstances change, except as required by law. I'll now turn the call over to Catherine for opening remarks.

Thanks, Al, and good afternoon, everyone. I'm pleased to report that ACADIA delivered another strong quarter, capping off a milestone year for our company. We achieved adjusted total revenues of $298 million in the fourth quarter, up 16% from the prior year. And for the first time in our company's history, annual revenues exceeded $1 billion, reaching $1.08 billion in adjusted 2025 revenue, which represented 14% growth from the prior year.

This achievement underscores the strength of our commercial execution and positions us for sustained growth in the coming years. We are presenting adjusted revenues because during the fourth quarter, we received our Inflation Reduction Act invoices from CMS for NUPLAZID, which were higher than anticipated and required a nonrecurring accounting change in estimate that you see reflected in our financials.

Mark will walk you through the details later in the call. As a result, we delivered adjusted NUPLAZID net sales of $189 million in the fourth quarter and $692 million for the full year. These results were up 17% and 15%, respectively, and in terms of volume represented 13% in the fourth quarter and 9% for the full year. together demonstrating the continued strength of NUPLAZID and further reinforcing our confidence in its long-term growth trajectory.

So now looking forward to 2026, we expect NUPLAZID net sales of $760 million to $790 million, which would represent between 10% and 14% growth over 2025 adjusted net sales, placing the brand on a strong trajectory towards our expectation of achieving blockbuster status with $1 billion of net sales in 2028.

Turning to DAYBUE. We delivered net product sales of $110 million in the fourth quarter and $391 million for 2025, representing 13% and 12%, respectively, year-over-year sales growth. This growth was driven primarily by our expanded reach into the community physician setting in the U.S. and our ex-U.S. named patient supply programs, including countries outside the European Union, where we're seeing strong interest to access DAYBUE.

We're excited about the launch of DAYBUE STIX, our new powder formulation, which is still in the very early stages, but already generating significant interest from both health care providers and caregivers. Tom will share more details on how this new formulation is being received and the opportunities we see ahead. I do want to briefly address the regulatory developments in the EU.

As we shared, following our oral explanation to the Committee for Medicinal Products for Human Use, or CHMP, which we gave to support our trofinetide marketing application, we were informed that the outcome was a negative trend vote. Liz will provide details on our plan to request a reexamination subject to the formal opinion.

Our commitment to advancing access to trofinetide in the EU remains unchanged. Importantly, our named patient supply programs remain active, ensuring patients maintain access to treatment as we move through the regulatory process. For our 2026 DAYBUE guidance, we expect global net sales between $460 million and $490 million, which would represent between 18% and 25% growth over 2025, driven by contributions from the STIX launch in the U.S. and continued growth of our named patient supply outside the U.S.

Due to the current status of our application within the EMA, this 2026 guidance does not include potential commercial sales that would result from this regulatory approval. However, it does include contributions from our global named patient supply programs, including countries within the EU where we continue to see strong interest. Longer term, we continue to project 2028 global net sales for DAYBUE of $700 million, inclusive of the EU, and we'll update our expectations after clarity on the final EMA opinion.

Just for perspective, of our projected $700 million in 2028 sales, the EU sales represent less than 15% of the total, meaning we have ample opportunity for growth ahead under any scenario. Turning to our robust R&D pipeline. We are excited for the Phase II readout of remlifanserin in the August through October 2026 time frame as this presents a key event for our company this year. Beyond that, we see several important catalysts, which Liz will detail.

Importantly, we have 4 unique molecules targeting large addressable markets with a combined full peak sales potential of $11 billion. Approximately $4 billion of that potential is specifically attributable to remlifanserin across both the Alzheimer's disease psychosis and Lewy body dementia psychosis indications, highlighting the transformative potential this asset represents for ACADIA's future growth trajectory. I'll now turn the call over to Tom for an update on our commercial brands.

Thank you, Catherine. I'm pleased to share the strong fourth quarter performance delivered by our commercial portfolio, beginning with NUPLAZID. NUPLAZID delivered another outstanding quarter with adjusted net sales of approximately $189 million in the fourth quarter. Importantly, as Catherine mentioned, underlying quarterly volume growth remained exceptionally strong at 13%, accelerating the momentum we've built throughout the year. This growth was broad-based with strength across all channels.

For the full year, volume increased 9%, reflecting sustained and durable demand for NUPLAZID. Several key metrics underscore this commercial momentum. New prescriptions led the way, growing 18% year-over-year in the fourth quarter. This performance reflects continued traction in the marketplace and validates the effectiveness of our commercial strategy to improve awareness and diagnosis of Parkinson's disease psychosis while positioning NUPLAZID as the preferred treatment option earlier in the course of the disease.

This has been supported by a refined approach to targeting and segmentation. While on the direct-to-consumer front, our new branded campaign launched in the fourth quarter, and we expect pull-through benefits to build throughout 2026. From an execution standpoint, we have now completed a 30% expansion of our customer-facing teams to better support our evolving prescriber base with representatives now fully deployed in the field.

Based on our experience with DAYBUE, we expect a 6- to 9-month ramp before the full impact of this investment is reflected in results. Our expanded team is now equipped with enhanced tools and resources to engage a broader and evolving prescriber base. Notably, 40% of NUPLAZID's prescribers in fiscal year 2025 were new to brand, and we are now even better positioned to meet the needs of this growing group of HCP writers.

Overall, 2025 was a very strong year for NUPLAZID, and we are well positioned to build on this momentum in 2026 and beyond. As reflected in our guidance, we expect another year of solid growth. And as Catherine noted, we remain confident in NUPLAZID's path to approximately $1 billion in annual sales by 2028.

Now turning to DAYBUE. We delivered another quarter of meaningful progress across multiple growth drivers. Fourth quarter sales were approximately $110 million, driven primarily by strong U.S. performance with growing contributions from our rest of world programs. This represents 13% year-over-year sales growth, supported by 12% volume growth. In the fourth quarter, 1,070 patients received DAYBUE shipments globally, which represents record highs in both the U.S. and outside the U.S.

This milestone highlights our continued success in reaching more patients who can benefit from therapy. As the business matures, we expect to increasingly emphasize sales-based metrics over patient counts as our primary performance indicator. Core business fundamentals remain consistent with what we reported last quarter, including strong persistency, low discontinuation rates and continued penetration within the approximately 6,000 diagnosed Rett syndrome patients in the United States, reinforcing the significant opportunity that remains.

We continue to see growing momentum from our community expansion strategy. In the fourth quarter, 76% of new prescriptions originated from community-based physicians, validating our strategy on expanding access beyond specialty care centers and bringing DAYBUE closer to where patients receive their ongoing care.

Now turning to DAYBUE STIX, one of our most exciting recent developments. In December, the FDA approved this new formulation of DAYBUE, a powder for oral solution. We believe this represents a meaningful advancement in how we can serve patients and families. DAYBUE STIX has been developed based on the feedback we've heard directly from caregivers and HCPs.

The powder formulation allows flexibility in mixing with different liquids and adjusting volume based upon patient preference. It requires no refrigeration, offers enhanced portability through compact packaging and contains low sugar and carbohydrate content with no red dye or preservatives. Based on our analysis, we believe there's an incremental opportunity of over 400 patients, including treatment-naive and those who have previously discontinued DAYBUE due to formulation concerns.

We've been very encouraged by the early response to the approval of DAYBUE STIX across the Rett community. Initial product is already in channel, and the first patients have already begun receiving shipments. Early patient mix is tracking in line with our expectations, and we remain on track for a broader commercial launch in early Q2 as we ensure appropriate inventory levels and a smooth transition for patients. Outside the United States, we continue to make progress expanding global access to trofinetide.

DAYBUE liquid is now approved in 3 markets, including Israel, following recent approval by the Ministry of Health, further expanding our international footprint. Looking ahead, we see a strong growth outlook for DAYBUE reflected in our 2026 guidance. Key drivers include the U.S. launch of STIX, continued benefits from the expansion of our customer-facing teams and ongoing contributions from the named patient supply programs internationally.

Overall, the fundamentals of the DAYBUE business remains strong with multiple demand drivers in the U.S., coupled with a runway for continued growth as we expand access globally. I'd like to thank the ACADIA commercial organization for their outstanding commitment to both NUPLAZID and DAYBUE in 2025. I look forward to further building on the strong momentum we've established as we head into 2026. And with that, I'll turn the call over to Liz.

Thank you, Tom. I'm pleased to have the opportunity to discuss progress on our robust R&D pipeline, where we continue to see real momentum building across multiple programs and to provide some regulatory updates. As we updated last month, across our 8 disclosed programs, we anticipate initiating 5 additional Phase II or Phase III studies by the end of 2027, demonstrating the breadth and depth of our development portfolio. Over recent quarters, we've achieved several important milestones with new study initiations.

Among these, we initiated a Phase II study of remlifanserin in Lewy body dementia psychosis, initiated a Phase III study of trofinetide in Japan and launched our Phase II study of ACP-211 in major depressive disorder. Soon, we expect to initiate our first-in-human study of ACP-271 in healthy volunteers, marking an important advancement for this novel asset into clinical development.

As a reminder, our current target indications are tardive dyskinesia and Huntington's disease. We continue to expect to deliver 4 Phase II or Phase III study readouts by the end of 2027.

The next milestone will be top line results from our Phase II study of remlifanserin in Alzheimer's disease psychosis. Based on the pace of enrollment, we remain confident in the updated August to October 2026 time line we shared last month. Recruitment in our remlifanserin study for Lewy body dementia psychosis is getting off to a solid start and is tracking in line with our expectations.

Turning to our trofinetide regulatory and international development updates. As we announced earlier this month, we were informed of a negative trend vote from the CHMP. We expect to receive the final opinion this week, which we expect will be adopted following the CHMP meeting currently taking place. Based on the trend vote, we do anticipate that final opinion to be negative. We are currently intending to follow the normal regulatory process for reexamination. In total, this process would be expected to take approximately 120 days from the adoption of the negative opinion.

Assuming that time line holds, we would expect the reexamination process to lead to a new final CHMP opinion around the end of Q2. Again, our intention to request reexamination is based on our current understanding of the trend vote, but we will need to review the final opinion to determine our optimal path forward. While we look to bring trofinetide to patients in the EU, we continue to make progress on other fronts.

In Japan, as I mentioned, we recently initiated our Phase III study, which represents an exciting opportunity to bring trofinetide to Japanese patients with Rett syndrome. We anticipate results from this pivotal study between Q4 2026 and Q1 2027, which would position us for a potential regulatory submission in 2027 in this important market. The strength and diversity of our pipeline continues to position ACADIA for sustained growth with multiple potential opportunities to bring truly meaningful innovation to underserved patients living with rare and neurological diseases. 2025 was a milestone year for ACADIA in many ways, and I am particularly proud of what the R&D team has done to continue to move our science and our pipeline forward. And with that, I hand the call over to Mark.

Thank you, Liz. I'm pleased to walk you through our strong financial performance for the fourth quarter and full year 2025. Fourth quarter total revenues were $284 million and for the full year were $1.07 billion on a GAAP basis.

Turning to NUPLAZID. Fourth quarter GAAP net product sales were $174 million and for the full year 2025 were $680 million. We are also reporting results on a non-GAAP basis to adjust for the accounting impact on NUPLAZID from receiving our first invoices for inflation cap rebates under the Inflation Reduction Act, or IRA.

While we've been accruing for inflation cap rebates since Q4 2022 based upon historical data that we received from the federal government and our customers, the invoices we received from CMS indicated that our Medicare volume for NUPLAZID was higher than we had been accruing for. This volume difference required us to make a change in estimate for our IRA rebate accruals in fiscal year 2025, which is accounted for as an increase in gross to net and resulted in a nonrecurring $20 million reduction in net sales.

A reconciliation from our GAAP results to non-GAAP adjusted NUPLAZID net sales and total company revenues is presented on Slide 15. The adjusted net sales methodology apportions the previously described $20 million change in estimate to the years in which the applicable NUPLAZID net sales volumes occurred. As you can see on this slide, the change in estimate is only a modest change in net sales when looking over the entire 4 fiscal year period. For the fourth quarter, adjusted NUPLAZID net sales were $189 million, up 17% year-over-year.

For fiscal year 2025, our adjusted NUPLAZID net sales were $692 million, up 15% year-over-year. For the quarter, gross to net for NUPLAZID was 29.4% on a reported basis and 23.6% on an adjusted basis. Our gross to net for NUPLAZID for the full year was 25.9% on a reported basis and 24.6% on an adjusted basis. For DAYBUE, we achieved $110 million in net sales in Q4, up 13% year-over-year, demonstrating continued strong momentum in this brand. The gross to net adjustment for DAYBUE in the quarter was 19.5%. Full year DAYBUE net sales were $391 million, up 12% year-over-year. DAYBUE gross to net was 22.3% for the year.

Turning to our operating expenses. R&D expenses for the fourth quarter were $85 million, down from $101 million in the fourth quarter of 2024. The decrease was primarily attributable to the $28 million upfront payment for ACP-711 in the fourth quarter of 2024. SG&A expenses for the fourth quarter were $156 million, up from $130 million in the fourth quarter of 2024, primarily driven by increased marketing investments to support NUPLAZID and from our DAYBUE field expansion and marketing investments.

With regard to taxes, we released the valuation allowance on the company's deferred tax assets, resulting in a onetime noncash income tax benefit of approximately $250 million in the fourth quarter. Our cash balance at the end of 2025 was $820 million. Looking ahead to fiscal year 2026, I'm pleased to provide our financial guidance, which reflects our confidence in the continued growth trajectory of both NUPLAZID and DAYBUE. While we will be making some foundational SG&A investments this year, we expect them to deliver meaningful top line and operating income growth as we move forward into 2027 and 2028.

For total revenues, we expect to achieve between $1.22 billion and $1.28 billion, representing meaningful year-over-year growth that builds upon our strong 2025 performance. For NUPLAZID, we're guiding to net sales between $760 million and $790 million Sales growth is primarily expected to be driven by expanding volume.

Gross to net is expected to be in the range of 22% to 24%, and this aligns with the Medicare volume mix implied by our IRA inflation cap invoices received from CMS. For DAYBUE, we're guiding to net sales in the range of $460 million to $490 million, driven by DAYBUE STIX and continued growth in our named patient supply programs. Given the delay to any potential EMA approval, this guidance range does not assume EU commercial sales.

Gross to net is expected to be in the range of 22% to 24%. We expect R&D expense to be between $385 million and $410 million. The increase in R&D spend expected in 2026 compared to 2025 is primarily attributable to an increase in clinical and personnel costs as we advance and have broadened our R&D portfolio. Our R&D expense guidance assumes our remlifanserin program continues into the Phase III portion of the program.

We expect SG&A expense to be between $660 million and $700 million for the full year. The growth in SG&A year-over-year is primarily due to our expansion of customer-facing personnel and marketing investments for NUPLAZID and increased spend to support the launch of DAYBUE STIX as well as the annualization of our DAYBUE field force expansion that took place in Q2 2025. This guidance reflects our confidence in the underlying strength of our business and positions us well for continued growth as we advance towards our 2028 objectives.

And with that, I'll turn the call back to Catherine.

Thank you, Mark. Looking ahead, in addition to the strong revenue growth we've highlighted on this call, we have a series of exciting milestones to support our growth in 2026 and beyond. Our most significant catalysts arrived later this year with top line results from the Phase II study of remlifanserin in Alzheimer's disease psychosis expected between August and October, an opportunity with the potential to meaningfully shift our long-term growth profile.

We also plan to initiate our first-in-human study of ACP-271 before the end of the first quarter. With a strong balance sheet, we also have the flexibility to pursue business development opportunities that complement and support our future growth. Taken together, our commercial execution, advancing pipeline and financial strength, ACADIA is well positioned for sustained growth and value creation.

And with that, I'll turn the call back to the operator to begin our Q&A session.

[Operator Instructions] Your first question comes from the line of Tess Romero of JPMorgan.

So how should we be thinking about ramp to your 2028 global net sales targets that you outlined at our conference last month? Any additional color you can give us now that your 2026 guidance has been outlined for both DAYBUE and NUPLAZID?

Thanks, Tess. I'll give you a top line view and then maybe ask Tom to add some specifics. So if we take NUPLAZID and we look at our midpoint guidance for '26 at $775 million, that's about 12% above this year's growth on the adjusted basis. And so would indicate we're expecting low to mid-teens growth out to the $1 billion. So we feel very confident in that incremental growth that we see, and Tom will explain maybe a bit more about how that tracks through to the marketing execution.

And then with DAYBUE at the midpoint of our guidance, 21% over last year, again, expecting for next year and out to '28 sort of low 20% growth to continue. So those -- that's how we bridge between today and our guidance for 2028. Overall, the company's CAGR during that time will be about 16%. But Tom, in terms of the confidence to ramp, perhaps you'd add some stuff for Tess.

Sure, absolutely. So as you can see by our results through 2025, both brands are coming off a very strong year. And just looking at NUPLAZID and in particular, our Q4 performance, you can see the acceleration that we actually saw in some of our metrics through Q4. This gives us real confidence going into 2026 but now with our 30% expansion of the field force in place, we can really begin to further capitalize upon the underlying demand that we are seeing in the market for NUPLAZID.

Obviously, we mentioned on the call that we are really kind of positioning NUPLAZID earlier in the treatment paradigm for these patients with PDP. We are continuing to focus on our unbranded efforts. We think awareness for this patient population is incredibly important. And as we begin to tap into just some of the underlying dynamics that we see on a weekly and a monthly basis, especially as it relates to kind of our expanding a new writer base, that gives us real confidence that our strategy moving forward is going to continue to pay dividends for us.

Turning to DAYBUE. We obviously got the approval for DAYBUE STIX back in December. We've been really encouraged by the early signals that we're seeing through January. And just recall, we're not anticipating a full launch for that formulation until Q2. But what we're seeing already, I think, really underpins the excitement that we had leading up and then through that approval just given the encouraging stories we're hearing both from caregivers, but also HCPs and their interest in continuing to use DAYBUE and try the new formulation, either for those patients who are naive to therapy or potentially may have discontinued due to formulation concerns. So there's 2 big opportunities that we see for DAYBUE in the U.S.

Outside of the U.S., obviously, it's going to be a continuation as we further bolster our named patient supply programs. So we continue to see plenty of inbound interest from across the various countries where those programs are available, and we'll support those patients where we can.

Your next question comes from the line of Ritu Baral of TD Cowen.

I wanted to ask the team what good remlifanserin ADP data will look like later this year. What are you hoping to show on the primary endpoint that SAPS-HD at week 6? And if you could go through some of the powering. And in the January presentation, you noted a key exploratory endpoint of the NPIC. Is there anything in particular that you're looking for in that exploratory endpoint of note that sort of fills out the clinical story of what remlifanserin benefit in this population could be? And then I have a quick follow-up.

I'll get Liz to give you her response.

Sure. Thanks for the question, Ritu. So broadly speaking, what we're looking for in our Phase II study with remlifanserin is continued evidence that we are developing a molecule that's in line with our target product profile, what we think a drug really needs to be meaningful in this patient population. And that has a number of different components to it. And then I promise I will come to your questions about powering.

But some of the components are, we know that we think it's important here to have a drug that's going to be easy for people to take and easy for them to be compliant with, particularly in this patient population. You can imagine the challenges in having people take their medicine appropriately and the potential big impact if they don't. And so something that is once a day, something that can be taken with or without food, something that doesn't have significant DDIs with other medicines or beyond.

Those are all things we think are important that we feel pretty good about with remlifanserin to date. We think it's going to be important, obviously, to show efficacy and a good safety profile. And frankly, if we see something that's in line with the established NUPLAZID safety profile, I think we'll be very pleased with that.

And finally, certainly, we're not going to answer this just with this Phase II trial, but we think it's going to be important to see data that's directionally supportive of other things that we think matter that we're not going to have a negative impact on motor, for example, that we're not going to have a negative impact on cognition. So those are all the kinds of things that we're going to be looking for in this study.

In particular, around powering and the SAPS-HD, from a primary endpoint perspective, what we have powered for here is a moderate effect size, so 0.4 in particular. We'll be pleased, of course, if we see statistical significance on that at week 6.

Around NPIC, I'm not really ready at this point to comment on specifics of what we're looking for there. That is a more recently added endpoint, and so we certainly did not power the study around that. So it's more exploratory in nature, and that's reflected in where it is in our hierarchy at this point.

Your next question comes from the line of Marc Goodman of Leerink.

Yes. Can you just give us a sense of what's going on behind the scenes with DAYBUE and just the persistency and how patients are being compliant with the drug, just how that's changed? We haven't heard you talk about that at all today.

Yes. I think Tom talked to it at a high level in his comments. So Tom, do you want to add any more color for Marc?

Yes. I mean, essentially, Marc, everything is kind of in line with what we shared in previous quarters. Our discontinuations remain in the pretty low single-digit range. They've really stabilized. Consumption kind of remains as we've shared before, which I think for the full year was kind of the high 60% range.

Yes, I mean, our story really now is -- now we've stabilized the business. I think now we're kind of back on a growth trajectory. Now we're kind of really seeing the benefits from the expansion that we made back in Q2. And our strategy as we expand into the community is working for us. It's really now a case of utilizing STIX to really unlock that next wave of growth, and that's what we anticipate doing as we head into 2026.

It's been single digits all year. Is that what you're saying, all 4 quarters?

Yes.

Yes.

Your next question comes from the line of Rudy Li of Wolfe Research.

I have a follow-up question for the upcoming Phase III trial in ADP. Can you maybe just talk about the time line, how long it would start -- it would take you to start and finish the trial? And a second question regarding the EU opinion for DAYBUE. What specific concerns regarding the pathway? And how do you plan to fix that with the upcoming request for reexamination?

So Liz, I think that's clarity on the ADP II/III enrollment time line and then you can fill them in on EU.

Sure. Rudy, welcome and thanks. So first, on the remlifanserin Phase II to Phase III. So when we originally designed this program, we were building it on a wealth of information from pimavanserin. And so we took an assertive approach to clinical development, where we've got a combined program, a master protocol that includes the Phase II and 2 Phase IIIs.

And the advantage of this is that they're statistically separate. So I've been talking about how we're going to provide detail or we're going to provide top line results on the Phase II in the August to October time frame, but they are operationally seamless. And so what that means is that as soon as we stop enrolling in the Phase II portion of the ADP program, sites can start enrolling in the Phase III portion of the ADP program. So we look to move from Phase II to Phase III enrollment later in the course of this year.

Switching over to the reexamination. So we don't have the final opinion in hand. We expect that to show up over the course of the coming days. So I can't tell you exactly what is going to be in it. What I can say is that we do anticipate, throughout the process, we have gotten questions on things like the relevance of the endpoints to the patient population, the clinical meaningfulness of the results that we saw on our endpoints, the duration of therapy and the mechanism of action of DAYBUE and how that could be extrapolated to the kind of impact you might expect to have on the disease.

So those are the types of things that we anticipate we're going to see in the final opinion. But again, that's going to come in the following days, and we'll put out a press release that provides more information on it when we have more information on it to share.

In terms of -- I think there was also embedded in there a question about what we might do differently this time around. Some of that is going to depend on the nature of the questions that we actually wind up seeing. But I will say in terms of reason to believe, there is precedent for reexaminations taking a negative opinion and turning it into a positive opinion.

If you look over the last 5 years, depending on how you cut it, you get something like 20% to 30% of reexaminations result in a positive opinion. There are a number of factors that can go into this. Certainly, part of the process is that you do have a new rapporteur and co-rapporteur. You have an opportunity to come in specifically addressing only those grounds that are the grounds for refusal of the application, and we have an opportunity to potentially bring some new voices into it. We're really committed to the EU patient population and are looking for ways to get our way through this regulatory process.

Your next question comes from the line of Yigal Nochomovitz of Citi.

This is Caroline on for Yigal. Could you tell us how remlifanserin is differentiated from Cobenfy, which has upcoming Phase III readouts in ADP this year?

Sure. So mechanistically, these are different approaches to coming at psychosis. Overall, psychosis is really understood to result from an excessive ratio of your serotonergic -- sorry, I'm having a hard time talking today, serotonergic versus your cholinergic signaling, neurotransmission pathways. And we come at that from sort of different angles of the seesaw, if you want to think of it that way.

One is taking down one side versus increasing the other side. So there's reason to think that either could be impactful in psychosis. Certainly, there are going to be a number of differentiators in terms of how the drugs are taken. We have a good understanding, I think, of what the dosing paradigm looks like for remlifanserin as well as what it's likely to look like for Cobenfy. And you need to think about the profile of each of these in the context of an elderly frail patient population.

So we think that remlifanserin could be a good treatment option for patients if we see a safety profile that continues to be consistent with what we've seen for NUPLAZID.

Your next question comes from the line of Sean Laaman of Morgan Stanley.

As DAYBUE STIX rolls out more broadly in early -- I think it's early Q2 '26, you said, how should we think about net new patient capture versus switching? And do you think STIX meaningfully expands the addressable Rett population over time?

Yes. Sean, it's Tom here. Thanks for the question. Yes, I mean, first off, just to reiterate, we've been really, really encouraged by the early excitement that we're seeing from the Rett community regarding STIX. As we mentioned on the call, by our own internal estimates, we think there's around 400-plus patients that we could unlock in addition to just having the liquid on the market with the STIX formulation.

And that's made up of both patients who are naive, but also those that may have discontinued or maybe never started due to formulation concerns. So you take that in totality, and we believe that there is clearly additional upside that we can capture over the next few years. Worth noting that, that 400 patients that we're talking about, we don't think we're going to see all of them in 2026. We anticipate unlocking those over the next 2 to 3 years.

But taken together, coupled with all of the efforts that we've already employed in 2025, obviously, we have the expanded field team. We now are doing more in terms of direct-to-consumer, we've been doing a significant amount of education, especially as we move into the community setting, we believe that there is an opportunity to further penetrate the Rett marketplace with DAYBUE, and potentially continue to expand it further.

We now estimate that there's around 6,000 Rett patients diagnosed in the U.S., which is a modest increase in what we've shared previously. So I think taken together, absolutely, we believe in the long-term growth outlook for DAYBUE.

Thanks, Sean. We are excited about STIX and getting patient stories in already with a few -- the patients now in the channel and look forward to really giving you a full insight into DAYBUE STIX at our next call.

Your next question comes from the line of Brian Abrahams of RBC Capital Markets.

This is Nevin on for Brian. Just a couple of questions on 204 remlifanserin. So I think at the R&D Day last year, you had shown that there was a dose dependence in the exposure response signal with pimavanserin in the ADP and Lewy body patients where some of that higher exposure have correlated to greater symptom reduction. So I guess what drives your confidence that the 30 mg and 60 mg doses of remlifanserin would reproduce that exposure response relationship in the same way in the RADIANT trial.

And is there any way to maybe quantify that target gap or target efficacy gap versus pimavanserin's marketed dose based on some of the preclinical and Phase I PK data that you have?

So all right. Let me think how to come at this one. So yes, first off, we do -- part of our reason to believe with remlifanserin is based on the fact that with PIM, we did see what appears to be an exposure response from an efficacy perspective. And in neither ADP nor Lewy body, do we appear to be at the maximum or near maximum plateau level of that efficacy. I will say that, frankly, even if we were able to just reproduce similar levels of efficacy with remlifanserin that was seen with 34 milligrams of pimavanserin and do it in a more robust study that is focused specifically on the Alzheimer's population, we think that, that would be meaningful in and of itself.

And so additional efficacy, I would say, is sort of the cherry on top. We do think that there are good reasons to believe that, that exposure response relationship is true and will play out when we're able to really actually test it with 2 different doses, but we do have to do that test. So I would say that even if we don't see as much of a differentiation between the 30 and the 60 as you might expect based on that exposure response, we still could have a meaningful therapy here just in the context of a more robust, more specifically designed therapy or designed trial.

Your next question comes from the line of Ash Verma of UBS.

So as we think about the increase in the OpEx this year, does that mostly now enable you to get to your 2028 goals? Or is there more incremental investments coming in the subsequent years that would be key to delivering that? And then just secondly, I know like on Cobenfy ADEPT-2 trial, there's been just a lot of focus on the irregularities that they saw in terms of clinical trial execution. Just can you give us some confidence that when you look at your study execution, you don't necessarily see any type of an issue like that?

Thanks, Ash. I'm going to get Mark to talk about the OpEx strategy and then Liz can further discuss Cobenfy. So Mark?

Yes. Thanks, Ash, for the question. So I would say that from an SG&A standpoint, kind of you'll see incremental increases from here. this is kind of the foundational investments that we're making to achieve our goals in 2027, 2028 and beyond. From an R&D standpoint, it certainly is how the portfolio advances as it continues to be successful with the broader and bigger portfolio, it can increase. And if we see normal rates of attrition, it will increase less.

We do think our margin achievement will significantly expand from here. And our expectation is really depending upon how the R&D portfolio evolves that we could see kind of mid-teens operating margins with no attrition. But if you think about normal rates of attrition in the R&D portfolio, you'd be in the low 20% operating margin in 2028.

As far as the question about the BMS situation and the irregularities, I mean, I'll note, like everyone else, we don't know the specifics of the irregularities that we're seeing in the BMS situation. That said, on an ongoing basis, we do look at blinded data in a number of ways. And what I can say is, at this point, we're not aware of any substantial irregularities that suggest that we have a problem. Obviously, this is an ongoing thing. We're very committed to good clinical practice. And so we do continue to look on an ongoing basis, but so far, so good.

Your next question comes from the line of Evan Seigerman of BMO Capital Markets.

Hi, I'm Malcolm Hoffman on for Evan. I know this study is early, but can you take a second to talk about what you are looking to see from the Phase I ACP-271 healthy volunteer study that you expect to initiate this quarter? Given the mechanism and preclinical work, it seems obvious that you want to see improved levels of sedation relative to the VMAT2 inhibitors. But I just want to get a sense of whether there's other key measures you're looking to assess here.

Very exciting. This may be the first 271 question I've gotten, well, maybe ever. No, thank you for the question. So it is early here. But what I will say is we're -- this is some of the most novel biology we've got in the pipeline. And so part of it is we're just -- it's -- this is the first step of a GPR88 agonist into humans in clinical trials.

So we are interested in understanding overall how that behaves in humans. We're interested in understanding PK and to whatever extent we can, the PK/PD disconnect that we did seem to see in some of our animal models, suggesting the potential for a long PD effect that outlasts the PK. So some initial exploration there.

And yes, obviously, understanding what this looks like from an adverse event potential profile is going to be important in terms of the degree to which it bears up our hypothesis of how this could work in people. So thank you for your interest. Looking forward to talking more about this as we go through the upcoming months and years.

Your next question comes from the line of Sumant Kulkarni of Canaccord Genuity.

I know you mentioned a couple of times today that you're running 2 Phase III trials for ACP-204 in Alzheimer's disease psychosis. But what does the FDA's recent publication of its official position on needing one robust pivotal trial plus confirmatory evidence mean for ACP-204 in ADP and Lewy body dementia psychosis, especially if your Phase II data turn out to be "very good."

That is -- sorry, shall I just go -- that is a great question. We are obviously really excited to see any regulatory innovation that could mean that safe and effective products could get to patients faster. That is great. There's a lot that at this point, this has been discussed in a journal article and certainly in some presentations, there are a lot of questions that I think we don't know the answer to yet that makes it hard to know exactly what this could mean for ACADIA's future development program. So obviously, we're watching this very closely.

Things like what the impact is on the required safety database as an example. And of course, we always do have to think of this in terms of globally acceptable development program. So there is a fair bit to work through there. That said, I do think this, I would always want in a situation where one had amazing data to think about whether there were ways to bring something to patients further, faster. I think this gives us a little bit of additional reason to think we should try having those conversations, if nothing else.

That's great. And just to reiterate, as we come through our top line results in between August and October and Liz and team develop the Phase III protocol from those results, we will continue to inform you how those Phase III trials will be redesigned or designed according to what's happening in the policy environment as well as also what's driven by the data.

Your next question comes from the line of David Hoang of Deutsche Bank.

So maybe first, just one on remlifanserin commercial opportunity. I think you've mentioned a potential $4 billion peak sales number for ADP and LBDP combined previously. Could you just help put some arms around that number in terms of anything like what would be the split between ADP and Lewy body?

Is that just the U.S. market? Does that contemplate competition from Cobenfy? What would ramp to peak sales potentially look like? And then just to come back on the IRA rebate accrual for NUPLAZID. Could you just help reconcile what is actually cash versus noncash for the quarter and full year? And is this a situation that may repeat in the future and would require another reconciliation?

So let me just talk to ADP and LBDP in terms of the $4 billion, and then we'll move to the next part of the question. So we haven't disclosed the split that we see exactly between the 2 indications, but we have said that they're roughly equally weighted. Obviously, the populations are slightly different in the U.S. and the unmet need is different as well as the population fragility. So there are some differences between the 2 indications that we will work through both commercially and financially as we come through our clinical trials.

But overall, we feel this is a very strong opportunity for us in much larger markets than we are in now. And with the confidence that we have behind the design of remlifanserin for these specific populations, we feel like if the data bears out, they're going to make a huge difference to this patient population and provide us a robust value story for both our health care environment, but also patients more broadly, both in the U.S. and hopefully beyond the U.S. In terms of NUPLAZID and the IRA, do you want to talk a little bit more about it, Mark?

Sure. Thanks for the question. As far as kind of cash versus noncash, we did pay our invoice in the quarter. And for the first 2 years of the program, that was $108 million payment that went out. Over the course of the year, if we factor in the payment plus additional accruals that we made, it was kind of a net cash flow over the year of about $30 million.

The adjustments that we made to net sales, those are all kind of noncash adjustments, but they're meant to be reflective of our operational performance so you can compare periods when we shared the data going back to 2022 that if we had full information, these were the accruals that we would have made rather than needing to make the change in estimate that we made now that we got the information from CMS for the first time this year.

Hopefully that answers the questions, David.

Your next question comes from the line of Jason Butler of Citizens.

Just understanding it's still early. Any initial comments you can speak to out of the increased NUPLAZID field force? And how are you on an ongoing basis, assessing ROI on the full commercial investment for NUPLAZID, specifically the non-field force components?

I'm going to get Tom to talk to you about the field force. But just to reiterate that we assess ROI on our marketing and commercial mix on a very regular basis. That's the basis of how we manage the business and the decisions that we make in order to ensure that our investments are really driving both efficiency and effectiveness. But in terms of the team, Tom, why don't you share a little bit more about how it's going?

Sure. So as we mentioned, Jason, we fully executed the expansion of the field team in January of this year, and I'm very pleased to announce, obviously, that the team are now out in the field. We've actually been really encouraged that they've hit the ground running, probably in a manner that was maybe kind of earlier than we thought, quite honestly.

I mean, we are already seeing a very nice uptick in terms of their activity. Just as a reminder, with this expansion, we're able now to kind of capitalize on or meet the needs of around 60% of the overall PDP market in terms of prescribers. So we've kind of increased our target universe from about 7,000 writers to about 11,000 writers. And we believe that, that additional 4,000, 5,000 that we're now going to be targeting is really going to help us unlock this incremental growth that we anticipate seeing through 2026, '27 and '28.

So I think very pleased with the early activity, early metrics that we're seeing. And we're following our top of the funnel metrics very tightly, as you would imagine, and we're actually beginning to see already a noticeable increase just in terms of referral volumes. So excited to see that, that will carry on through the year and looking forward to seeing the continued impact of that expansion and that investment over the next 2 to 3 years.

Yes. And just to reiterate, you can see the step-up in SG&A for 2026 versus '25, and that is being contributed by both the annualization of the DAYBUE expansion as well as the NUPLAZID expansion. And as Mark said on a previous question, we don't expect that to continue to ramp at the same rate. We expect this to be the step-up this year and then a more sort of incremental increase as we head into '28. We sort of feel like we've got a good base right now. And this will be our base with minor adjustment moving forward. So again, just to reiterate that point in terms of the OpEx to support this incremental growth.

Your next question comes from the line of Jack Allen of Baird.

Congrats on the progress made over the course of the quarter. I wanted to ask on DAYBUE and the $700 million in sales expectations by 2028. Can you just help us understand a little bit more about the assumptions that are going in behind that number that you're throwing out there, $700 million? Does that include ex U.S. sales? And what are your thoughts around potential competition for gene therapies within that period?

Yes. So I'll answer it at a high level and then maybe either Tom or Liz can have a response on gene therapy. So the $700 million consists mainly of the U.S. business, which is driven through growth of STIX and liquid and expanding the patient population from where we are now into the community. It does include global sales from the named patient programs.

And so that is within there where we have the ability legally and through the regulatory framework to supply the named patient programs. And it does include EU commercial sales for now. Our current assumption is that we will have an EU approval before 2028. However, obviously, once we get the decision from the final decision, we will reguide for that 2028 number.

But to reiterate, now the EU commercial sales within that $700 million number is less than 15%. I hope that's a good explanation. And then...

I can make a couple of comments and then if there's anything you want to add, Tom. So generally, I guess there's a couple of components to your gene therapy question. One is it's probably better for you to ask the gene therapy companies when they're speculating that they're coming to market. I'll just note that the developmental milestones do take some time to mature. So whether that's going to feature into 2028 or not, we probably should leave for them to comment.

In terms of the, I guess, the implied idea of whether there is room for more than one type of agent out there. I mean, I think what I'd say is that the data that we've seen so far suggests that there is -- while we all wish that these would be cures, I don't think that the data so far suggests that they are. And so I think that the predominant likelihood is that patients are going to require more than one aspect to their care.

Your next question comes from the line of Paul Matteis of Stifel.

This is Julian on for Paul. Just wondering what you guys think is the biggest risk to the ACP-204 readout? And are there different sort of indication-specific considerations for ADP versus LBDP that you've thought of? Any chance that you plan on sharing baseline information ahead of the Phase II or anything else that you could share would be helpful.

Okay. So a few things here. So we're not currently anticipating that we would be sharing baseline information prior to the readout. So just to get that out there. In terms of any specifics of ADP versus Lewy body, I think there are a few things that we think about, one, of course, is psychosis is obviously impactful in both patient populations, but it is very frequent in Lewy body.

So I think we do see that being a much more substantial proportion of that patient population. That's something that's important to keep in mind. And I think that while in both cases, you're generally dealing with obviously a more elderly population, I think it is also considered that the Lewy body population may be a bit more frail. And so we are especially mindful of appropriate safety profiles in that patient population.

In terms of biggest risks, I mean, I think that we have done a great deal to build upon pimavanserin in terms of how we put the molecule together, how we put the program together. In these kinds of spaces, of course, you always have to be concerned about placebo effect. We are doing what we can to manage it in terms of good training of investigators, looking for outliers, all that good stuff. But that is something that you always have to be mindful in these kinds of trials.

We've run out of time for any further questions. I will now turn the conference back over to Al Kildani for closing remarks.

Thank you, everyone, for joining us today. We look forward to speaking to you on our next conference call.

This concludes today's conference call. You may now disconnect.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the senior biotech analysts here at JPMorgan. Our next presenting company is ACADIA Pharmaceuticals. And presenting on behalf of the company, we have CEO, Catherine Owen Adams. Catherine, over to you.

Thanks so much, Tess. Good morning, everybody, and thank you for joining us at the 44th Annual JPMorgan Healthcare Conference. As Tess said, my name is Catherine Owen Adams, and I'm the CEO of ACADIA Pharmaceuticals. And today, I'm really delighted to share our progress, building a leading neurological and rare disease company. I'll be making forward-looking statements in this presentation, so please refer to our SEC filings for the risks and uncertainties relevant to our business.

At ACADIA, our mission is to deliver meaningful innovation to underserved patients with neurological and rare disease. And this slide illustrates how we intend to deliver on that with products that are either first-in-class or best-in-class. Starting with our neurological franchise. The momentum of NUPLAZID is leading the way and expected to continue this year and beyond. We're advancing exciting pipeline candidates that I'll give more detail about in a minute, anchored by our new 5-HT2A agonist, remlifanserin, formerly known as ACP-204. Also our Phase II program with ACP-211, which is deuterated R-ketamine, our program in major depressive disorder. With ACP-711, we have the opportunity to move into essential tremor and with ACP-271 to move into tardive dyskinesia.

In rare disease, we're making great progress with DAYBUE and have the opportunity in 2026 to serve many more patients in the U.S. and beyond into the EU, including the launch of our new powder for oral formulation, DAYBUE STIX. Beyond that, we have ACP-2591, ACP-271 and an association with our colleagues at Stoke Therapeutics for a SYNGAP1 program. We're actively evaluating additional areas of rare disease expansion, primarily through our business development activities.

Importantly, for the company, we're also -- sorry, investing in areas of core capability that of precision medicine, where we intend to continue driving biomarkers used across all of our trials, data innovation with the introduction of AI across many of the areas of our business, globalization with the intent to serve patients both in the U.S. and beyond; and finally, patient empowerment, ensuring that our patient voices come into both our R&D and commercial functions. Several recent and upcoming milestones underscore the momentum that we're building across our pipeline.

Recent milestones are the start of our Phase II ACP-211 study initiated already in major depressive disorder, the initiation of our ACP or remlifanserin trial in LBDP, Lewy body dementia psychosis and the initiation of our Phase III trofinetide trial in Japan. Important upcoming milestones in Q1 of 2026, we expect to start our first-in-human study of ACP-271, which is our GPR88. We also expect to get a CHMP opinion for trofinetide. And we also have announced today more specific timing for our remlifanserin top line results, now guiding to between August and October of this year.

So from our 8 disclosed and undisclosed programs, we expect 5 additional Phase II or Phase III study starts between now and the end of 2027 and 4 Phase II and Phase III study readouts by the end of 2027. We are building a really strong foundation for growth with our 2 commercial brands now delivering more than $1 billion in sales in 2025 and sharing for the first time today, our expectation for these commercial brands, which we believe can grow to about $1.7 billion in 2028 with about $1 billion coming from NUPLAZID and $700 million from DAYBUE. In addition, we see substantial future sales opportunity for the key programs in our development pipeline.

Our pipeline includes 4 molecules entering larger markets with high unmet need, and we believe these molecules have the full peak sales potential to reach $11 billion combined if they were all to reach market. Importantly, within this, we're highlighting the specifics of a $4 billion potential peak sales opportunity from remlifanserin across both indications that we're pursuing. Now you understand that this is not guidance. We all understand that drug development carries risk and not every program will succeed, but we felt it important to illustrate the value that we see in our programs, and we understand it's our responsibility to build our case and unlock that value.

In 2025, we developed a very strong focus on building AI in all that we do at ACADIA. We appointed a new Chief Information and Data Officer and are now leveraging AI throughout key areas of our business to accelerate growth of the enterprise. Within the commercial business, we're looking to better target and engage customers and drive quicker uptake. Within R&D, we're excited to announce a new clinical command center, which we will use to monitor trials on an ongoing basis to enable us to drive quicker decisions. And in our regulatory group, we expect to use AI to develop documents more quickly and expand our internal capacity. We're committed to utilizing data and technology to grow our business and advance our pipeline as quickly as we can. We're also focused on being the difference to patients everywhere around the world, and 2026 will be a critical year for our global expansion. Focusing on DAYBUE, we're now approved in 3 markets as we announced Israel approval today and anticipate CHMP opinion in the first quarter of this year. And I've already said we've initiated our Phase III study in Japan.

We also will continue to make DAYBUE available to patients around the globe through our named patient supply programs, where we have patients from countries in the EU, the Middle East and Latin America. Turning to R&D. Our development pipeline leverages clinical trial sites across the globe to ensure we're suited to meet the needs of our diverse patient population. And now for a deeper dive into neurology and Parkinson's disease. Just to level set, in the U.S., there's about 1 million patients with Parkinson's and about 50% of them are expected to develop the symptoms of hallucinations and/or delusions during the course of their disease. These symptoms place a tremendous strain on families and caregivers. And even with a high-profile successful unbranded campaign with Ryan Reynolds, still less than 20% of patients and caregivers are aware of these symptoms. So there continues to be a major educational opportunity for us.

Currently, there are about 130,000 patients treated with full hallucinations and delusions with off-label antipsychotics. And so we believe there's really a potential growth opportunity here for NUPLAZID. NUPLAZID is still the first and only approved treatment for Parkinson's disease hallucinations and delusions. Since launch, we've treated 97,000 patients. And we estimate we currently have about a 25% market share of those 130,000 patients who are treated. We also now have patent protection through 2038, which we achieved following the successful defense of our patents in 2025. We're excited to share today that we do believe we can achieve $1 billion for NUPLAZID in 2028, which will be driven by our investment and our excellence in commercial execution. We're going to continue our direct-to-consumer campaigns, which are accelerating patient and caregiver awareness.

I shared a moment ago that the awareness has been driven from about 10% to 20% through our campaign with Ryan Reynolds, and we will continue to leverage this highly successful campaign. We announced last year that we're also going to increase the size of our commercial field force for NUPLAZID. Starting this quarter, we intend to increase it by about 30%. At the same time, leveraging AI to ensure precision execution across this larger field force. And our goal is to become the standard of care in patients treated for hallucinations and delusions of Parkinson's disease. And now for DAYBUE and Rett syndrome. Rett syndrome is a rare disease, highly debilitating caused by mutations in the MECP2 gene, primarily affecting females. These girls develop normally until the age of about 18 months to 2 when they see developmental deterioration.

Our latest figures indicate that there are about 6,000 diagnosed patients with Rett in the U.S. This is up from our recent ranges that we've been talking about, which has between 5,500 and 5,800. And that diagnosed population has increased by about 30% since the launch of DAYBUE. As we look to EU and our possible approval there, we see a prevalent population in the EU even larger than the U.S., between 9,000 and 12,000 patients. Again, with DAYBUE, we have the first and only treatment for Rett syndrome. Since its launch in 2023, we've treated over 2,000 patients. We've seen really strong persistency with now 55% of patients still on treatment at 12 months, underscoring the sustained benefit that families and patients see from DAYBUE therapy. We now have over 300 patients in our real-world evidence LOTUS study, which continues to develop and publish data.

And looking ahead to our global ambitions, as I've said, we anticipate our European approval in Q1 of 2026. Again, for the first time today, we're giving you our ambition for DAYBUE in 2028 at $700 million in global sales. We see that there are 3 drivers of this ambitious growth. The first is the approval of DAYBUE STIX in the U.S. I'll give you a little bit more about that in a second. The second is the continued impact of the expansion of our U.S. sales team, which we initiated in Q2 of last year. And the third is our continued international expansion. We're really excited for the approval of DAYBUE STIX that we received on December 12, which is a new powder for oral solution. DAYBUE STIX, as you can see here, is in a small packet, a little bit like the liquid IV that you get. And the key attributes of this STIX formulation is primarily the ability for patients and their caregivers to mix with different liquids to potentially reduce the volume, no refrigeration required, highly portable as a result of that.

And importantly, for our patients in the Rett community who many of them are on a keto diet to control their seizures, DAYBUE STIX has a much lower sugar and carbohydrate content. It offers us several potential benefits, including that customization of the taste. You can formulate this in many different fluids from apple juice to orange juice to Gatorade. We believe this will enable patient growth from families who have previously declined to try the liquid formulation for whatever reason and enable growth from patients who will restart DAYBUE with this new option now available.

As we've said in the press release this morning, we're rolling this out on a limited basis as we build up stock through the first quarter with full availability by the beginning of Q2 this year. And now a deeper dive into our pipeline. As we've already outlined, we have a series of molecules in both our neurological and rare disease portfolios, and I'm going to take a few minutes to highlight some of those for you now. I'm going to start with Alzheimer's disease psychosis, a condition where a person with Alzheimer's disease experiences hallucinations and delusions. This is a huge unmet need with no approved treatments as yet. Of the 7 million patients who suffer from Alzheimer's disease in the U.S., about 30% of them will experience some kind of psychosis during the course of their disease. We're excited for the opportunity for remlifanserin, our next 5-HT2 agonist that's been built on the knowledge of our previous pimavanserin and we're very excited about our potential to transform this disease area if our clinical development program is successful.

The remlifanserin program was designed and developed based on significant learnings from our pimavanserin studies and the program and the molecule are differentiated in a few critical ways.

From the molecule perspective, we've designed it so that the structural differences minimize or eliminate the QT prolongation. We've designed it to generate a faster time to steady state as well as the ability to give patients higher doses and exposures to hopefully drive increased efficacy. From the program perspective, we've learned and we're really ensuring that we have an appropriate study patient population included in our 204 studies with the use of biomarkers. Remlifanserin has also been designed with patient-centric dosing in mind, once-daily dosing, the ability to be taken with or without food, which we believe is really important in this elderly and frail population and importantly, few drug-drug interactions.

Our remlifanserin study in Alzheimer's disease psychosis is our RADIANT study. It's a global double-blind, placebo-controlled Phase II trial currently enrolling 318 subjects. We're looking at 2 doses, 60 milligram and 30 milligram versus placebo. And our primary endpoint is SAPS and HD at 6 weeks. This is an operationally seamless but statistically separate trial that's moving into 2 Phase III studies with similar design. And again, from our press release this morning, top line results expected from our Phase II portion of these seamless studies between October -- sorry, between August and October of this year.

We also believe Lewy body dementia psychosis holds great opportunity for remlifanserin. Lewy body dementia is a progressive brain disorder that affects thinking, movement, mood and behavior. And essentially, the difference between this and Alzheimer's, it's associated with abnormal alpha-synuclein deposits in the brain. It's thought that over 1 million patients in the U.S. suffer from Lewy body dementia with 50% to 75% of those patients experiencing some kind of psychosis during the course of their disease.

Again, there are no approved therapies for Lewy body dementia psychosis, but there are 200,000 patients currently treated for this with off-label antipsychotics. So a significant unmet need in the market. Lewy body dementia psychosis includes 2 distinct patient populations with highly related symptomatology, both related by alpha-synuclein biology and both displaying hallucinations and delusions associated with it. In dementia of Lewy body, the cognitive symptoms in the patient tend to precede the motor symptoms. And conversely, in Parkinson's disease psychosis, motor symptoms preceded cognitive impairment. As mentioned, with remlifanserin, we are leveraging our learnings from our pimavanserin studies. A subset of data from the HARMONY study supports the potential efficacy of remlifanserin in Lewy body dementia psychosis.

In HARMONY, patients who achieved a response were randomized to continue treatment with pimavanserin or to have treatment withdrawn for up to 26 weeks. Of those patients, there was a notable difference in the patients experiencing relapse between the 2 groups, as you can see here, with only 5.3% of patients relapsing with pimavanserin compared to 55% relapsing for those patients receiving placebo. With that in mind, we've recently initiated our remlifanserin study in this patient population. It's a global, double-blind, randomized placebo-controlled Phase II study, again, looking at the same 2 doses, 60 and 30 versus placebo. And we're enrolling both of those 2 subpopulations, patients with Parkinson's disease dementia and psychosis and patients with Lewy body dementia psychosis. As I've said already, both patients share that alpha-synuclein biology.

The primary endpoint here is SAPS-LBDP at 6 weeks, which is identical to the endpoint that I just mentioned in the pimavanserin HARMONY study. And we look forward to updating you on our progress with this trial.

Turning next to our candidate for major depressive disorder. Major depressive disorder, we probably all know fairly well, a pervasive loss of sadness, loss of interest, multiple symptoms. Current treatments are there, but we believe are limited by their efficacy and particularly the onset of treatment requiring extensive monitoring in a physician's office. ACP-211 has been designed for ketamine-like efficacy, but with minimal in-office monitoring. It's orally dosed, and we believe addresses a significant treatment gap.

There are 21 million patients in the U.S. with major depressive disorder, but only 9 million of those are treated. And within that, 3 million are actually treated for treatment-resistant depression. It's the second highest cause of disability in the U.S. economy, and there remains substantial unmet need, both clinically and obviously, economically. We've recently initiated our Phase II study of ACP-211 in major depressive disorder. This is a 4-week randomized, double-blind, placebo-controlled study, enrolling 153 patients with the primary endpoint looking at a change in MADRS score at week 4. So we look forward to providing you updates on this study as we proceed through the year.

Essential tremor. Essential tremor is a movement disorder. It's a high-frequency postural and/or kinetic tremor mainly affecting the upper limbs. It represents a huge unmet need as current treatments are very often ineffective and there have been no new approved therapies for the last 50 years. ACP-711 is a selective GABA alpha3 modulator targeting cerebellar GABA. We have a Phase I data starting to support -- so we already have Phase I data to support the potential absence of cognitive or sedative effects and a potential negative impact on sleep. Essential tremor affects about 7 million patients in the U.S., so about 2% of the U.S. population. So it's 10x more prevalent than Parkinson's disease.

And of those patients, about 1 million sought treatment between 2015 and 2019. And those are really those that are affected by the more moderate to severe tremors. So currently, we have a Phase I elderly cohort underway to look at this molecule in the elderly population, and we project a Phase II study initiation in the fourth quarter of 2026. The plan right now is to enroll 150 patients in a double-blind placebo-controlled study, and we look forward to giving you more information as we develop details on the program. And finally, turning to ACP-271, which we view as one of the most novel chemistries in our pipeline. It's a GPR88 agonist that we believe may modulate the balance of D1 and D2 signaling without affecting dopamine levels. We're about to initiate a healthy volunteer study in Q1 '26 and plan to develop this candidate for both tardive dyskinesia and Huntington's disease.

So looking ahead, we're really excited for a number of important milestones in 2026. In the near term, the next quarter, we have the CHMP opinion on the initiation of ACP-271 in healthy volunteers. The highly anticipated top line results of remlifanserin in Alzheimer's disease psychosis will come between August and October of this year. And in between Q4 and Q1 of next year, we expect the top line results of our Japanese Phase III trial with trofinetide. In Q4, we expect the initiation of our Phase II study in ACP-711 in essential tremor. And beyond that, in 2027, the results of our Phase II study in major depressive disorder with ACP-211.

We have a continued strong focus on business development, fueled by our strong balance sheet, looking for partnerships and acquisitions within these 2 focused spaces for ACADIA. And I conclude by reiterating our mission as a company, turning scientific promise into meaningful innovation for underserved communities with neurological and rare disease. We're excited to have shared this today with you. Thanks for your attention. And Tess, I think we've got some time for questions, should there be any from the audience.

Thank you, Catherine, so much for the presentation. Would you like to invite the rest of your team?

Sure. We have Liz, Tom and Mark here. Head of R&D, our CCO and our Chief Financial Officer.

Okay. Okay. Great. Well, welcome, team. So I thought I might start the conversation here with a couple of kind of overall business questions. As you think specifically about your commercial franchises in 2026, what are the specific priorities that you have for the year? And how should we be thinking about the key drivers for revenue growth this year?

I'm going to let Tom to get that question.

Yes, certainly. So I think Catherine has probably laid out the case for both brands pretty clearly. So starting with DAYBUE. Obviously, near term, we're excited about the approvability in Europe, which we think provides an additional leg up for DAYBUE and us to help more patients outside of the U.S. Within the U.S., we're going to be very much focused on building on the expansion of the field team that we pulled through Q2 of last year, really maximizing the opportunity that we see with DAYBUE STIX. We've already seen significant interest from both the patient and the HCP and advocacy communities around this new formulation because it really addresses some of the unmet needs that we believe exist for DAYBUE today, just having that greater flexibility, removal of some of the ingredients that they don't necessarily like in terms of the liquid formulation. Worth noting that we will continue to promote both moving forward.

For NUPLAZID, really, it's a story of continuing the momentum that we've built in 2025. I think we had a very, very solid year in terms of growth. We're seeing new writers come to the fore, as Catherine mentioned, significant amount of engagement with the broader PDP community. And we think that, that gives us a tremendous platform to build from with our expanded field footprint in 2026.

And maybe I know it was kind of hot off the presses today. So maybe you could just talk a little bit about that combined net sales outlook that you outlined for 2028. What are the key underlying assumptions to that and any key risks?

Yes, I'll take that and then maybe ask Tom to add some. So we thought it important for us to put out there our ambition for both NUPLAZID and DAYBUE. We have strong conviction that we can grow both of these brands to the $1.7 billion that we've stated. And so just a couple of assumptions within those growth trajectories. With the DAYBUE assumption, we are assuming that we get approval in Europe, so it does include that. And with NUPLAZID, we just -- we're continuing to see that growth. So we assume that, that continues to grow as we move through the next 3 years. Anything additional, Tom?

No, absolutely. I think for DAYBUE, clearly, ex U.S. is going to be an opportunity with STIX, we do anticipate that, that's going to help us unlock additional growth, both in terms of patients who may be considering DAYBUE and ensure based upon formulation, but also those who have discontinued. We think that there's a real opportunity for those who may have stopped due to formulation concerns that we can reengage with those families as well. And then for NUPLAZID, really, it's a case of continuing that -- building on that momentum, really maximizing the opportunity that we've seen in 2025. I mean 40% of our writers in 2025 were new to brand. And I think that that's a really nice indicator of not only commercial execution, but also how our campaigns are working for us, and that's an opportunity that we continue to lean in heavily as we move into 2026.

Okay. Okay. That's helpful. And then over this time frame, however you kind of want to kind of lay it out for us, how should we be thinking about your OpEx line and how it's going to be evolving over the next couple of years and on both the R&D and SG&A lines? Mark?

Thanks for the question. I think -- so we -- we'll give guidance for expenses this year when we announce our fourth quarter results. But qualitatively, to think about it, we've talked about the investments that we've made and are making. So you'll see an uptick in OpEx certainly this year, year-over-year as we have an expansion of the NUPLAZID field force that we talked that's starting now, making investments to continue to advance in Europe as well as STIX and just annualization of some expenses like the DAYBUE field force that came in the second quarter of last year that will be involved in our OpEx for the full year this year. So there will be a year of investment.

The pipeline is advancing with all the excitement and additional work that we're doing. So you'll see further investment there. And I think as you think about over the next coming years, up until 2028, you'll see operating leverage in the business. I think from a commercial and SG&A perspective, you'll see modest growth from where we kind of go in 2026. And then the pipeline obviously is dependent upon how it advances. So I think the more success that we have the greater the expense will go forward, but that will be with value creation and advancement of the pipeline.

And then, of course, there's just normal attrition that ultimately happens in a pipeline. So we'll see how that evolves with the R&D line going forward, independent of whether or not -- or not whether or not, but how we add to the pipeline through business development.

Okay. You kind of beat me to the punch on my next question. Just on the business development front, what types of products is ACADIA interested in for 2026?

So I think just starting with therapy areas, it's very clear. We're a neurological and rare disease company. We have an ambition to expand our rare disease aperture beyond just neuros. We're looking at opportunities in other rare diseases, cardiac rare, endocrine rare, metabolic rare, et cetera. In terms of the type of opportunity we're really interested in, we have really thought through where we believe a strong fit would be from a BD perspective.

I think something later stage is something that we're really looking at very hard right now. We would love to have something that we can commercialize in the next few years, added into the portfolio. But we continue to look for pipeline innovation. I know Liz and I are very keen to look at larger molecule opportunities and again, back into the rare disease beyond neuro. So we have a very wide aperture. Tina and her team are very active right now. We have a nice strong balance sheet, and we're looking forward to bringing some business development deals to the fore in 2026.

Okay. Great. So maybe turning to the pipeline here. There is a lot of data that has been generated for NUPLAZID across dementia-related psychosis and how you're exploring the potential for -- okay, I'm going to try it out, remlifanserin, ACP-204. Liz, can you maybe give us a little bit of your broad strokes for why you think this study has a reasonable probability of success? And how confident are you that you pick the right doses here and the right primary endpoint?

Absolutely. So remlifanserin, very well done. We're all getting used to saying that instead of 204. It is informed at both the molecule level and the programmatic level by a wealth of information from pimavanserin. And so Catherine mentioned this in her presentation, but just to touch on it very briefly. NUPLAZID is a great drug that has done really good things and continues to do really good things for many patients out there. It does have some QT -- some suggestions of a QT signal. And certainly, if you get at doses above the marketed dose, it gets to the point where we were not able to dose range higher with NUPLAZID.

So minimizing or eliminating the QT signal, which we've been able to do with remlifanserin is important in and of itself, but it's also important because it lets us explore higher exposures. And there is a suggestion in the PIM data set that suggests that there is an exposure response relationship from an efficacy perspective, such that if we're able to go to higher exposures, we might actually be able to get more efficacy out of this mechanism.

The final thing is that we were looking for higher -- faster time to steady state, which we'll have to prove it out in the clinic, but there is the possibility that, that gets you faster onset of efficacy and maybe more robust and similar efficacy across time points. So those are the things we did from a molecule perspective that make us feel good about remlifanserin's profile. In terms of how we translate that to the program itself, we do have several points of data with pimavanserin in Alzheimer's disease psychosis.

First of those is a positive Phase II study. It was on a different endpoint that we think is less sensitive to change than SAPS-H and Ds. So we think we've maximized our probability there. There was also a subpopulation in the HARMONY trial where really we didn't design the study to look specifically at the Alzheimer's population. That's one of the other big learnings we've taken forward into our program here is that it's important to be able to really look at the disease that you want the eventual approval in. So our study is not just clinically diagnosed Alzheimer's that we're focusing on, but also further biomarker confirming it.

We think that, that gives us a better likelihood of regulatory success in the instance of a positive program. Hopefully, that addressed what you were looking for.

Yes, it does. It's a much longer conversation. I think that was helpful.

I tried to make it as short as I could.

No, no, that was helpful. So this morning, you announced that when you expect the data to be this year, I think it's a little bit later than what we thought previously. Just on like getting the patient population right in the study, can you just maybe help us understand that element and what might have driven the delay or slight delay here?

Yes. So I'd say that we've really refined our estimates of what this timing could look like as we get further into the trial. So I don't think of it as a delay necessarily as such as much as a refinement. That said, there are some things that do play into this. We were very keen to make sure we were getting the right patient population in this study.

So again, looking not just for that clinical Alzheimer's diagnosis, but also biomarker confirmation. And the part that is helpful for our hypothesis is that, that did actually help us identify some patients who were not biomarker positive for Alzheimer's. So we feel better about the patient population we have compared with what we would have gotten if we hadn't put that criterion in.

Otherwise, we did learn from our prior PIM work for some moderate refinements of patient population looking for slightly more severe psychosis at baseline as an example. But really, this has been a focus on making sure that the patients that are in there are Alzheimer's in a way that we can very, very clearly document and defend to agencies.

Okay. Liz, any other key pipeline milestones for 2026 that we should have an eye on?

So in terms of readouts, there is a possibility or we're putting out at this point a 6-month time horizon for our Japan Phase III for trofinetide. So that 6-month horizon does span a portion of 2026. But what we were trying to give you all a flavor for was what the next couple of years could evolve into. And the fact that 211 Phase II data falls within that span, we thought was important to make sure people were aware of.

Okay. And in terms of like relative risk across your key pipeline, like how do you see that over the next several years? Like how do you think -- how much balance do you think there is?

Yes. We've got a couple of very important derisking events that come over the course of the next couple of years with our Phase II data coming out of both the remlifanserin ADP program as well as 211. I mean to make a massive overgeneralization, the earlier you get in the pipeline, the more risk you're going to have just associated with how much we know about the molecule itself as well as the biology.

I think it's certainly fair to say that 271 is the riskiest thing in our pipeline because it is also the most novel biology we have. So we've been working over the last 1.5 years that I've been here to try to have a real diversification of risk profiles, some riskier things as well as things where we think we have important pieces of data that help us derisk them.

And of course, as you heard from Catherine, we are keen to continue to expand that pipeline, potentially diversifying our risk into some larger molecules as well.

Okay. Great. Well, I think we are just about out of time here. So I think this might be a good place to close our conversation. Thank you so much for the team.

Thank you.

Welcome to the second session of the biotech conference. I'm Yigal Nochomovitz, one of the biotech analysts here at Citigroup. The next session is with ACADIA Pharmaceuticals with Mark Schneyer, the CFO. Welcome. Thank you so much.

Yes. Thanks for having us.

We just started covering you, as you know. So we're very excited to be officially following the story. I know we had the management team here last year, but we weren't officially covering. So that's good. So maybe...

We're glad you are. So thank you very much. We appreciate it.

Thanks. So maybe we could just start, just give us a bit of an overview. Obviously, you have 2 approved products that are growing. You have a significant pipeline with several important catalysts coming, one big one, in fact, in the middle of next year. But if you could just start with kind of an overview of the business, how did the last quarter...

I think you added a few words to that. That would be the elevator pitch for ACADIA. I can jump off on top of that. Yes. So at ACADIA, we're a neurological and rare disease company, both commercial and development stage. The 2 commercial products are NUPLAZID that treats an indication called Parkinson's disease psychosis and DAYBUE that treats an indication called Rett syndrome. Together, those products will have over $1 billion in sales this year. On the robust pipeline behind that, kind of the most advanced is ACP-204, which is our next-generation 5HT2A program. We're studying in 2 indications, Alzheimer's disease psychosis. And last quarter, we've initiated a second Phase II in Lewy body dementia psychosis. As you just mentioned, the kind of the big catalyst or milestone upcoming mid-next year is the Phase II readout for the Alzheimer's disease psychosis Phase II trial for 204.

Behind that, we have a robust early-stage pipeline, which we're happy to talk about. And then from a financial perspective, since I'm the CFO, I can plug back to we're cash flow positive, got a strong balance sheet with over $800 million of cash, no debt. So strong ability to invest in the existing business as well as add to the portfolio through business development.

Okay. So you had a very strong quarter last quarter. Maybe if you could just summarize the commercial performance for NUPLAZID and DAYBUE and how you see the trajectory? I know you've given some forward-looking thoughts as far as where those 2 products are going.

Yes. So I think for us, we gave at our R&D Day this past year, we gave a view on kind of peak sales potential for both brands. We've started to talk to investors about splitting that out next year and giving a peak sales estimate for both brands, which we will do. As far as the quarter is concerned, both brands are growing strongly. There's kind of a -- as any pharmaceutical brand, there's kind of unique things going on with each. So starting with NUPLAZID, if you roll back a year or even more than a year, right? This is the only approved branded product in the indication. If you kind of roll back a couple of years during COVID, without wasting too much time on that, we pulled back investment just because we had mortality and less opportunity in this elderly and frail patient population. But kind of fast forwarding to last year, we made renewed investments. And the biggest one that we did was we restarted kind of a branded and unbranded direct-to-consumer campaign through targeted media on the unbranded side, brought in a celebrity spokesman partner, Ryan Reynolds.

Because as we looked at our data, we recognize that the awareness came down through COVID and our retrenchment -- appropriately retrenchment in spend, but the willingness of physicians to prescribe NUPLAZID was still very high. And so that was a clue to us that there was a ripe opportunity now to start to reinvest. And what we saw this quarter kind of coming back to your initial question, kind of was like the strongest quarter in new patient starts in a long time where we had over 20% increase in both referrals as well as new patient starts in the quarter. And it's amazing for a brand that's been on the market for 9 years to have that level of performance, and that's where we've now really arced the growth trajectory for NUPLAZID because any brand that's been on the market for a while in any given quarter or any given year, the kind of volume performance is mostly driven by refills. So it takes numbers of quarters, if not years, of kind of increased referrals and new patient starts year-over-year, quarter-over-quarter to arc that trajectory, and we've done that with NUPLAZID. And so we're -- and then on top of that to kind of continue the trend in growth in NUPLAZID, we've announced that starting next year, we're going to increase the size of our customer-facing field force to continue to advance the growth and profitability of the franchise.

And then on DAYBUE, we've kind of for different reasons, but kind of a little bit of a similar theme and more advanced in the investment profile, we increased our commercial footprint earlier this year, around the second quarter time frame, to be able to reach out and have higher reach and frequency and calling customers in the community setting where we're underpenetrated relative to center of excellences, and we just needed more people to be able to do that. And then what we saw in the third quarter was a significant -- a meaningful increase in new referrals, the largest we've had since the third quarter of 2024. So it's just the early signs that, that investment in our U.S. infrastructure is proven to be successful in the short term, though kind of the financial performance of that will play out over the next quarters and into next year. And then as we look forward to next year to expanding outside the U.S. with an expected European approval next year.

Okay. So you did the branded and as you pointed out, the sort of not relaunch, but sort of enhanced messaging on the branded and the unbranded as you pointed out right now. But then you also decided in addition to that, to boost the sales force. Can you maybe kind of talk a little more about the stepwise thinking there? You felt that, that would be necessary or helpful as well to also boost the sales force in addition to the...

Yes. Well, I think it's a combination of things, right? I think it's kind of a continuation and evolution. I mean, when you make a new investment, you have expectations and then you have learnings. I think our expectations have been met that we are seeing significant increase in referrals. The learnings and maybe not unexpected are where is that coming from, right? So if you have a targeted field force, you're only calling on certain level of physicians. When you do a direct-to-consumer kind of targeted media campaign, we're reaching patients and caregivers that are cared for by physicians that we're not covering. And so we've seen a meaningful number of our prescriptions coming in from this campaign from accounts and customers from a physician standpoint that we're not covering.

So then the question is, well, is it productive to cover them? And how would you cover them? And so we've had -- with Catherine and Tom being new to the leadership and Catherine is our new CEO over the last year, they've kind of revisited everything. And their background is commercial expertise, and we haven't done a meaningful kind of reset of kind of the targeting and positioning of the NUPLAZID field force in a very long time. And so we kind of part of the exercise that we did over the course of this year is, we're going to take a blank piece of paper, what would be the optimal targeting for NUPLAZID based upon 8, 9 years on the market as well as the experience over the last 12 to 24 months with the renewed investments coming out of COVID, and that's where we've landed on. And I think where we're calling on or will be calling on is expanding. So we're essentially recutting every territory. So you'll have a little bit deeper reach into that territory and ability to call on physicians that are -- some PCPs as well as nurse practitioners. If you're having -- it does take some time for patients to hit neurologists, right, because they're not the easiest physicians to get appointments with. So if you're earlier in your disease progression for PDP, your first point of call is probably to your primary care, some existing physician in your kind of care network. And that's a lot of the prescriptions we're seeing with our existing campaign. And so to be able to cover the call on those, we need an expanded footprint. And we've done all the commercial math and metrics to see that this is in our expectation, a good investment to make, which is why we're kind of taking that next step next year.

But I guess the point on what I was driving at and what you're driving at is that by doing this branded and unbranded, you sort of revealed where you should be making those incremental investments in the...

Yes. Partially.

So it's synergistic from that perspective.

Yes. Exactly.

Okay. And then you've given some guidance for NUPLAZID for this year?

Yes.

Do you want to remind everyone what that is?

So we're just under $700 million in guidance. So we've narrowed our range to $685 million to $695 million.

Okay. And that was -- you moved it up a little bit.

We narrowed it and moved it up, like if you're looking at midpoint of the previous range, it shifted up.

It. Shifted up. Yes. Okay. And then any general thoughts for how -- I mean, you obviously -- we're talking about making some significant investments in the scale of the operations. So next year, you would expect continued significant momentum.

Yes. I mean we expect continued meaningful growth in both franchises, right? And certainly, as we're talking about NUPLAZID now, yes, NUPLAZID. And so we'll guide next year for NUPLAZID. And as I believe I mentioned earlier, we'll give a perspective on peak sales for NUPLAZID itself.

We sometimes -- now that we're covering you and we're covering some of the other neuro names as well, as you may know. So this is the question of the IRA negotiations coming into play. Does it factor in for you in a significant way with NUPLAZID? I mean, you've gotten -- you had the very important legislation win -- with the IP win with the taking [indiscernible].

So there's kind of a yes and no to that. I think for commercial investments, you're looking over kind of a 2- to 3-year horizon, right? So from an IRA standpoint, kind of the next -- while there's intricacies in kind of the next couple of years, which we can get into if you want to get really wonky. But I think the big question is, well, when and if NUPLAZID will get negotiated, right? And so from that standpoint, 2029 is the year that we would expect, unless there's changes in the legislation such as kind of fixing the pill penalty, that's the year to kind of think about from a modeling standpoint of what negotiation can happen. But that's still far enough off that it is not really influencing what we're doing in kind of 2025 or 2026 when we've shifted our R&D investments in this area to 204. So kind of that long-term investment decision that -- maybe those things would start to play. We've kind of already made previous decisions to shift the effort there for the really long-term investments. But of course, we're mindful of it, right? So I think as we think about what could happen, yes, there'll be some price decrease that comes through that. At least in the first couple of years, there's limitations on what it will be for a small company. But the business will still be profitable at that point as you go through the negotiation and profitable enough that supporting our existing infrastructure, including the incremental investments that we're making to drive -- still drive volume growth. It's not like a patent cliff scenario where you would say, "Oh, this is going to happen and you're going to lose 90%, 95% of your sales and you just retrench everything." That's not what we anticipate this is going to be. But yes, there'll be a step down in price. So there'll be a step down in profitability, but profitability will remain and driving growth to grow profitability overall will still be part of the strategy as we get into the 2030s.

So you don't have a notable competitor in this space.

3

We do not.

Right. So that's another benefit as compared to some other companies. Okay. And now let's -- so DAYBUE, obviously, you talked about starting to see the benefits of the investment there. Tell us more about what you're hearing about in the field about the benefits of the medicine. Obviously, there's nothing else for Rett syndrome. It's a really, really, really tough disease. How is it looking in terms of the growth going forward?

Yes. I think from what we -- we've been on the market over 2 years now. And I think -- and what we have -- maybe as a way to answer your question is we have a very stable patient base. So greater than 70% of our patients have been on therapy for 12 months or longer. And so that just speaks to the benefit that DAYBUE is bringing for these patients and these families. They are seeing a meaningful increase in the quality of life that they get from taking the medicine versus prior to.

And I think what we're looking for as growth, at least in the U.S. is, as in any rare disease drug, you really focus on your key opinion leaders and your centers of excellence where the kind of highest concentration of patients are and we have significant market share and penetration in those segments. But 2/3 of Rett patients are still treated by their community physician, neurologists or otherwise. And so to be able to expand out to reach those physicians, those caregivers, those patients; that's kind of the next wave of kind of focus and investment for the company. And that's why we did the increase in field force earlier this year, and we're starting to see the fruits of that investment.

And what -- so you mentioned, I think, the duration of therapy of a year, 12 months, is that right?

Well, there are a couple of metrics that we point at. Sorry, go ahead.

So how are you helping people stay on drug even longer? Or is there a point where there's -- just a point where there -- it's done what it needs to do and they come off...

No. I mean, you've seen and we have open-label extension -- or not only just our open-label extension, but our real-world evidence study, LOTUS, that shows that patients are continuing to improve the longer they stay on therapy. So it's not that you just take it for 12 months and then it's done what it can do and you come off it. No, you're continuing to get benefit. And the opposite is true, too. If you come off therapy, the benefits that you're receiving go away. So it's not that you get something, stabilize and stay. You can continue to -- you can stabilize, continue to improve. But if you take the medicine away, the benefits that you're receiving from the medicine will go away. So that supports why patients are -- who've received benefit are staying on.

I think what we're just -- that metric is not -- I mean, there are lots of metrics that people look at for commercial performance. It's really for us, if you're going to ask me how do I grow the revenue base from here, that was what I was trying to address is that we have a stable patient base there that should be staying into the future. Of course, like any medicine, there's a reason why you [indiscernible] or even if you've been on it for 18 months may come off tomorrow for whatever reason, that happens in any medicine, it happens with DAYBUE. But for the most part, we have a stable base that we're now adding patients on top of it through our renewed commercial efforts.

It's really -- maybe getting back to your other question, it's really more early in the treatment regimen that people -- that patients, caregivers and their physicians are trying to find kind of the most effective dose and managing the potential tolerability issues that come along with DAYBUE where many patients experience diarrhea or vomiting. So they're trying to titrate or find the most effective dose to be able to manage the side effects if they're experiencing them. But kind of once you've hit -- you're out 6, 9, 12-plus months, you found that for yourself for an individual patients. Our efforts on getting people to see efficacy are really focused on that earlier part of treatment.

Okay. And what are you doing in terms of identifying or diagnosing earlier in life? Is that -- I mean, it's generally recognized that someone may have Rett syndrome fairly early on.

Yes. This is not a disease that it's hard to diagnose. I think what -- unfortunately, what you'll have is a healthy normal advancing, from a milestone standpoint, child and that child starts to regress around 18 months, and they lose function and cognitive ability that they had gained up to that point. It can take some time, but fairly quickly, if families are seeing the right physicians or ultimately get to the right physician, it's readily diagnosed. There's a genetic test. It's not one of the rare disease that it's just very, very hard to find patients. So I think what will -- but what you do see more -- less on the younger side of the patients, it's more on the older side of the patient. So if someone from our generation or older than us, who's still living with Rett syndrome, that patient might not have been diagnosed with Rett syndrome way back [indiscernible], maybe they were diagnosed with some form of autism or some other disease associated with that. So that's where you're seeing an increase in diagnosis and DAYBUE works for those patients. It's not a type of disease that if you don't treat soon enough, you lose the ability to treat it. You can treat -- the way that DAYBUE works, you can treat any Rett patient at any point in their disease progression. I think what we've seen as is typical of rare disease is that when we launched, we said, while the prevalence would suggest there's 6,000 to 9,000 patients in the United States, we knew by claims databases, there weren't any medicines, but there are codes that identify patients as Rett patients that there were 4,500 patients that were diagnosed and treated in the United States when we launched. When we look at that data now, it's more 5,500, 5,800 patients. So similar to other rare disease, when there's something to treat, you want you see that more patients are identified. And today, about 40% of those kind of 5,500 to 5,800 patients have tried DAYBUE. And so there's many more out there for us to talk to and if it's the right treatment for them to get them on therapy.

And then for the ones that may experience some initial challenges, as you pointed out, with some of the early side effects, do you have ways to help educate physicians and prepare them and set expectations so that they know what's coming and so they can be better positioned to stay on the therapy?

Yes. So we do. That -- our success in getting people to restart has improved over time. I think if you'd asked me this question a year ago, we'd say, yes, you see a very small number of patients that would come back and retry. We're seeing more of that now. I wouldn't say -- it's not the lion's share of our new patient starts. It's still, in the realm of numbers, smallish, but it's increased a lot from a percentage-wise from where we were maybe a year ago. And then yes, what we -- but usually, what you've had is you have a family that's come back and they have a reason that they want to try, maybe they've learned something. We know more now than we did a year ago. Their physicians know more now than they did a year ago. And so what we're seeing is the families that come back, they tend to have a better experience than the -- when you look at them as a whole from a standpoint of persistency, are they staying on therapy, those families have had more success than them.

Can you talk a bit about the broader strategy outside of the U.S. in terms of how you're going to market the drug in Europe, for example?

Yes. So we're going to market on our own in Europe. And so we've started building a team, and we've done some of that this year since have a leadership team, some key commercial payer market access people, MSLs. We didn't -- trofinetide or DAYBUE wasn't studied in Europe. So it's important to start to have those scientific conversations even over the course of this past year. It's one of also the reasons why we've started an inpatient supply program is to enable physicians that are comfortable and want to have DAYBUE prescribed to their patients. There are programs that can get access today and also give these physicians, some key physicians experience with the medicine in patients. And so that's kind of setting the stage of where we are today. And then we expect the time line for approval is kind of towards the -- by the time we go to opinion and then the timing for approval is probably in the late first quarter, second quarter time frame. We'll start to build -- of next year. We'll start to -- we've said that we'll go through a typical launch sequence with Germany being the first market. So we'll start to make the right kind of hires incrementally from there as we kind of start in Germany and expand throughout the major markets in Europe.

Okay. And is it sort of the way you would pitch the drug, the way you would sell it there, is it different in terms of the types of key opinion leaders you have to with to get uptake? Or would it be a similar sort of strategy as in United States?

It's similar and different, right? I think it's country by country. Some have centers of excellences, some don't. Some have big hospital centers. I think it's -- the kind of customer call point, there are differences across markets, but there's experience that we have from the people that have done this before as well as the knowledge that we have with what's been successful in the United States and how do we adapt it to the different markets in Europe, kind of we're well prepared to launch the drug.

Okay. Well, let's make sure we talk about the very important pipeline.

Sure.

So let's start with 204. We started to talk about it a little bit. So what can you say about how you're thinking about that readout and the significance of that readout in terms of expanding the market and getting approval in both ADP and [indiscernible]. I know this is only a Phase II trial, but still it looks like...

Yes. I mean, listen, we're very excited about both of them, right? So the Phase II readout next year is in ADP, right? So the Lewy body dementia psychosis, we just started. With the wealth of kind of data that we have over the various studies that pimavanserin, which is our -- for those new to our story is the other 5-HT2A program. So the wealth of information that we have from pimavanserin and the ability to leverage those learnings to what we think is -- optimize is probably too strong of a word in drug development, but just to best position 204 for success, that's what we're doing. And we're very excited about what the readout next year for a Phase II asset, just -- it's still drug development. There's still risk, but we view this as kind of your higher probability of success versus just some de novo Phase II asset first time ever in patients. So we will see what the data tells us.

From an ADP standpoint, we do have this seamless enrollment. So since we do have a lot of knowledge here, what that just means is that as our sites finish and complete enrollment for the Phase II, they'll just continue rolling in Phase III, and it's just an effort to be able to save time in the overall program from the Phase II to Phase III program to trial readouts.

And just to remind people, again, that are less familiar, this new molecule, this 204, it is related to pimavanserin in some respects. So can you maybe walk through [indiscernible] what's the...

Yes. So it is a new molecule, right? It's not a reformulation of pimavanserin. What we've done is we've designed it to try to optimize the potential performance of 204 relative to what we've known with pimavanserin. What pimavanserin, well, it doesn't really impact the commercial setting for NUPLAZID in PDP, kind of the limitation on pimavanserin is it's a modest QT signal. And so what it did was prevent us from dosing beyond what's in the commercial dose for PDP in other indications. And I think what we've seen in other indications is that increasing the dose has potential for greater efficacy. So what we've seen -- what we've designed for 204 and what we've seen in all the Phase I -- extensive Phase I work that we've done to date is no QT signal. And so what that's enabled us to do in our ADP trial is to study 2 doses. So one, the lower dose is essentially equivalent to the current marketed pimavanserin dose and the high dose is double. So that potential can give for greater efficacy and also potential for a shorter time to onset. So all of that together are the enhancements that we've kind of created and designed into the molecule and the program for 204. And obviously, we'll see what the -- we're very excited about the data readout coming mid next year.

Okay. And just in terms of the market sizing, how do they compare in terms of PDP versus ADP. What can you say about just the potential for marketing.

Yes. I mean ADP is a much larger market. It's multiples and multiples of what size the PDP market is.

Okay. And as far as the specifics of the readout, what are you looking for in terms of what would be kind of like a win scenario, just hitting on the primary endpoint?

Hitting on the primary endpoint would be -- I mean, there's -- to date, there's nothing approved for this indication. So I think that would certainly be a win. Less than that could be a win too, but that's not what we're expecting or hoping for. And -- so I think that -- and even though we have this kind of seamless enrollment, the Phase II is a Phase II program, and it's a distinct trial from the Phase III. So we'll get that data, and we'll share it with Wall Street.

And that's coming, you said. So what's the timing on that?

It's mid next year.

Mid next year.

Yes. So as we get closer to that, we'll kind of refine and put a more specific [indiscernible].

It's done enrolling.

it's not done enrolling.

It's not done. Okay.

Yes. It's a 6-week trial.

You don't need a lot of time on it.

You don't need a lot of time. So kind of as we get into next year, at some point, we'll be fully enrolled and that will kind of put a more of a pinpoint on what the time line will be for data readout.

And the other one we were about to talk about, the Lewy body one, that one is staggered to some extent? Or how far along is that one?

That just started last quarter, right? So we don't have -- so we need to -- we don't have time lines for that yet.

And obviously, that's a smaller market. It's more specialized.

It's a smaller market. It's more specialized. We are very excited. While -- in our HARMONY trial, while we -- it's a limited data set, we showed some of the strongest efficacy in this sub-patient population of Lewy body dementia psychosis. So we think there's a very strong opportunity there as well.

Okay. And just to sort of state the obvious, there's nothing -- we don't have drugs that can treat these conditions [indiscernible].

In either case, yes.

Okay. And then just quickly, the sort of the -- the patent on 204, I assume would be very good, quite long.

It's quite long, yes.

Given it's a new NC.

Yes.

All right. So then you have a few others, the MDD trial and then the [indiscernible] study. So let's start with MDD. And there, I believe the goal is to sort of differentiate versus SPRAVATO. so tell us a little bit more about that program and the molecule.

I think if you -- so if you look at that program, I think the kind of optimal outcome would be able to show SPRAVATO type efficacy, but have a side effect profile that avoids dissociation and sedation and that would then limit or minimize the amount of kind of time you need to spend in an office while you're taking the treatment and monitoring. So if we can get the same efficacy with a side effect profile that provides just kind of enhanced benefit and ability to take the medicine without having a dramatically negative impact on the time and effort that it takes to take the medicine, that could be really meaningful.

And the time lines on that one, have you been specific about when we would see the...

We haven't -- we've just started -- we started Phase II. We're going to start it this quarter, right? So again, another thing that's exciting yet just started the kind of its next step. So we'll need to kind of get through that to give you a little bit more time frame on -- or color on what time frame will be for data readout.

Okay. And with these sorts of MDD trials, you always run into -- I know this gets a little bit into the leads. But I guess just at a high level with your clinical development group, I guess they've got everything under control in terms of [indiscernible] checking the placebo effect, making sure there's good consistency at the sites so that you don't run a foul of some of these serious results where you have a drug that works, but it doesn't get -- you can't show it in the study.

Yes. I mean, listen, we've got very experienced teams. It's neuroscience, right? So there is an element of risk of like in any trial that you could say the drug worked, but the trial didn't. But we have a lot of experience and a lot of safeguards and set up to minimize the likelihood that, that happens, but you can't take that away completely in the line of work that we do.

And then at the R&D Day you had, which was now quite a few months ago, I remember one of your VPs of clinical development was talking about the essential tremor program quite eloquently. So that's interesting. Tell us a little bit more about the -- just the basics of the time lines, the study design.

Yes. So I mean, for the ET -- another disease where there's no approvals today and a number of these are -- it doesn't mean that other companies aren't investigating them. But I think for us, -- what we are excited about with 711 is the selectivity within the mechanism. And that where we think is within the GABA system, supports efficacy but doesn't touch on some of the other nonselective points that can bring about the side effects that come with this system. That's the thesis. That's what we're excited about, and we're looking to prove that out. We'll start the Phase II next year. So we've still -- since we licensed the asset, we've done additional Phase I work, including doing some elderly cohorts to help us pick dose and design the Phase II, and that's expected to start next year. So still early in development, but very exciting, very large market opportunity if it's successful, and that's why we're making the investment.

And of course, you are the CFO. So shifting back to the financials. Just kind of give us a high-level snapshot of the P&L dynamics. I know you're investing more in the sales, but just talk about how you see the OpEx trending and the cash.

Yes. I think from a CFO financial profile, I think it's an exciting P&L, if you could actually say that. We can all laugh. But I think for -- we have a growing revenue base, growing profitability. The company is and has been cash flow positive for a while. I've been CFO for over 4 years. What's been in and out a tough kind of biotech financing market. We've not financed since I've joined the company. So that's been a strong position to be. We have over $800 million of cash, no debt that I mentioned in my elevator speech. So that enables us to just invest across the business and to expand the business. I think what we see going forward is we're making some additional investments, some that we talked about. We'll give guidance for what OpEx will look like next year, but you'll see an increase from the variety of things that we're doing across the company. But we're also increasing sales, and it's something where if you look at multiple years, there's significant operating leverage in the business. But our goal is kind of to drive kind of total area under the curve profitability, and that's what we look to do from a business and financial standpoint.

On the R&D side, you sort of -- are you kind of comfortable with this level of investment in this number of programs? Or do you see that you have candidates in the discovery that are coming up the ranks that could be in the clinic in the next few years?

We have some other early-stage programs that we've yet to disclose. Most of those also have come in through business development. We don't have a big -- while pimavanserin and 204 are internally discovered molecules, we have -- so we have a limited discovery effort in certain areas. It's not a big focus of the operations of the company. So most of the assets in the portfolio, whether disclosed or undisclosed beyond those 2 have come in from business development. So yes, there's capacity. We don't manage the company from like a ratio of R&D to sales. We have operational and financial capacity to add to the portfolio. And then as Liz Thompson, our Head of R&D, always likes to say, we try to look at molecules, are they going to earn their way into our pipeline? And do they have data that supports staying in the pipeline. And that's how we evaluate it. And then whether or not the R&D line goes up or down, it's going to follow the science and the opportunity and then the commercial expectation from that science. So we can lean in and do more or we can pull back if things don't warrant advancing into the next stage. And that's how it will [indiscernible].

Awesome. All right. Well, thank you so much.

Thank you. Great discussion.

Thank you very much.

All right. Thank you. Enjoy the conference.

Okay. Good day, everybody. Welcome to UBS Healthcare Conference. With us, we have ACADIA Pharmaceuticals and Mark Schneyer, who is the Chief Financial Officer; and Ponni Subbiah, who is the Chief Medical Officer. Thank you so much for joining us. My name is Ash Verma, I cover SMid-cap biotech and spec pharma.

So I just want to go over the story and learn some of the exciting things that have happened. Just for the audience in the room, if there is a question that you want us to ask, feel free to send this to me by the QR code, and we can cover that. But maybe with that, I'll get started.

Yes, maybe, Mark, if you can give us a sense on like where you are in the story, just recently the third quarter earnings and take it from there.

Well, Ash, great to see you. Thanks for having us. We appreciate it. So at ACADIA Pharmaceuticals, we're a neurological and rare disease company. Both commercial and development stage. So we have two commercial products: NUPLAZID and DAYBUE that each treat, respectively, Parkinson's disease psychosis. NUPLAZID and DAYBUE treats an indication called Rett syndrome.

Together, the commercial franchises will cross $1 billion in revenue for the first time as a company this year, and we have a pipeline behind that. So with our latest-stage asset, ACP-204, we're investigating in two indications: Alzheimer's disease psychosis, which will have a Phase II readout in the middle of next year and Lewy body dementia psychosis.

We have an early-stage pipeline behind that, that we can talk about as well. And we're in a strong financial situation. The company's cash flow positive, have almost $800 million -- or over $800 million in cash on the balance sheet as of our last quarter and no debt.

Right. Perfect. So maybe, I know the NUPLAZID and DAYBUE, both sort of like different dynamics going on. Maybe we start with NUPLAZID actually. So this is interesting. Like we have seen the IP extension, which was a big positive news for you guys, like earlier this year, and I see that you have started to more talk about that you want to fuel the growth behind that. Just talk towards like where you are in that growth narrative. And as you're thinking of like expanding the commercial footprint, where can this go ultimately?

That's a great question. So NUPLAZID has been on the market 8, 9 years now. So it's kind of mid-life cycle. And I think like we do for all of our assets, we invest for returns, and we'll dial up and down that investment based upon the performance of the assets and the environment that we're facing.

And what happened with NUPLAZID during the pandemic, even though that's kind of in the rare view mirror, but it kind of helps to bring back a little bit to address kind of a more fulsome answer to your question with an elderly and frail patient population. Fortunately, there was mortality in this patient population, as well as patients just wouldn't go to their physicians for the same level of visits. So the traditional metrics that you test to say, all right, our commercialization and marketing dollars reaching returns didn't meet those thresholds in that time period. So we pulled back.

But then coming out of the pandemic, what we saw is that there was low awareness. We had some new information that Ponni can talk to you about some real-world evidence studies that we started to share with the market and gained traction kind of 5, 6 years into launch of renewed growth trajectory.

Over the last 12 months, knowing that we had low awareness in the kind of patient and caregiver community for this disease, but still a strong prescriber base and willingness to prescribe amongst our physician customers, we renewed our direct-to-consumer campaign, both unbranded and branded. The unbranded, we partnered with Ryan Reynolds to get the information out about Parkinson's disease psychosis.

And that is -- all of that together has led for renewed growth. In the last quarter, we had not only double-digit year-over-year growth in revenue, we had 9% volume growth year-over-year in the third quarter and to -- and then from the results of the direct-to-consumer campaign seeing where our new patients are coming from and those new scripts are coming from. We see an opportunity to expand our field force, which we also discussed this fall. And so come January of next year, we're going to increase our footprint by about 30% to drive further growth.

Together with kind of near term because commercialization, you think a 2- to 3-year investment horizon. But from what you mentioned earlier, Ash, for the kind of intro to this question, we did have an IP win earlier this year that gets us runway through February 2038. So there's a lot of life left in the franchise to properly commercialize it to maximize the value, at least from a financial perspective for the company and for investors.

Great. Great. Yes. I mean this type of sizable sales force expansion. Have you done this before with NUPLAZID in the past? And I'm just curious to see like when does it start to like generate the results in terms of like...

So we -- so I think from my -- I mean, I've been in the company 5 years. So we haven't done this direction with NUPLAZID, but we have a very experienced commercial team, personal leadership, our CCO, Tom Garner, and Catherine Owen Adams, our CEO have plenty of experience with optimally commercializing assets. So they've done it many times. And so -- and we're doing it also, as you know, and you may get there on your questions on DAYBUE, we did it earlier this year. So typically, you'll see a couple of quarter 2 to 3 quarter impact from when you start to make the investment until it's up and running fully and optimally and you see results at the top line.

Both from DTC and sales force expansion standpoint, like kind of the -- that type of time frame?

Yes. So I think both. It's a couple of quarter lag. I mean, the DTC usually happens a little quicker because as you're drawing -- you're targeting kind of the patient caregiver universe. And as they go and talk to their physicians, oftentimes, those physicians are familiar with NUPLAZID. And so there's some -- depending upon where they go, there's some lag.

But if you're talking to a new physician, whether it's NUPLAZID or DAYBUE it's kind of similar across, you need a number of conversations with that physician to make that relationship fruitful from a financial perspective. So it's about the same time frame. Usually, you see it a little quicker in DTC a little longer from a field force expansion.

Got it. Got it. And I see that just like roughly where consensus is at for 2026, like $730-ish million. Is that sort of looks reasonable given like the push...

We'll guide next year. I think there's two things we promised to do next year. One is typical, we'll guide for the year. And two, for both DAYBUE and NUPLAZID individually, we'll give some perspective on where we think the peak sales opportunity or the full opportunity of the [ ads ]. So let us get there. But it's an asset that we continue to see meaningful growth from in kind of the near, medium and long term and let us get into next year to be more specific on numbers.

Great. Great. And then just on the IP win, sort of as a follow-up to that, yes, I know there's like appeals process like when that can play out typically. Anything that you're seeing on that front?

There's one -- so the litigation -- the trial court that we -- or the trial that we won in the spring that moved the stock price was winning the formulation patent that covers our 34-milligram capsule of NUPLAZID. That litigation is subject to appeal. The appeal -- kind of briefing process is ongoing now, and we would expect to have oral arguments at the appeal sometime next year. We had very strong arguments that supported our win at the district court level, and we remain confident in our position in that case.

Yes. Great. Awesome. So maybe just like switching over to DAYBUE then. So here, just I think -- yes, I have to say this has seen quite a bit of a turnaround, right? I think back in 2024 or '23, you started to see a little bit of a stagnation, but with more of a focus on like the pushes that you're making. You're starting to see like more growth coming back. So I think like on this same kind of a situation that like you're expanding the field sales force, right? And then you're starting to look at more commercial opportunity. Like have you quantified like where is the sales footprint right now for DAYBUE specifically specifically and like where the expansion...

Like the number of reps, yes. So we have 38 territories, so 38 reps supporting the DAYBUE franchise today, and that's kind of full from after completion of our field force expansion earlier this year. I think the thinking behind that, as we had new leadership come into the company, both at the commercial level, the CEO level, we just felt that we were undersized in our DAYBUE customer-facing effort.

And -- and as about, I would say about 2/3 of Rett patients are treated outside center of excellence is we just didn't have enough people to have kind of the reach and frequency. So similar to what we're talking about, there's no mystery to it. If you're going to build a relationship with a physician, to try to educate them about a medicine for them to treat their patients. You just need a certain level of reach and frequency or frequency with that individual position to get them comfortable prescribing a medicine.

And so even though Rett syndrome is a rare disease and you have pediatric neurologists that are specialists in the area and pointing things about this better than I can, any physician can prescribe it. And it's not -- and so -- but we wanted to make sure is that, you have pediatric neurologists or even just normal pediatrician who's treating a number of Rett patients that they can feel comfortable prescribing the medicine to their patients.

And we just didn't have enough people to accomplish that at this stage of the launch or at this stage of the life cycle of the asset. And that's why we expanded the field force earlier this spring or this year. And as we reported on our third quarter call, we're just starting -- we're now starting to see -- kind of the fruits of that expansion with -- in the third quarter. We had an increase in referrals, and it was our highest referral count since third quarter of 2024.

Great. Maybe I can just add to Mark's point. So Rett syndrome can affect patients right from young age greater than 18 months, and they can be -- continue to live with the disease. And now because of better care for these patients, they're living into their 50s, right?

And so it's really important we started, of course, in the centers of excellence, the pediatric neurologists. But as you go into the community, they're not -- as they get older, especially, they are being taken care of by more adult internists, family practitioners, as well as advanced practice providers like nurse practitioners. So it's really important now that in order to help them understand, many of them maybe see one or two patients. So we're really spending a lot of time educating them, not just on our product, but also about Rett syndrome itself. And so that has been very important now with more people on the ground to be able to reach more of them.

Great. Great. Yes, I know you focused on like these three different kind of buckets in terms of like the COEs and high-volume institutions and then private new. So where is the most value that you can extract us for the next phase of the growth in terms of focusing in the channel?

Well, I think right now, we've now really established our relations with COEs. And so we've taken a lot of their learnings both from an efficacy, as well as the tolerability management perspective. We've published two papers on that with their opinions. So we're continuing to really share the experiences and rolling them out.

And so the high-value institutions, that's a low-hanging fruit because these are often academic centers, tertiary care centers, where patients do come. But to really reach those others, we're really trying to make the connection. And really educate them and at the same time, really educating the caregivers because many times, especially the older patients, they not really -- they're not aware that there's a product that's available. So that is also a very important channel that we're making sure that the awareness has increased.

Great. And then, yes, I mean, there is a fair bit of discussion on this around the persistency of the drug, right? And some of the data that you've shown, which has been kind of improving, I would say, like over time, like as you're saying, the -- more than 50% of persistency over 12 months and I think like 45% at 18 months. So do you think that you're -- like is there a room to go higher than that? And like patients that you have been tracking for, let's say, 2 years, like where is that shaking out to be in terms of the persistency?

Yes. So I guess the way the math works on it, right, those numbers have stabilized and more patients that we have that reach those time points just supports and maybe even uplift those numbers a little bit, right? So it's greater than 50% after 12 months and greater than 45% at 18 months of time. And those are -- for any chronic medicine are strong persistency rate.

So could they improve? It would -- you need like new patients that start today or like are on the patient to have greater persistency at that time point. So like the whole curve over time, as more patients go through it, can shift up and down. But I think as we've seen it over time, and we've taken -- we've waited to report those numbers just because you don't want five patients to reach there, right, because that will just be like this. So it's really -- those numbers are just robust and are supported as more and more patients hit those time points.

But it seems to -- a lot of the churn in the patient is happening like early on. And if it's like 50%, 45%, like at 12% and 18%, that means that longer to follow.

If you could see us in the room, and I guess I maybe not people on WebEx, there's -- it kind of plateaus out, right? So the greatest time point when people would stop taking therapy because they either didn't see efficacy or they had tolerability issues are in the first few months of therapy. So that's when we lose most of the patients that have started. But now more than 70% of our patient base have been on therapy 12 months or longer. So that's a very stable patient base. They're on the outer ends of that persistency curve that you mentioned. And then as we add new patients that start, that's how we're growing our patient base. today and in the future.

Great. Yes. And then just talking about like Europe for DAYBUE. So, I mean, I know you've discussed this kind of like starting in Germany and stuff like that. But, yes, how is the concept of the market different in Europe at all versus U.S. standard of care, the physician, how they prescribe for Rett. Maybe like if there are any differences between U.S. and Europe?

So it really varies by country. So let's take Germany, for example, our biggest market. There is really those centers of excellence like in the U.S. rather, there's a network of about 120 centers that provide care for children with neurodevelopmental disorder.

And so it's important that we're able to work with that kind of framework. But if you look at France, it's very similar to U.S. There's about four or five centers of excellence where many of the care is being provided and the management plans are coordinated with their local doctors.

Now if you look at Italy and Spain, also very similar to kind of the French model. So we are very much learning. We have our MSL team already on the ground. We're really interacting with a lot of these experts. And so really trying to understand the nuances within each country.

Yes. So -- and then just in terms of the pricing like where you might ultimately like realized price versus U.S. like what is the likely base case that you're running?

So I think it's a little early to talk about that. As we go through the approval process next year, then in Germany, there's a period of kind of unconstrained or free pricing as they call it. So we're probably about a year, if not little bit more than a year out of setting price and let us get closer to that before we share it with Wall Street.

Got it. Okay. Perfect. So yes, let's switch over to the R&D. So I mean, I think it's been a lot of kind of ups and downs, right? This year, I mean, particularly, a lot of excitement around the R&D Day when you outlined big -- sort of sales potential, but then, unfortunately, the PW did not work out. So I guess the question that I have just on that is, does that, in any way, change your kind of level of confidence in the rest of the pipeline? Or do you think that you still kind of firm believer that the overall revenue opportunity that you outlined for the rest of the pipeline is pretty intact?

I think from a revenue standpoint, not every science experiment works, right? So that's just the nature of the business that we're in. So we did share at R&D Day that we had a potential $12 billion of opportunity from everything that was identified in our pipeline and with 101 not being successful that number is around $11 billion. So it's still substantial, and we still have confidence across the pipeline that there are good investments to make. But I'll let Ponni talk maybe a little more specifically about the pipeline in general and what she sees in it.

Yes. So we're very excited about our pipeline. We do think it will be an important engine for growth of the company. The first is more on the clinical those stages that are in clinical is, first of all, ACP-204. We're very excited about that.

First of all, it was developed internally within the company based on all the learnings we've had with pimavanserin. We're probably one of the experts in the 5-H2A receptor science. And so based on that and really trying to improve the profile. And right now, based on the data from our nonclinical studies as well as Phase I, we do think we have a very interesting profile that's going to be very important in the populations right now we're studying.

So right now, we have a Phase II study that's in Alzheimer's disease psychosis as well as the Phase II study that just started in Lewy body dementia. So 2 very important and huge market opportunities, right? 7 million patients with Alzheimer's disease of 30% can develop psychosis versus an LVDP over 1 million Americans affected, of which 50% to 75% can be affected with psychosis. And psychosis can be extremely burdensome to the family. So we do think based on our learnings from PDP that we have a lot to offer here.

Now in addition to that, also very -- we are very excited in the neuropsychiatry space is ACP-211. This is our deuterated n-ketamine, which we will be studying in major depressive disorder with the Phase II study -- Phase II starting fourth quarter of this year.

Yes. I want to ask a few questions about each one of those. So maybe just like starting off with Alzheimer's disease psychosis. So this can be a very big opportunity, like you said. And like so far, the data that we've seen from preclinical or Phase I, I mean, you kind of showed that this next-gen pimavanserin effectively like no -- doesn't have the QT prolongation issue that pimavanserin does. So as you're getting to like the higher concentration of this molecule, are there any other side effects that might be triggered that NUPLAZID did not have with 204?

So let me step back first about the molecule. And as we said, based on the early nonclinical and the Phase I study. First of all, there's a few things that we are excited about that differentiates it and really part of our target product profile. One is that lacks so far, the data suggests it lacks QT prolongation potential. Now that really limited us on the NUPLAZID side to go above the 34-milligram dose, right? So that's a huge point. Now why is that important? Because if we don't have that potential, we will be able to test higher doses. Now that's important because based on our work in pimavanserin, we know that if there's a strong exposure response relationship.

So if we're able to get a higher platinum exposure, we think that will translate to better efficacy, right? And the third thing is that compared to NUPLAZID, ACP-204, its terminal half-life is about half of NUPLAZID. It's about 21 hours versus 55 hours for NUPLAZID. So we think that also have a shorter onset of action. So that will help translate to the population. Also, it continues to have a convenient, we think, once a daily dosing with or without food intake.

Now with regards to your point, now with the higher doses, there could be potentially dose responsiveness with regards to other events. But so far, we have tested single doses up to 180 milligrams, as well as multiple doses at 120 milligrams, and they've been generally well tolerated.

Now even in our ongoing study, we are testing both 30 and 60 milligrams. And so far, review of the blinded data is reassuring. And then we also have a Data Safety Monitoring Board, which has supported the continuation of the study. So for those reasons, we're feeling that the to profile will be very consistent with what we've seen at pimavanserin. And that has been a huge advantage for pimavanserin is the convenience. Also, it's the safety in the elderly population.

Got it. Great. Yes. I mean in this space, like there is a fair bit of just focus right now on Cobenfy, right, the Phase III trial reading out. I'm just curious like if you have any views on like their study kind of as a competitor. It seems that they -- I mean, like even on the schizo side has a pretty high discontinuation rate. And like for this study, they're using it twice a day, which in this population can cause even more discontinuation. So just in terms of like what do you think the profile of Cobenfy might be from a competitive standpoint when we get the data in the next few weeks, I guess?

Yes. So first, we don't really comment on other companies' compounds. But what I can tell you is, first of all, it's really good there's more investments in the space. Again, huge population huge unmet need. So -- but with ACP-204, as I mentioned, we have a pretty robust target product profile. And so far, what the profile looks like, that we think that this will be a very important option if we're able to consistently get it through the pipeline.

And one of the things, since you alluded to dosing, what I mentioned earlier, is that the convenient once-a-day dosing orally is going to be very important for this kind of fragile population.

Right. I was looking at like the -- I think the endpoints are also a little bit different versus what you guys are choosing versus them. So you have the SAPS-H+D versus I think they have NPIC-H+D. So yes, what is essentially like an FDA-validated endpoint, like registrational endpoint or is it kind of that situation that because it's totally new disease state that there's no consensus around it?

Yes. So the FDA hasn't really communicated a preference with regards to an endpoint. So we have a lot of experience with SAPS-H+D, right? So we have experience from the pimavanserin trials, both in the registration trial, as well as the HARMONY was a component of the relapse criteria. So we know that, that's sensitive to change. We were able to get registration in PDP.

And so with that, we have included the SAPS-H+D, the change from baseline at week. Now the NPIC is the neuropsychiatric inventory rated by the clinician. Now we have included that as an exploratory endpoint. But we, right now, our plans are to continue with this primary endpoint in Phase II into our Phase III studies as well based on the experience we've had on our program.

And remember, we also have experience with pimavanserin in Alzheimer's disease psychosis in a nursing home setting in the U.K. Now there, we did use a neuropsychiatric inventory, but we've decided to go with SAPS-H+D again because of its sensitivity change.

With this scale, like is there -- like what's the right like clinically meaningful effect size versus placebo for the duration of the -- like the time that you're running this study?

Yes. So we have powered the study for a moderate effect size of 0.4 and we also are looking at not just a key secondary endpoint is looking at the clinician's global improvement. And so we feel based on this, this will be clinically meaningful for these patients.

Great. Awesome. And then I had a couple of other quick questions on the rest of the pipeline. Before we go there, Subbiah, just on Lewy body, like what's the time line on that? You said like initiation by the end of this quarter.

We've actually started enrollment in the trial. And so we'll be -- we're hoping to be able to read out potentially mid part of next year.

Got it. Okay. Perfect. And then, yes, there are a few different early pipeline programs that I was looking at. So 2591 in Rett plus Fragile. So just kind of how you're thinking about that from a positioning standpoint versus DAYBUE for Rett?

No. So this is a compound that we licensed from Neuren, and this is a IGF-1 analog. And just early work suggests it may have better brain penetrant. And so we're continuing to work on this. Right now, we're very committed to bringing new solutions to the Rett community and in addition to, of course, ensuring that DAYBUE gets to more patients around the globe. So right now, it's in the early stages.

Right. And for this program, you have the rights for two indications, but Neuren has the right for, I believe, for the rest of them, one of them kind of including Prader-Willi, just given like you have shown excitement around Prader-Willi as an opportunity, is that something that makes like a logical step for you to try to secure that piece of the risk?

So as of now, Neuren is investigating 2591 in a number of indications. And as kind of the owner of the asset that they've chosen strategically, they want to keep those and invest them on their own. So we have Rett and Fragile X. And so we'll stick with those. And it's just the nature of the business relationship that we have with Neuren.

Yes. Is this one of those like sort of more broad approach -- applicability, excuse me, for different indications with this 2591 that it can work on a bunch of these different indications?

Maybe I can comment a little bit on that. So many of these disorders they're working on are neurodevelopmental disorders, right? At least the mechanism of action of trofinetide, for example, which is this is a next generation, is that at least based on animal studies, it appears to impact neuronal plasticity and dendritic growth, thereby improving neuronal communication.

And so I think in these neurodevelopmental disorders where there's not neurodegeneration, but immaturity of the neurons. This could play a role. And I think that's why, especially trofinetide was the first drug ever approved for neurodevelopmental disorder. So this has given a lot of hope into the other areas and enthusiasm investing in some of these other neurodevelopmental disorders.

Got it. Got it. Okay. And then, yes, I mean, I think you mentioned the Ketamine. Deuterated ketamine. Yes, can you talk about that a little bit? I think -- yes, what's the angle there? Like are you going for which subtype of depression or like how fast can you see onset of action that an approach?

Well, so we've been working to have a robust target product profile for this. So what our thesis is because 211 is a less potent on the NMDA antagonist, it will have less likely to have impact on and cause anesthesia. And also, it may be -- because of this, it could potentially be dosed at a higher level, which can enhance AMPA activity, which can lead this -- has impact on depression.

At the same time, with oral dosing and also one of the theses our target product profile is the ability because it's not as potent, potentially to be less sedating, and also have less association. Now why is that important? Because in the clinic, then they don't have to be there longer being monitored. So it will be convenient but at the same time, of course, the focus on efficacy.

Great. And then just on 271. So this is, yes, going after Rusteo, Ingrezza and a very, very underpenetrated market. So yes, I mean, I'm just curious like what's the angle there in terms of target product profile that you're looking at? Is it after those therapies? Or can it be for naive patients?

Yes. It's in the very, very early stages right now. So -- but it does have a very interesting scientific hypothesis, right? It's work on the GPR8, and it's an agonist there. And so we do think that it may have some potential in Huntington's chorea, Huntington's disease, both on the chorea movement disorder, but also potentially in the psychiatric manifestations as well. And then, of course, we're also thinking about it for tardive dyskinesia.

Would HD chorea would be the main indication and tarda is like secondary. Is that...

It's very early. We're hoping both. But yes, it's very early in stages right now.

All right. Great. With that, we can wrap it up here. So thank you so much.

Thank you.

Yes. This was great.

We enjoyed as well.

Good day, ladies and gentlemen, and thank you for standing by. Welcome to ACADIA Pharmaceuticals Third Quarter 2025 Financial Results Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to Al Kildani, Senior Vice President of Investor Relations and Corporate Communications at ACADIA. Please go ahead.

Good afternoon, and thank you for joining us on today's call to discuss ACADIA's third quarter 2025 financial results. Joining me on the call today from ACADIA are Catherine Owen Adams, our Chief Executive Officer, who will provide some opening remarks; followed by Tom Garner, our Chief Commercial Officer, who will discuss our commercial brand, DAYBUE and NUPLAZID. Also joining us today is Elizabeth Thompson, Ph.D, Executive Vice President, Head of Research and Development, who will provide an update on our pipeline programs; and Mark Schneyer, our Chief Financial Officer, who will review the financial highlights. Catherine will then provide some closing thoughts before we open up the call to your questions. We are using supplemental slides, which are available on our website, Events and Presentations section.

Before proceeding, I would like to remind you that during our call today, we will be making several forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, timing of events, future results and financial guidance are based on current information, assumptions and expectations that are inherently subject to change and involve several risks and uncertainties that may cause results to differ materially. These factors and other risks associated with our business can be found in our filings made with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date, and we assume no obligation to update or revise these forward-looking statements as circumstances change, except as required by law.

I'll now turn the call over to Catherine for opening remarks.

Thank you, Al. Good afternoon, everyone, and thank you for joining us today. I'm pleased to report another strong quarter for ACADIA with solid execution across our commercial portfolio and continued momentum positions us well for a strong finish to 2025 as we lay the foundation for sustained growth into 2026 and beyond.

We delivered total revenues of $278.6 million this quarter, up 11% from a year ago, reflecting the strength of our commercial portfolio. This performance underscores our ability to execute on multiple fronts while building for future growth.

Starting with DAYBUE, we're very pleased with our progress. Following the expansion of our field force earlier this year, the benefits of which are now starting to materialize. I'm excited to share that we achieved our largest sequential increase in referrals since launch. This meaningful sequential growth reflects the impact of our expanded team into the community setting, giving us confidence that we will continue to see benefits from our broadened physician reach.

During the third quarter, DAYBUE generated $101.1 million in net sales, including contributions from both U.S. sales and named patient supply programs outside the U.S. We shipped the highest number of DAYBUE bottles ever in a single quarter. In total, we shipped to over 1,000 unique patients globally, an exciting milestone for the company. Importantly, patient persistency remains stable, underscoring the sustained benefit DAYBUE delivers to patients and their families.

Moving to NUPLAZID. We delivered an exceptional quarter with net sales of $177.5 million, marking our strongest sales quarter ever. The momentum we are now driving gives us tremendous confidence in NUPLAZID's potential to unlock higher growth in the coming years. To ensure we capture this opportunity, we're making strategic investments in a meaningful field force expansion. The impact of this field team expansion, combined with our direct-to-consumer campaigns creates a powerful combination that we believe will drive sustained growth and value maximization for NUPLAZID. We're looking to build on our commercial success by advancing our pipeline of novel product candidates, including the recent initiation of one Phase II and one Phase III trial.

I'll now turn the call over to Tom to cover our commercial performance.

Thank you, Catherine. I'll begin with DAYBUE, where we delivered another strong quarter of commercial execution. DAYBUE sales were $101.1 million in Q3, representing our highest revenue and total prescription volume in any quarter to date since launch. As Catherine noted, for the first time since approval, the number of unique patients receiving DAYBUE worldwide exceeded 1,000 in a single quarter for an actual count of 1,006. This achievement reflects not only our progress in the U.S., but also from patients now starting to access DAYBUE through our named patient supply programs internationally. We're seeing strong early indicators from our field force expansion. Referrals are leading the way with the highest quarter-over-quarter increase since DAYBUE's launch in 2023. This momentum is translating into other key performance indicators such as broadening prescriber reach with 956 physicians having now written at least one prescription for DAYBUE.

Our sales teams are now gaining real traction with call volumes on our expanded target customer base increasing over 20% versus Q2, supported by a similar increase in the number of educational programs we delivered, both of which are important levers in helping to educate prescribers on the benefits that DAYBUE has to offer. Importantly, adoption is broadening beyond Centers of Excellence, or COEs, with community-based physicians accounting for 74% of new prescriptions in Q3. We're also seeing a meaningful uptick in scripts from nurse practitioners and physician assistants, reinforcing that our strategy to expand in-person efforts into the wider Rett treating community is working. These trends position us well to reach more Rett patients who could benefit from DAYBUE.

Even with this progress, overall market penetration remains relatively low at about 40% in the U.S. and only 27% in the community setting where the majority of Rett patients are treated. This continues to represent a substantial growth opportunity for the brand.

Looking at age demographics, penetration among patients under the age of 11 is over 60%, but amongst older patients is significantly lower despite growing real-world evidence of DAYBUE's positive impact in this group. As we expand our reach beyond COEs, we see this segment as a significant growth driver for 2026 and beyond. Long-term persistency remains a key strength for DAYBUE, reflecting its sustained clinical benefit and strong patient engagement. With another quarter of maturity in our data, persistency rates remain above 50% at 12 months and greater than 45% at 18 months. The strength of these metrics are important as they further reinforce not only our confidence in DAYBUE's therapeutic value, but also our outlook for sustainable long-term growth in the U.S. Internationally, our named patient supply programs continue to gain traction. All 3 distribution partners are now actively shipping to patients in the EU, Israel, Middle East and Latin America.

Looking ahead, we remain confident in DAYBUE's growth outlook, driven by sustained demand generation supported by our strategic field force investments, strong persistency metrics and expanding global access. These factors are critical because they are not only validate the long-term value of DAYBUE for patients, but also create a durable foundation for revenue growth. While we began to see the initial positive impact from the field force expansion in Q3, we expect meaningful benefits to accelerate through Q4 and into 2026.

In summary, DAYBUE is well positioned to capture significant market opportunities in the U.S. and internationally, reinforcing our commitment to delivering both patient impact and shareholder value.

Now turning to NUPLAZID, where we delivered record performance with net sales of $177.5 million, representing 12% year-over-year growth, driven by 9% volume growth. This reflects strong underlying demand for NUPLAZID among patients with Parkinson's disease psychosis, or PDP, and the success of our commercial strategy, coupled with the unwavering focus of our customer-facing teams on executional excellence. Referrals were a key driver of this momentum, increasing 21% year-over-year. This growth signals increasing awareness and confidence among health care providers in identifying and treating Parkinson's-related hallucinations and delusions earlier in the course of the disease. New prescription volumes grew 23% in Q3 compared to the same quarter last year, representing the strongest year-over-year increase since 2019 and were up 9% sequentially.

This inflection point demonstrates that our patient engagement campaigns and HCP outreach are translating into tangible prescribing behavior. It also underscores their belief in NUPLAZID's differentiated profile as the first and only FDA-approved therapy for PDP with a well-established safety and efficacy record. Taken together, we believe these trends are an important leading indicator of future prescribing behavior and reinforce the strength of NUPLAZID in meeting a critical unmet medical need.

As a reminder, the U.S. PDP market represents a significant opportunity. There are approximately 1 million Parkinson's patients with an estimated 50% experiencing hallucinations and delusions at some point during the course of the disease. This translates into a substantial number of patients who could benefit from NUPLAZID, underscoring the long runway for growth.

Looking ahead, we see significant opportunity to build on this momentum. Our reach and frequency model is driving broader prescribing patterns across a wide range of HCPs and our direct-to-consumer campaigns are raising awareness of PDP symptoms while highlighting NUPLAZID as the first and only approved treatment.

To fully realize NUPLAZID's long-term potential and capitalize on the brand's strong momentum, we are making strategic investments, including a 30% increase in our customer-facing team starting in the first quarter of 2026. This expansion will allow us to reach newly activated physicians and improve pull-through. We are approaching this expansion thoughtfully to maximize near-term efficiency and long-term impact. Our various consumer initiatives are driving awareness and creating demand with our expanded field force ensuring we efficiently convert that demand into prescriptions.

In summary, the NUPLAZID fundamentals are strong. The market opportunity is substantial, and we have a proven strategy designed to capture it. With a differentiated product profile, accelerating demand indicators and targeted investments in our commercial model, our ambition is not just to grow, but to become standard of care for these patients.

I'll now turn the call over to Liz.

Thank you, Tom. I'm pleased to share some updates on our pipeline, where we continue to make encouraging progress across multiple programs that hold meaningful potential for the future. We've achieved some important milestones recently, including the successful initiation of our Phase II study for ACP-204 in Lewy body dementia psychosis and the initiation of our Phase III study of trofinetide in Japan.

Looking ahead, our next expected milestone is the initiation of a Phase II study for ACP-211 in the fourth quarter of this year. We are developing ACP-211 in major depressive disorder, a common condition with significant unmet need. Then in Q1 2026, we expect to initiate our first-in-human study of ACP-271 in healthy volunteers. To our knowledge, this will be the first time a GPR88 agonist enters the clinic, and it moves us along the path of development, targeting the indications of tardive dyskinesia and Huntington's disease.

We also have important projected study readouts coming. We anticipate reporting results from 4 Phase II or Phase III studies between now and the end of 2027, underscoring both the breadth of our pipeline and the momentum behind our R&D strategy. Our next major readout is expected to be ACP-204 in Alzheimer's disease psychosis in mid-2026. We're particularly excited about this opportunity and what success could mean for the future trajectory of our company. The unmet need here is substantial. The market opportunity is large, and we have built this program based on a substantial body of learnings from pimavanserin at both the molecule and the trial level.

Now switching gears to our international expansion efforts. First, I wanted to provide an update on the regulatory process in the EU for trofinetide. We've been informed by EMA that the earliest that a scientific advisory group could be held would be January. Given this, we now anticipate a CHMP opinion in the first quarter and the EC regulatory decision following the standard regulatory time line. Meanwhile, in Japan, we've successfully initiated our Phase III study, representing a key step towards potentially bringing trofinetide to patients in this important market.

Now before I close, I wanted to take a moment to acknowledge and thank everyone involved in our COMPASS Prader-Willi syndrome study and the ACP-101 clinical development program. We are so grateful for the dedication and contributions of the patients, families, study site personnel and physicians who participated. While the outcome wasn't what we hoped for, we hope that learnings from the trial will benefit the Prader-Willi community, and we're actively sharing our insights while we work to add the findings to the scientific literature.

Our pipeline continues to represent a powerful engine for future growth as we look to advance therapies for underserved neurological disorders and rare disease communities. We anticipate continued activity across our pipeline over the coming years with multiple programs progressing through key stages of development. As a reminder, across our 8 disclosed programs, we anticipate initiating 5 additional Phase II or Phase III studies between now and the end of 2026, demonstrating the depth and diversity of our development portfolio. And of course, we anticipate reporting 4 Phase II or Phase III study results in 2026 and 2027.

And now I'll pass over to Mark for a review of our financials.

Thank you, Liz. Let me walk you through our third quarter financial results. We delivered an excellent quarter that underscores the robustness of our commercial portfolio, which enables us to generate strong revenue and cash flows while continuing to invest strategically in growth opportunities.

The third quarter was strong across the board with $278.6 million in total revenues, up 11% year-over-year. DAYBUE achieved net sales of $101.1 million, up 11% year-over-year, all of which is attributable to volume growth. The gross to net adjustment for DAYBUE in the quarter was 22%. NUPLAZID delivered net sales of $177.5 million, up 12% year-over-year, with 9% of that growth attributable to volume. The gross to net adjustment for NUPLAZID was 25%.

Turning to operating expenses. R&D expenses were $87.8 million in the third quarter, up from $66.6 million in the third quarter of 2024, with the increase primarily attributable to higher clinical trial expenses from our ACP-204 LVDP and ACP-101 programs and personnel expenses, partially offset by lower clinical spend from programs that have completed. SG&A expenses for the third quarter were $133.4 million, essentially flat with the prior year. Turning to the balance sheet. We ended the quarter with $847 million in cash compared with $762 million at the end of the second quarter.

Looking ahead to our full year 2025 guidance, we're making targeted updates that reflect our strong performance and outlook. For NUPLAZID, we're raising the lower end of our guidance range and increasing at the high end to $685 million to $695 million, up from $665 million to $690 million, reflecting the momentum we're seeing in the business. For DAYBUE, we're modifying to include contribution from our named patient supply programs and narrowing our prior guidance range and now expect $385 million to $400 million compared with prior guidance of $380 million to $405 million for U.S. only.

Regarding operating expenses, we now expect R&D expenses of $335 million to $345 million compared with prior guidance of $330 million to $350. For SG&A expenses, we now expect $540 million to $555 million compared with prior guidance of $535 million to $565 million. Our financial strength positions us exceptionally well to finish 2025 strong while making the investments necessary to drive sustained growth in 2026 and beyond.

I'll now turn the call back to Catherine for closing remarks.

Thank you, Mark. As we wrap up today's call, I wanted to emphasize our commitment to finishing 2025, getting over $1 billion in total revenue, positioning ACADIA for continued growth in 2026 and beyond. We continue to be confident in the stability and growth trajectory driven by our new sales team for DAYBUE, reflected by the over 1,000 patients globally who are now on treatment.

We're focused on unlocking NUPLAZID's full potential with our strategic field force expansion and proven patient engagement campaigns. And we now have the elements in place to further accelerate that growth. We are dedicated to advancing our robust pipeline, as Liz has described, and look forward to the 4 major readouts expected in 2026 and 2027.

We also continue to focus on expanding our portfolio through business development with our strong balance sheet providing flexibility to pursue partnerships and acquisitions. Ultimately, our mission drives everything we do to turn scientific promise into meaningful innovation that makes the difference for underserved neurological and rare disease communities around the world. We are here to be their difference. I'm excited about what lies ahead for ACADIA, and I'm confident that our strategic investments and unwavering focus on our patients will deliver value for all of our stakeholders.

And with that, I'll turn the call back to the operator for questions.

[Operator Instructions] The first question comes from the line of Ritu Baral with TD Cowen.

I wanted to ask about the expanded NUPLAZID client-facing force. Catherine, how is that organized? Is it along the lines of focus on the newly activated prescribers? How should we think about it in terms of community versus long-term care facilities, which is a way that historically ACADIA has broken up the population for NUPLAZID? And which of those 2 has the most likelihood for continued growth as you see the market right now?

Thanks, Ritu. Appreciate the question. I'm going to ask Tom to explain. He's been leading this charge for us. So Tom?

Thank you for the question. So as we think about the expansion that, as we mentioned, we plan on executing in Q1 of next year, there's a few different factors, I would say, are playing into our thinking.

So as you think about kind of the new writer base, if we look at kind of dynamics during Q3, we actually saw that in terms of our overall prescription volume, 26% actually came from new writers. So I think this really talks to the way that our campaigns are working, the execution of the field force. And it's been that kind of underlying dynamic that we've actually seen throughout the year, but actually accelerated in Q3 that's really given us the confidence to pull forward this investment into Q1 of next year.

In relation to your question regarding community versus LTC, actually, we're seeing growth across all channels. We're seeing growth both in the community setting and in the LTC setting as well. And there are various channels that we see the NUPLAZID scripts being pulled through. So in essence, we're investing in both. If you're looking at it from an absolute kind of percentage terms, we're actually investing slightly more on a percentage basis in the community. But at the same time, we are going to be modestly increasing our LTC team just given the dynamics that we're seeing in that space as well.

So long story short, we're investing in both. And at the same time, making sure that wherever we see a NUPLAZID script, we're able to pull that through as optimally as possible.

Your next question comes from the line of Yigal Nochomovitz with Citigroup.

I have one on ACP-204. With the top line data for Phase II coming out middle of next year, I'd be curious if you could comment briefly on what you would see as a clinically meaningful score on the SAPS-HD score? And also, if you could just discuss related to that, why that particular scale is a good one to use in this context?

Thanks, Yigal. Liz is leading that for us. So I'm going to ask her to comment on the scales and the confidence around both...

Yes, absolutely. Thank you. So I'll go in reverse order, I suppose, and start with SAPS-H and D and why we landed there for Alzheimer's disease. So SAPS-H and D is actually an endpoint that we do have some experience with in our prior pimavanserin trials. It was involved in the pivotal study for PDP, and it was also part of the relapse criteria in HARMONY. And so overall, we feel like we have a good understanding of that endpoint and its responsiveness. It is well set to measure the domains that we think are important in this patient population. And it's one of several endpoints that are in the literature that are supported as being relevant for this patient population. We are measuring other things as well. So that is how we landed on this as the primary endpoint for the Phase II portion of this study.

In terms of how we're looking at this, I'll -- first, I'll note the powering piece, and then I'll talk a little bit about what we're looking for in this trial. In terms of how we size the trial, we actually did this on effect size, and so we're looking for roughly a moderate effect size, a 0.4 effect size on SAPS-H and D. But really, what we're looking for in the Phase II is to continue to understand how we progress towards our overall target product profile for 204 and that certainly has an efficacy component to it, but it also is about making sure that this is appropriate for use in this patient population. I think there are a number of important unmet needs here, sparing cognition, avoiding daytime sleepiness or sedation, avoiding increasing risk of falls or fractures, avoidance of motor adverse effects.

So there's a number of things we're going to be looking for that we feel good about based on what we know about 204's profile, but we're sort of holistically going to be looking at the profile of the drug in this trial.

Your next question comes from the line of Tess Romero with JPMorgan.

So for DAYBUE, you cited the highest quarter-over-quarter referral growth since launch this quarter. Double-clicking, how do you think new patient starts will look sequentially here over the next few quarters in light of the growth you are seeing? And second one is just a quick housekeeping. When do you think you will finish enrollment in the Phase II trial in ADP?

Thanks, Tess. I'll ask Tom to kick off about the referral dynamics we're seeing and we saw in the quarter and then about...

Yes. So thank you for the question. In terms of DAYBUE and referral dynamics, we're really encouraged by what we saw. In Q3, we saw actually our highest rate of referrals since essentially launch. And if you look over the last 12 months, we're really growing at a pretty decent rate now, which is very encouraging.

In terms of pull-through, just given standard dynamics that you would expect, it does take some time for a referral to then become an actual new-to-brand prescription. Given the dynamics that we saw during Q3 and the acceleration that we saw, we would anticipate that we'll continue to see growth in actual active patient counts through Q4 into 2026 and beyond.

Liz, do you want to touch on that?

Right. Sorry, 204. So again, just reiterating the predicting midyear for top line results here. We're really keeping a careful eye on enrollment for the right patient population. I don't have an exact date of final enrollment here, but we anticipate that, that would be occurring sort of in the Q2-ish time frame to enable that midyear.

Your next question comes from the line of Brian Abrahams with RBC Capital Markets.

Congrats on the quarter. Maybe another question on 204. Can you talk a little bit about maybe the overall study conduct, how you're feeling about that? And are there any -- I guess, any -- have there been any -- or will there be any looks at the blinded safety data that might inform the potential around having the QTc prolongation advantage or anything you could learn about things like risk of falls or some of the other aspects of the profile that you talked about that could give you kind of an early read into that?

So first, overall, pleased with how the study is progressing thus far in terms of behavior of sites, investigators, the patient population that we're getting in there. We are laser-focused on making sure that we are getting the right patients in here, trying to -- not trying to, we are verifying them with biomarkers to make sure that this is a biologically confirmed Alzheimer's diagnosis, which we think is going to be important.

From a blinded safety perspective, I'd say a couple of things. We do have a DSM-V that looks after this on an ongoing basis. So we would get any indication of anything that is concerning from that perspective. And thus far, they've been supportive of continuing the study on as planned. And we do monitor on an ongoing basis from just sort of medical monitoring perspective. That said, I don't like to comment on data from ongoing blinded trials because you never really know how that's going to sort out across arms.

Your next question comes from Ash Verma with UBS.

This is [ Leana ] on for Ash. Just wanted to get back to the risk-adjusted peak sales guide that you have provided at your R&D Day. What is your latest thought on the $2.5 billion and $12 billion peak sales you provided on risk-adjusted and nominal basis?

It's a little bit difficult to hear, but I think what you asked was how our -- how we're commenting on our peak potential that we talked about at R&D Day and our expectations for the commercial portfolio within that same discussion.

So let me talk about the overall aspirations for ACADIA. R&D Day, we shared that we aspire to achieve a $12 billion top line should all of our pipeline programs hit during the next 2 to 3 years. And as you know, unfortunately, our 101 program did not hit. And so we would take about $800 million to $1 billion from that top line expectation. So we would now -- if we were speaking about the same thing, aspire to achieve the $11 billion total peak sales of our currently shared portfolio within that same group of compounds.

In terms of our commercial aspirations, we shared the $1.5 billion to $2 billion for our commercial brands, NUPLAZID and DAYBUE, and we are still absolutely committed to deliver on that and look forward next year to share a little bit more clarity about both of those brands and our expectations for each of them so that you can understand where we see both of those in the next 2 to 3 years.

Your next question comes from the line of [ Sam Beck ] with Deutsche Bank.

This Sam on for David Hoang. Just a quick one from us on NUPLAZID. If you could just provide a little bit more detail on any drivers you're seeing behind the higher average net selling price in the quarter, that would be great.

Yes, I'll ask Mark to take the net selling price question around NUPLAZID.

Yes. I think at this point, I think when you take all the puts and takes that go into pricing and the fact that the majority or the super majority of sales for NUPLAZID are for Medicare-based patients, kind of our year-over-year pricing is about the rate of inflation. That's been our expectation the whole year, except for the kind of onetime pricing benefit in the first quarter, and that's really what we saw in this quarter.

Next from the line of Evan Seigerman with BMO Capital Markets.

Malcolm Hoffman on for Evan. For DAYBUE, with the CHMP opinion expected in the first quarter next year, how can you make sure scripts kind of get off the ground quickly after what could be a positive opinion there?

I'll let Tom take that. He's leading our European team. We're all getting ready for that right now. So Tom, why don't you share that?

Absolutely. So thank you for the question, Malcolm. So as you'd imagine, there's a significant amount of energy being put behind our launch readiness planning in Europe. We're going to be following kind of the standard track that you see for any approval in Europe. So we will be out of the gate first in Germany. And I can tell you, we're already gearing up to make sure that the team is ready to go there. So we already have a small group of key account managers. We have a handful of folks working on the medical side of the organization. And they've been very actively engaged already with prescribers -- well, actually with Rett treaters from across the universe. I mean, as you would imagine, each of the European markets looks very different to the U.S., but we are making sure that we have the right infrastructure in place, the right focus in place.

And I'm pleased to announce that actually in this quarter, we opened our compassionate use program in Germany and have already had a number of requests from German HCPs to enroll their Rett patients in that program, which we think is a very nice kind of early indicator of enthusiasm to use the product. And obviously, we'll be making sure that, that experience is positive as we build out towards the launch.

You want to share a little bit more about the other countries who have also opened their program in the last quarter?

Sure. So also pleased to announce that we have just opened programs in Italy and France. Again, we're pursuing wherever the regulatory and legal frameworks allow us to do so in early engagement programs. And as we mentioned on the call, we also have our ongoing rest of world patient access programs as well, which, again, encouragingly, we continue to see ad hoc requests in an unsolicited fashion coming through to the...

Your next question comes from the line of Sean Laaman with Morgan Stanley.

I have a question on the 30% increased investment to NUPLAZID. I guess, could you describe in percentage terms of how many new prescribers you might be reaching with that investment? And what's the headroom there before you get near saturation? And if you can provide any guide on quantifying what the cost of that investment is, that would be really useful.

Yes. I'm going to let Tom talk about the increase. And we'll go from there.

So as I mentioned a few minutes ago, we actually saw a very nice uptick during the quarter in terms of new prescriptions increasing through actual new writers, which was over 25% in the quarter. As we look ahead to kind of opportunities for growth and as we've really kind of done a deep dive on what that assessment looks like and where we see the opportunity, we see a ton of opportunity across a wider group of customers that we've been actually calling on to date. Just for reference, historically speaking, we've generally called on neurologists. We've called on some movement disorder specialists and some psychiatrists.

But as we look at that 26% who are new to writing prescriptions for NUPLAZID, a ton of those are now coming from primary care. There are often nurse practitioners or advanced practitioners that are now writing NUPLAZID. And in reality, we want to ensure that wherever that prescription is written, whether it be for a patient in the community or in the LTC setting that we're really highlighting the benefit that NUPLAZID can offer.

And just as a reminder, in terms of [ petroom ], our share in terms of NBRx remains in the mid-20% range. So if you just think about the upside opportunity that we have, given the size of the overall PDP population in the U.S., there is still significant headroom for growth, and that's what we're aiming to tap into in 2026.

And I'll let Mark share a little bit more about how we plan to make that investment.

Yes. I think in terms of people, it's about 50 customer-facing reps I think you can certainly use standard benchmarks for what that cost is. We don't dive into the exact cost at this level of detail, but consider 50 reps plus some home office support and other things that go around that for the kind of overall investment. And we'll just share this kind of within our guidance for SG&A expenses next year.

Your next question comes from the line of Tazeen Ahmad with Bank of America.

I maybe just wanted to ask about why you think now is the right time to add to the field force for NUPLAZID? And how are you deciding like what is the right size? Is this a final change or final increase that you think you need to make? Or are there certain targets that you might be monitoring? And if so, can you kind of share a little bit about how you are thinking about needing more or less people as this launch matures?

Yes, Tazeen, let me start, and then I'll let Tom dive into a little bit more of the details. I think as I came on board last year in September, the team had just started their DTC communications, both the unbranded and the branded. And we weren't sure how impactful that was going to be. We knew it probably would have some traction. But again, we haven't really been in the DTC space for a while since pre-COVID, and we wanted to understand the impact of that type of DTC investment. We've now got a year under our belt, and we can see, and you can see in the numbers, real traction in terms of cares and their families being made aware of what the symptoms of Parkinson's disease can be beyond motor. And then those sort of awareness levels now translating into moving into the physician office and physicians now also with our increasing real-world evidence and data generation around NUPLAZID being confident in prescribing it for the right patient to treat their hallucinations and delusions.

So all of those metrics have come together. And with the important IP win that we had for NUPLAZID, allowing us to continue to feel confident about our IP runway in the U.S., we felt it was time to reassess the opportunity for NUPLAZID. Tom has been leading that reassessment. And from that, he has made the decision and we have as a management team that it's right to invest now.

And so maybe, Tom, you can talk a little bit more about some of those investment decisions.

Yes. I mean I think Catherine captured it really well. I mean it's really been a story of momentum this year for NUPLAZID. And Q3, in particular, has really seen this kind of step change in how we're seeing referrals across the board. And I think given that momentum, that gave us the opportunity in the lens to really have another look at what our customer model look like, especially as you think about the world where we're seeing a number of new prescribers outside of our core kind of target base really beginning to latch on to the benefit that NUPLAZID can offer and really engaging with this community in terms of where they're engaging with health care professionals, which, as a reminder, it can be quite challenging to get time with the neurologist or with a PDP specialist.

And we think that with this expanded reach, we'll be able to actually help these patients really understand the benefit that they can afford and see with NUPLAZID beyond what we're doing today. So it's about really capitalizing on momentum and then ensuring that we have the right structure in place for both today and tomorrow to your question that we believe will put us in a really very strong position to maximize the opportunity ahead.

And just a final thought. We've been very focused at ACADIA on ensuring that we are building a company that's built on a foundation of analytics and insights and data. And within the new expansion, it's being fueled by analytics, data and insights, and we'll be using both that and AI on top of it to ensure that we really efficiently now find our patients and target them.

And so I think the combination of the new data being sort of driven by a focus on analytics technology. We have a new [ CIDO ] in place to help us drive that. And so I feel very confident that it will not only be an efficient focus, but also a very effective one.

The next question comes from the line of Jack Allen with Baird.

Congrats to the team on the progress made over the course of the quarter. I wanted to ask on the European opportunity for DAYBUE. I just want to...

Jack, you just cut out the end. I heard reimbursement in Europe. Could you just maybe just repeat the question for us?

Yes. Sorry about that. I hope you have me better now. Yes, I wanted to ask about reimbursement in Europe. I know there were in Canada over the summer. And what your thoughts are and your early conversations are around payers in Europe ahead of a potential European launch for DAYBUE?

Thanks, Jack. So yes, we are obviously in the middle of discussions and thinking right now around reimbursement in Europe. And you're right, we did have a disappointing decision in Canada.

Tom, do you want to share a little bit more about how we're thinking about reimbursement in terms of the sequential approach to that in Europe?

Absolutely. So as I mentioned a few minutes ago, our plan would be that we launch first in Germany. And as a reminder, in Germany, as we launch, we have 6 months of repricing, which we will obviously think very carefully about what that looks like, especially just given some of the other dynamics that we continue to monitor across the board, such as MFN. But I think given the engagement that we've already started with payers and clinicians, we remain pretty confident actually that our European clinicians and the broader environment are seeing the benefit that DAYBUE can offer.

And I think as we continue to generate new real-world evidence in the U.S., we're going to ensure that we leverage that as we go into discussions with European payers and beyond as well to really ensure that the value of DAYBUE is fully understood and realized across the markets where we're launching. So more to come. But again, I think we're excited about the opportunity in Europe and look forward to putting DAYBUE into the hands of many more patients who clearly deserve this treatment.

Your next question comes from the line of Paul Matteis with Stifel.

This is Julian on for Paul. I guess just on ACP-204, I was wondering if you guys could clarify the exposure response relationship you've sort of seen from pimavanserin and the work you've done on ACP-204. You often allude to like your learnings that you've had from development as well from an execution perspective as well as from a scientific and biological perspective and why you believe greater potency with ACP-204 will translate to greater clinical benefit?

All right. I'll try and get all the things that were in there. So starting with the exposure response. So both in the Alzheimer's disease population as well as in Lewy body, we do have some information from pimavanserin suggesting that with higher levels of exposure, you are able to get to higher levels of improvement on the clinical endpoints and that the median exposure that we're able to achieve with pimavanserin leaves some of that efficacy on the table. So it's sort of midway through that exposure response downward curve. And the reason for that, of course, is that unfortunately, with pimavanserin, there was a tendency towards QT prolongation, which limited the ability that we could dose range. So we were not able to push the average patient up to the near maximal efficacy that you could get with higher exposure levels.

With 204, we don't have that problem. So thus far, our nonclinical and our clinical data are supportive of the fact that there is not a signal of QT prolongation here. And overall, our experience has been such that it is supportive of moving to our current clinical doses, which we're looking at in our Alzheimer's and Lewy body programs, where the lower dose is roughly equivalent to the exposure with the marketed dose of NUPLAZID and the higher dose is roughly twice that. So those are the pieces that give us some optimism that we have the possibility of exploring higher levels of efficacy. But even if we are not able to actually achieve higher levels of efficacy with the higher doses, we do think that there are some program learnings that we're able to apply here.

Certainly, in both cases, we have programs that are focused specifically on the disease under study. The pimavanserin data in Lewy body is promising, but it's a limited number of patients. And the Alzheimer's program had a single dedicated study and then a subgroup in an overall study. So here, we're going to be able to bring to bear much more robust data evaluating both of these disease states. So those are the things that we take together to give us some real enthusiasm about 204, which, again, we see as potentially having the possibility of really changing the trajectory of this company.

Your next question comes from the line of Marc Goodman with Leerink Partners.

This is Basma on for Mark. We have a question on DAYBUE. You mentioned that the penetration is lower in the patients older than 11 years old. Do you believe that this lower penetration is driven by the higher discontinuation in this age -- in this older age group? The reason why we're asking this question is we would expect that the improvement in communication skills and other effects may be minimal in the older patients and maybe that's a lack of effect will drive greater discontinuations.

And also, could you clarify whether the age of Rett patients in general seeking treatment is skewed to the younger age group or it's basically uniform across the different age?

Thank you. I think there's some important opportunities there to clarify what the data actually says about DAYBUE efficacy across the age groups and to share a little bit more about what we're seeing in the field.

So Tom, do you want to answer it? And if Liz, you've got any efficacy points to add on top, that would be good.

Absolutely. So thank you for the question. So I mean, going back to the original premise, do we think that the reason that we are slightly lower penetrated in patients greater than 11 years and older is discontinuations? I don't think that that's the case. I mean, essentially, what we have to remember is the vast majority of patients who have been kind of treated so far, again, if we look at penetration by age are those in the 2 to 4 age bracket. Newly diagnosed patients, they're easy to identify, and they generally fall under the focus of the center of excellence. And I think that that's a group that we've been able to penetrate very early on.

If you look at the last quarter, interestingly, 65% of our patients were actually older than the age of 11. So it's a group of patients that we believe that we can really begin to penetrate further still. And especially with our LOTUS real-world evidence generation, which, as a reminder, has patients as old as 60 included in it, we do continue to see a group of -- well, we continue to see patients seeing benefit irrespective of age. And this has been part of the strategy as we've extended our reach beyond centers of excellence because many of these patients who are slightly older, unfortunately, they sit within the community setting, they may not be under the care of a COE, and they may not even be aware of DAYBUE. In fact, we just heard about a patient story yesterday for a patient in Kansas, who was receiving -- sorry, DAYBUE for the first time, but before they came into the center have never even been made aware of DAYBUE.

So I think it really does talk to the fact that we have more work to be done, both in terms of educating the community about what Rett is and what to look for and at the same time, ensuring that they understand the benefit that DAYBUE can offer to these patients irrespective of their age.

Liz, do you want to enhance a little bit on that? Or is there anything you want to add about the data that we've shared?

Sure. I mean -- so I agree with everything that Tom said there. I think that going back even to the original clinical trial, there is supportive data suggesting that there's efficacy in patients above 11 as well as below 11, though it is a somewhat smaller proportion of our overall patient population. But exactly, as Tom said, we've also been tracking these patients in LOTUS as well and see evidence of improvement in those patients as well. So I think that it is an increasing body of evidence that supports the fact that DAYBUE does bring benefit to patients in line with the indication, which is not restricted in terms of the age...

Yes, I think that's the key. We see DAYBUE efficacy across age ranges. And we want to ensure that neurologists and treating physicians are educated about the data and don't have preconceived notions about specific efficacy in specific age groups. And that's a big focus of Tom and Allyson and the team as we move into next year to really ensure that, that data is shared specifically to encourage the physicians that aren't so well versed in rat to really look at the data and think about it for all patients, not just younger patients. So with that, it's a good question.

Your next question comes from the line of Ami Fadia with Needham & Company.

This is [ Puna ] on for Ami. Congratulations on the quarter. My first question is we've seen some IRA impact feedback coming for therapies such as [ AUSTEDO ]. Is there any read-through for NUPLAZID based on this? Is this more positive than you expected? And my second question is, how is ACP-211 differentiated from SPRAVATO and the emerging psychedelic class in depression?

I'm going to ask Mark to answer the IRA question first, and then I'll ask Liz to talk about the differentiation of ACP-211.

I think on the IRA there's not a great comp yet for NUPLAZID as NUPLAZID is the first and only approved therapy for its indication. And so it doesn't have competition with other branded agents as well as we haven't seen a comp like that go through the IRA negotiation. So simply speaking, I think we'll see how this evolves as and if NUPLAZID goes through negotiations or others in a more comparable situation and that may or may not have read-through for what a NUPLAZID negotiation may look like.

As far as switching gears quite a lot to 211 as far as 211 is concerned. So we've designed 211 as an oral therapy. And what we're hoping for here is the potential for ketamine-like efficacy or SPRAVATO-like efficacy with a very different patient experience in terms of the degree of required in-office monitoring. And the data that we have so far supports that, both in terms of animal models that suggest efficacy as well as lacking sedative impacts or dissociation. And in healthy volunteers in our Phase I study, we've demonstrated the ability to reach high doses with no sedation and minimal dissociation.

We think if this reads through in our upcoming clinical trials, we are looking to start this Phase II in 211 before the end of this year. And we designed this, of course, to look at efficacy, but also very importantly, to rule out unacceptable levels of sedation and dissociation. So we think that there is a potential for a really appealing product here.

Your next question comes to the line of Salveen Richter with Goldman Sachs.

On the LBD psychosis study, can you just help us understand the rationale for enrichment of the Phase II with the additional patient groups, including [ LPP ] and the PDP population instead of just focused on Lewy body dementia psychosis specifically?

So Lewy body dementia psychosis is sort of an umbrella term that actually encapsulates dementia with Lewy bodies as well as Parkinson's disease dementia psychosis. And so what we're looking to do in our Lewy body program is actually ensure that we're looking at roughly equivalent numbers of both of those 2 patient populations to understand any similarities and differences in terms of how they behave. This will help us in terms of designing what future studies could look like.

When we look at the population in the pimavanserin data set that is specifically that Lewy body dementia psychosis, the numbers are relatively small, but it is very promising data, and that's part of what had us move this program forward and part of what makes us enthused about it.

Your last question comes from the line of Sumant Kulkarni with Canaccord Genuity.

You're investing more on NUPLAZID, and there have been some questions already about that. But we're finally seeing some excitement in the Parkinson's market then AbbVie recently announced the sales force expansion on the strength they're seeing for Vyalev and the potential approval for tavapadon. So how do you think this additional focus on the Parkinson's market from a relatively large player might influence the market or diagnosis rates for psychosis associated with Parkinson's?

So I'll start and then maybe give a perspective from Tom. I think -- so let's just start by reminding everybody that NUPLAZID is the only branded product approved for Parkinson's disease psychosis. But as we see more activity in an overall Parkinson's market, I think what history would tell us is that once more -- once larger companies are in the market talking about Parkinson's disease more fulsomely with more people, there does tend to be an increase in terms of awareness of different elements of the disease.

And as Tom has already alluded to, 50% of patients suffer from psychosis or suffer from the hallucinations and delusions of Parkinson's at some point during their journey. And so it wouldn't be unsurprising to sort of see that rate increase. What we do know right now is that there's a relatively low level of awareness amongst families and caregivers of those symptoms, which is why we've been putting effort behind the unbranded campaign. And that would still have to be true because those sort of non-motor-related symptoms generally go undiscussed and unfocused on by the physicians and their families. And what we have understood is that we need to continue to talk about them to ensure that those questions are raised.

As we continue to educate physicians with our expansion Tom, I think we probably hope to see that the physicians are starting to learn more about it themselves. But I don't think without us, it's going to be sort of a natural place for them to go with other companies, what would you say on that?

No. I mean one thing I would say, I mean, I think it's well recognized that Parkinson's in general is one of the fastest-growing neurological disease types in the United States. As a reminder, there's estimated to be about 1 million patients with Parkinson's in the U.S. And as we kind of then take a step down into those patients who are actually diagnosed with hallucination delusions, it's somewhere between 40% and 50% of that population at any given time. By our estimate, there's about 130,000 of those patients who are actually diagnosed atypical antipsychotic, pardon me, during the course of the disease.

That's not to say there's more work to be done here because I think if you look at most patients as they go through their Parkinson's journey, to begin with, they are fully focused on the movement elements of the disease. And unfortunately, not everybody is educated on hallucination delusions that can commonly concur. And I think one of the key calls to action that we're trying to drive at the moment that if a patient, even if early in their disease course is experiencing hallucinations or delusions that, that is a trigger point to start treatment. That's a trigger point to make sure that they're engaging with an HCP, whether it be a neuro or it be their primary care physician to make sure that they're having that dialogue to ensure that appropriate action can be taken. We believe that, that's where, quite honestly, NUPLAZID can play a really critical role just given its profile, given its safety profile and given the growing body of evidence that Catherine mentioned earlier on.

So I think taken together, clearly more upside, and I think that that's one of the reasons that we have decided that now is the time to really up-invest in our customer-facing approach to NUPLAZID as we look forward.

Now is the time is a great way, I think, to end that question. Thanks very much.

Since there are no further questions, I'll pass it along to Mrs. Owen Adams to proceed to closing remarks.

Thanks, everybody, for your questions. We're really excited about what lies ahead for ACADIA, and we look forward to our next call.

Thank you for your participation in today's conference call. This concludes the presentation. You may now disconnect.

Good morning, everyone. Welcome to Morgan Stanley Global Healthcare Conference. I'm Sean Laaman, Head of U.S. Mid-cap Biotech Equity Research here at the firm. For important disclosures, please see Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales rep.

For this session, we have the pleasure of hosting from ACADIA CEO, Catherine Owen Adams; CFO, Mark Schneyer; and EVP, Head of Research and Development, Elizabeth Thompson. Thank you for the time to you, and welcome.

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We'll get through just some macro questions just at the beginning, as I said I would. But Catherine, with China's rise in biotech innovation, how are you thinking about your competitive position here? And will this influence your R&D or business development strategy?

I think for us, with our focus on neuroscience and rare disease, for now, our focus on China has been, I guess, minimal. But I think what Liz and I recognize that there's a lot of activity going on in China. And part of the strategy of bringing on our new Chief Business Officer, Tina Katcheves, was that she has built up a big in [indiscernible] Asia Pacific, not so much R&D, but sort of BD Group. And so she has experience of looking for innovation in that region, and we are interested and looking forward to becoming more involved in the innovation in China. But for right now, not really.

Not really. And how are you currently leveraging AI or thinking about AI's future disruption potential?

Well, again, back to the C-suite. We've just brought on a new Chief Innovation and Data Officer, Scott Cenci, he came to us from Genmab. We understand the importance of getting ahead in AI. We believe it could be a differential growth driver for ACADIA being the size we are, we can actually possibly leapfrog others in terms of the way we use AI in terms of growing our business.

For now, we're looking at the possibilities in R&D and building that up in terms of using AI for all the things that probably other people are saying trial selection, data monitoring, trend analysis, all that good stuff, commercial as well and also then data mining our own internal data. So we're doing probably all the things that others are doing, but bringing Scott on is really going to help us accelerate that.

And last macro question for me, at least for now. What's been the most impact for ACADIA? Has it been Taris, MFN or FDA regulatory?

I'm going to let our CFO answer that.

Yes. I think we're monitoring MFN at the moment. Just with DAYBUE us going for regulatory approval outside the U.S., expectation for potential approval in Europe in the first quarter of next year and then pricing discussions with those countries thereafter, that's the element of these kind of 3 themes that we're kind of most focused on. No decisions really need to be made for more than a year from now. So we'll have some time to see how that evaluates. But that's what we kind of think the most about. I mean I could just touch on the other 2. What Liz is probably best to talk about kind of interactions with the FDA, but I'll mention that at least thus far for our portfolio, we've really seen no changes in our engagement with the FDA for the discussions that we've been having over the past number of months or year.

And on the tariff side, that's kind of more just small. I mean we do have inventory in the United States for multiple years for both our commercial products. So at least for the near to medium term, there's really no meaningful impact from tariffs.

Great. Any more color on the FDA part?

I mean, honestly, Mark covered it very well. Look, we're watching the space closely. I mean there's tremendous amounts of activity there, both in terms of overall employee level at the agencies as well as most recently as last week, there was a workshop talking about the potential for new regulatory pathways. So certainly a lot that is in flux there. But honestly, from a day-to-day basis, thus far, our interactions really have been unchanged.

Awesome. Maybe to get down to the central thesis a little bit, but NUPLAZID continues to perform well. And following on from the ruling on the 721 formulation patent exclusivity now out to 2038. Can you talk about the various factors that should influence NUPLAZID's uptake in the medium and the longer term?

Yes, absolutely. So NUPLAZID, as you know, we have reported really strong growth this year. And we put that down to the impact of our direct-to-consumer campaign. And why is that important? We have reestablished that this market is highly promotionally sensitive. And that when patients learn about the symptoms of Parkinson's disease that includes hallucinations and delusions, they tend to go to their doctor and ask about treatment, and we are the only branded treatment approved by the FDA, and therefore, NUPLAZID does get its fair share of prescribing and has a relatively high grant rate.

And so with that, we have continued to invest in our DTC campaign, and we'll continue to do that. We've also looked at our commercial structure. And I'm pleased to announce actually today that we're going to be expanding our NUPLAZID commercial footprint by about 30%, and we're going to go from roughly 160 reps to around 210. We haven't looked at our commercial footprint for 8 years since launch, and we've learned a lot.

Tom coming in, has reexamined it completely, and we're redesigning a lot of how we go to market and where we're going to go and where that growth could come from. But just in a nutshell, we have about a 20% branded share in the market, which with the only branded competitor, one would understand there's a lot of headroom for growth. And so we're looking forward to driving that harder. And we do expect that we'll be able to see more physicians in different parts of the country at a more frequent rate, but also more community physicians. So PCPs and what we've learned through the DTC campaign is more PCPs are prescribing for patients with Parkinson's disease. They don't necessarily go and see a motor specialist. So we're learning a lot about where we should go, how we should activate. And this will probably be in place by Q1 of next year.

Wonderful. It was kind of stealing a little bit from my next question, but I'll still ask it. How do you see NUPLAZID performing in terms of market share between community versus the long-term care setting? And how does that evolve over time as we move further out?

Right. So just a couple of numbers. Long-term care is about 22% of our business right now and we have in the mid-20s market share there. So actually slightly higher than our community, which is more of the low 20s, but obviously much more of our business. So we are looking to really drive harder at the community setting. As I've already sort of stated, going after a broader group of doctors who prescribe for patients with Parkinson's and really trying to also ensure that we're communicating our clinical data set, which has a very strong mortality benefit versus the off-label antipsychotics. And also trying to target patients earlier in their journey with Parkinson's. What we've done with Liz's team has looked at our data a bit more closely. And if you use NUPLAZID earlier in the journey, we tend to see better outcomes for patients.

So again, trying to move patients earlier in the journey, treat broader numbers of patients in the community.

Great. And still on NUPLAZID, could you map out the pathway with regulatory -- potential regulatory hurdles in front of us, whether it's IRA and remind us what the split between Part B and Part D is? And how do you think that unfolds?

Yes, I'll start and then Mark.

Yes. I mean the overall Medicare population as a percentage kind of the total book of business to NUPLAZID is kind of in the low 70s percent. So as the IRA has been implemented and what may or may not stick and change over time, certainly will influence our sales and net pricing for NUPLAZID. I think what you -- what kind of between now and the potential kind of next big event would be when would negotiation potentially happen.

So we think the -- where kind of our analysis does of NUPLAZID rankings in Medicare sales, we think 2029 is the first year that NUPLAZID will be eligible for negotiation, and we think that's a good estimate to make unless the pill penalty has changed. And if that comes into place, we'd probably add one more year of non-negotiated sales to NUPLAZID just be since the time of launch for NUPLAZID. So that comes into play. And I think when we think about it, there's no analog now for what NUPLAZID, it's the only indication -- only approved drug for its indication.

So those that have gone through negotiation, that's not been the fact pattern. So we're still going to have to see how this plays out. But I think you can think for modeling purposes, that we're a small company biotech. So between now and the end of the decade, I think net pricing will be kind of less than inflation for NUPLAZID. And then if we get to 2029 and beyond, we'll be subject to negotiation. So there could be a step down in net price. The first 2 years, whether it's 2029 or some later year, the first 2 years will be subject to protection for small biotechs and then after that could be full negotiation.

Got it. Got it. That's clear. Maybe moving on to DAYBUE. Can you comment on the changes that you've implemented over the past period? We've seen some good patient growth there. And given that, wondering if you can comment on what the issues were and what steps you've taken to address them?

Yes. So when I came in, in September of last year, the focus was very much on DAYBUE and stabilizing the commercial uptake of the brand, bringing Tom Garner in with his expertise. What we focused on originally or initially was execution as well as expanding the field force. So we did expand the DAYBUE field force by about 40%. That went into place at the kind of end of Q2. So we're really just seeing the start of that impact now.

The reason for that was we had initially focused our efforts on the centers of excellence, where about 35% of Rett patients treated, which gives you about 65% that are not treated there. They're treated in the community. And our sizing was such that we weren't able to get to those community physicians at the right reach and frequency. So with the new sizing, we're able now to get to those physicians. These physicians on average have 1 or 2 patients. They're less in the know about Rett. So they do need a little bit more education. They need a little bit more understanding. So we have a whole program to support them, starting to feel confident to prescribe DAYBUE.

And we believe that inflection in terms of additional new patient growth will start to kick in, in Q4 of this year, which is coming up soon. And so we're looking forward to that. And then beyond that, we've seen a stabilization of the discontinuation rate on DAYBUE. We've really learned a lot since the launch of the product. And we feel very confident now that we're able to talk patients and their families as well as physicians through how to start DAYBUE, what the options are around titration, all the management issues that are important in those first 3 months, and we're just seeing a much more stable patient base now. So we're now building on that compounding growth of stable patients.

Awesome. Thank you, Catherine. How should we be thinking about the overall launch trajectory or trajectory from here given maybe only 20% penetration in the community setting.

Yes. We're definitely in the mid-20s, low 20s for the community. So we're looking to get that up, where compare that to the centers of excellence, we've got about 50% to 60% of penetration. So those are the sort of the 2 ends of the bookend right now. That will be slower to get there because, as I say, it's doctors who treat 1 or 2 patients, but we have a long patent life on DAYBUE out to 2036. So we're steadily going after it. So we'll see that inflection point as the team kicks in. And then on top of that, I think it's important to remember, DAYBUE is -- our mission is to make it a global brand.

We have regulatory approval ongoing in Europe right now. We're looking to get it approved in Q1 of next year. We also have initiated a named patient program globally for patients who are interested in countries that have a regulatory framework where they can access the product. And we're now seeing patients from around the world being able to access DAYBUE through our named patient program. So we're on our way to ensuring that more patients around the world can access DAYBUE.

Wonderful. It certainly seems like there's a whole new rigor since you came along. Maybe some pipeline questions and -- sorry, Elizabeth. But ACP-204, can you give us an overview of the molecule and how it's differentiated from NUPLAZID?

Sure. So ACP-204 is our new 5-HT2A inverse agonist. And we built this really to build upon learnings from NUPLAZID from pimavanserin. I've got to say that NUPLAZID is a great drug doing really good things for patients. There were some things that we were looking to optimize with a next-generation molecule. And so the first disease is that NUPLAZID does have some QT prolongation. At the marketed dose is low enough to not be clinically meaningful. But in elderly and frail patients, you need to think about that just in and of itself, and that was going to be the target population we were looking at for 204. And the other important thing about that is that it limited our ability historically to dose range with pimavanserin. So -- and why that matters is that there is within the PIM data set, some suggestion of an exposure response relationship for efficacy, suggesting that we might be able to get more efficacy out of this mechanism with higher exposures.

So 204 does not, based on our learnings from both nonclinical and Phase I data so far, doesn't appear to have this risk of QT prolongation. And so that gives us the ability to dose range further. So in our currently running programs, we're looking at a 30-milligram dose and a 60-milligram dose and roughly how to think about that is that the 30 milligrams is roughly the exposure that you see with currently marketing NUPLAZID and the 60 milligrams is twice that. So there's a possibility in this program that we could be looking at higher efficacy.

The other thing to think about is that we were looking for faster time to steady state. NUPLAZID takes a while to work, and that has been one of the reasons that has been sort of a challenge with it in some of these urgent cases. Even 204 probably is not going to have an onset of action that's going to be enough to deal with a true urgent situation. But we're looking at a substantially faster time to steady state. So there's at least that potential for faster onset of efficacy. So those are the things we were looking for with 204, and our data thus far are very supportive of them.

Sure. So confidence is reasonably high, it sounds like on 204. And maybe map out for those newer to the ACADIA storage, the opportunity in ADP versus PDP.

Yes. So 204, we're looking at it in 2 different areas: ADP as well as Lewy body dementia psychosis. But for now, I'll focus on the ADP and then I can expand as desired. So Alzheimer's disease impacts roughly 7 million patients in the U.S. and about 30% of those have psychosis, which is hallucinations and delusions. So it's a pretty substantial patient population and really a critical unmet need. These aspects of disease are one of the main driving forces that make it difficult for the patients to stay in the home, for example.

So clear screening unmet need in this area. NUPLAZID historically was looked at in ADP in a Phase II trial as well as that was a component of a Phase III program that was run. And there were some encouraging data there, but definitely not enough to get over an FDA regulatory hurdle. We think that we have the opportunity here with a study that is designed focusing in specifically on the ADP patient population to demonstrate impact clinically and statistically in that patient population.

We have a currently running Phase II study that's part of an overall Phase II, Phase III program. There's seamless enrollment, but statistically, they're separate. And so that means that we're going to be able to analyze and report on data from the Phase II component, and we're currently anticipating that will be roughly middle of next year that we'll be able to do that and then take those learnings to anything that needs to be applied to the Phase III.

Wonderful. And I guess maybe map out the competitive landscape in ADP. What's it look like?

Yes. So I think that Alzheimer's disease broadly is a very dynamic space right now. Certainly, we have the disease-modifying mechanisms, which is potentially a great step. That said, no matter how you look at those data, they slow progression. They don't stop it. And so we do anticipate that psychosis is unfortunately going to continue to be a part of these patients' journeys. There are a number of different mechanisms that are looking at ADP, are looking at agitation or looking at irritability.

There's a constellation of different symptoms that are impactful in this patient population. This is -- again, I'm going to go back to, this is a huge number of patients and massive unmet need. I fully anticipate there's going to be room for multiple agents to address multiple facets of the disease.

Wonderful. Thank you. Another asset, there are many, but another asset we're particularly interested in is ACP-101, and we got a lot of investor inbound on that one because of the successes at Soleno and it went from 0 market cap to a lot of market cap, almost approaching your own on one product. And that's really interesting to me from an investment standpoint.

But earlier this year, you accelerated the Phase III readout. So that's the hyperphagia and Prader-Willi syndrome to early Q4.

Can you help us walk through what this disease is? It's much more serious than what I anticipated from your R&D Day presentation. And how does it manifest? And what are the current standards of care?

Yes. So Prader-Willi, and thank you for the call out to R&D Day. For those of you who aren't able to take part of it, we not only provided our perspective on it, but had one of our key physicians as well as a patient advocate and mom, to talk about what this disease really is like for a family on a day-to-day basis. And it's extraordinary listening to her talk about it. Briefly, Prader-Willi is a rare neurobehavioral genetic disease. It results from abnormalities on chromosome 15. It is complex in its manifestations, but one of the key facets is something called hyperphagia, which is this just driving need to eat.

These patients never feel full. And as Susan, who is our mom who talked about it, they feel like they're starving all the time. And this can result in a number of different kinds of behaviors. But as you can imagine, there's a lot of anxiety and food-seeking behaviors. And unfortunately, these kids and these adults, they will eat food out of the trash. They will eat things that are spoiled just because they have this continuous need. So it is hugely impactful, both in terms of just a family's everyday life, they have to have their cabinets locked and their refrigerators locked and take out trash every day. They're not able to go out to eat often. It impacts every aspect of life.

And if untreated or if not adequately treated, these patients will eat without ceasing. It can result in obesity. It can result in acute terrible outcomes. So just impactful across the board. I've referred to a lot of how patients are managed right now, and it's by limiting their access to food and then a lot of sort of cognitive behavioral, getting people comfortable with the fact that they're going to be told exactly when they're going to eat and exactly how much food they're going to get so that they can predict to help manage some of the behaviors associated with it.

There is a new entrant in this space in terms of an actual FDA-marketed medication. VYKAT is the first. This was a great step for patients because there has been nothing, and this is a patient population that has been questing for something for a very long time. But -- we think that there is, one, 8,000 to 10,000 patients in the U.S. And so there's certainly enough patients that more than one medicine is going to be necessary.

And two, we think that it's very -- and Dr. McCandless, one of our KOLs, who spoke at R&D Day, talked about the fact that you're going to want to be able to match the medicine to the patient in front of you and what their needs are as well as the things that you want to minimize the consequences of for them. So we think it's going to be a great thing if we're able to have more than one medicine here. And if we see the kind of results out of this Phase III trial that we're hoping for, we think this will be a great thing for patients.

Wonderful. And why do you have confidence in carbetocin as being an effective treatment for this? And on to the Phase III data. What's the bar for the HQCT9 score that you think you need to demonstrate.

Yes. I'll start with -- there was a prior Phase III that was run, and I can talk a little bit about the details there. But basically, in terms of what would make me happy to see from a data set, I'd be very pleased with something coming out of our currently running study where we expect those results in early Q4 with the magnitude of results that looks similar to what we've seen with the magnitude of results with the 3.2 milligram dose in the prior trial. We believe that this is going to be meaningful, but we also hear it routinely from KOLs as well as the patient advocacy community.

Wonderful. This is a very Michael Riad question, but I think it is. ACP-211, very exciting program, but one I think the Street is yet to wake up to. Can you talk about deuterated non-ketamine? Maybe touch on the history with SPRAVATO and ketamine.

Okay. ACP-211, thank you, is our oral deuterated [indiscernible] ketamine, which is targeted at treating major depressive disorder. It is related to but distinct from SPRAVATO, which is Esketamine and [indiscernible]. That said, I think SPRAVATO has been a great drug for patients who are struggling with depression from an efficacy perspective. From a patient experience perspective, based on the fact that there has been sedation and dissociation seen with it, patients do need to stay in the office for many hours under observation to make sure that they are not having one of these impacts that would get in the way of them being able to go about their daily lives. What we're hoping for, for 211 and what thus far, animal data and our early Phase I data seem to be supportive of is an efficacy profile that is similar to what's seen with SPRAVATO, but avoiding the sedation and dissociation that really limits that patient experience. I think it would be pretty impactful for patients to be able to get that kind of benefit without having to sit around in their physician's office.

Sure, sure. Thank you. Catherine, it seems like on the top line, it's kind of more cemented in for growth, and there seems to be a bit of a confidence from investors around that given the stock price performance. And I think people begin to focus more on the bottom line and what to expect from OpEx and R&D. And what planks can you throw out there for investors to think about how does the cash flow from this business look like? And it seems that the R&D pipeline is a bit of an underappreciated element of the story. So putting that all together.

I'm going to let Mark talk about it.

I mean we have tremendous operating leverage in the company, right? I think for us, you can see sales grow from here. Catherine mentioned an additional investment that we're going to make in expanding our commercial footprint for NUPLAZID, but that's modest in the grand scheme of our total OpEx spend. And then for long-term growth, we're going to be investing in the pipeline and continue to invest in business development to broaden that.

If you assume kind of just normal rates of attrition between the total OpEx and the sales growth, as I just kind of started with, there's tremendous operating leverage, and that will bring increased cash flow. If we wind up in the embarrassment of riches where everything in the pipeline is successful, maybe the leverage is different, but the value creation would be phenomenal. That would be a very -- not necessarily predictable or expected, but it's certainly a welcome result.

To sort of build on that, I think what we wanted to do at R&D Day was really sort of put some numbers to the underappreciation of the pipeline and try to describe what we think these drugs could do if they were each successful in their own right. And we believe every drug we talked about at R&D Day could be a blockbuster drug, each of them over $1 billion, some up to $2 billion, $3 billion, $4 billion, depending on how successful. So I think to your point about underappreciation, it's definitely there. But what we haven't done, I think, so much in the past is talk about it more specifically, which is what Liz is now bringing to the equation and really talking about our belief and our trial design and all the things that we're doing differently. And so I think those 2 things together gives us a lot of confidence to the pipeline. Hopefully, a couple of those will be positive shots on goal.

Sure, sure. Awesome. And how much inbound do you get now on the pipeline? I mean we get a bit more from the Soleno angle, but it most...

Mostly. I think since Liz and I joined, which was roughly around the same point last year, we've gone from talking about diarrhea with DAYBUE to actually talking about the business, which we have in front of us, which is our pipeline.

Now that must be a pleasant change.

It is quite pleasant.

I talk much more than I used to...

And the pipeline is bubbling away and you are generating cash. And how do you balance that looking forward, investment in earlier-stage programs, looking at potential business development opportunities. How is that balance?

Yes. So I think as a team, we're excited to invest our pretty strong balance sheet into some more opportunities to enrich our pipeline. We know that to get us to the next level of growth, which we aspire to get to, we need some inorganic growth. I think in terms of putting our money where our mouth is, bringing in a new Chief Business Officer, who has more experience in more complex larger deals as well as global deals should tell you a little bit about the strategy that I have, we have for the company moving forward.

We have a lot of early-stage programs as well that Liz hasn't shared yet. She will in the fullness of time. But in terms of our BD approach, we're looking at rare as a totality, not just neuro-rare. And we're looking at enhancing our pipeline with some later-stage molecules. And we're still holding our bar pretty high. We have a first-in-class or best-in-class filter as well as an opportunity to put the product into Liz's team and have their capability to really accelerate its potential as well as the commercial team we're building.

So we're looking at it through, I think, some pragmatic lenses of what can ACADIA do for molecules and how can we compete to win in that space, but we're excited to spend the money appropriately and we're keeping our balance sheet steam, which Mark keeps us focused on.

Yes. I mean we let the data speak for the investment. So I think for us, we'll lean in to invest behind strong data, strong commercial opportunities. And then when it's not there, we'll pull back. And it's not a metric of R&D to sales that we're managing towards. It's towards leaning in to invest for growth and value and finding the things externally to add to the pipeline and continuing to rigorously invest behind what's in the pipeline as long as the data supports the next investment.

Sure, sure. And I know we touched on this just before we came up on stage, and we did talk a little bit about China, but I'm not sure how much this is appreciated. If you look at the innovation in China, it's really focused on oncology, immunology, cardiovascular. But where it doesn't overlap in terms of therapeutic indications is not much anyway, is neurology and rare disease, and there's probably reasons for that. But just to reiterate your views on that, are you seeing competition in those areas in China? Or it's still going to remain the hub of U.S. innovation?

No, I think, listen, we're interested in what's going on in China. As I said to you off stage, when I was at Bristol, I ran at Asia Pac, I know the space, and I'm interested to find innovation there that is going on. I think neurology particularly has been a little bit of a lagging place of innovation. Rare, I think actually is sort of bubbling up in terms of opportunity. And we're looking hard at where we can either source innovation and/or expand our ability to do clinical trials outside the U.S. and Europe, again, looking at more global footprints for our clinical trial space. We're looking at everything. And we're a company of 800 people with 4 billion market cap. So again, we have to do that within the bounds of possibility for ACADIA, but I think we are excited to look outside of the U.S. and look at China and Asia and Japan.

Wonderful. We've got a few minutes left. So with that said, is there anything that I should have been asking that I didn't ask?

I think you've been fairly comprehensive. I can't think of any topic that we haven't covered.

I think it's the full gamut.

Okay. Well, maybe one last thing, just give you an opportunity to leave investors with a message.

Yes. I think, listen, we're excited about the opportunity that ACADIA has to drive value inflection points over the next 2 to 3 years, which we think are potentially significant. Liz, I think, showed that at R&D Day. We've got our Q4 results for ACP-101 coming up soon. We have a big readout next year for 204 on our Phase II data. And beyond that, your pin number, 25.

2679...

[ 252679 ]. All the opportunities we have for Phase II and Phase III studies coming up for the next 2 to 3 years. We are a solid now C-suite team of very experienced executives who are here to ensure that we drive and grow the top line for our business, but also really represent those underserved patients who have high unmet medical need in both neurological and rare diseases.

And we're excited to bring some new innovation, even more innovation than we've shared already in the coming years.

Well, wonderful. We're 1 or 2 minutes early, but I think that's...

Could I explain my pin really...

That would be great.

Just for anyone who didn't catch that at R&D Day, 2 is the number of currently marketed products that we have. 9 is the number of disclosed programs. There are more undisclosed programs. 7 is the number of Phase II and Phase III starts that we expect to have in the next couple of years, and 6 is the number of Phase II and Phase III readouts we expect between now and 2027.

Nicely done, Liz, well remembered.

All right. Well, thank you team. It's been wonderful to host you, and thanks for attending our conference. Most appreciated.

Thank you, guys. Appreciate the time.

Good day, ladies and gentlemen, and welcome to the ACADIA Pharmaceuticals Conference Call. My name is Gerald, and I'll be your host for today. I would now like to turn the conference over to Al Kildani, Senior Vice President of Investor Relations and Corporate Communications at ACADIA. Please proceed.

Thank you. Good afternoon, and thank you for joining us on today's call to discuss ACADIA's second quarter 2025 financial results. Joining me on the call today from ACADIA are Catherine Owen Adams, our Chief Executive Officer, who will provide some opening remarks; followed by Tom Garner, our Chief Commercial Officer, who will discuss our commercial brands, DAYBUE and NUPLAZID. Also joining us today is Elizabeth Thompson, PhD, Executive Vice President, Head of Research and Development, who will provide an update on our pipeline programs; and Mark Schneyer, our Chief Financial Officer, who will review the financial highlights. Catherine will then provide some closing thoughts before we open up the call for your questions. We are using supplemental slides, which are available on our website's Events & Presentations section.

Before proceeding, I would like to remind you that during our call today, we will be making several forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, timing of events, future results and 2025 financial guidance are based on current information, assumptions and expectations that are inherently subject to change and involve several risks and uncertainties that may cause results to differ materially. These factors and other risks associated with our business can be found in our filings made with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date, and we assume no obligation to update or revise these forward-looking statements as circumstances change, except as required by law.

I'll now turn the call over to Catherine for opening remarks.

Thank you, Al, and good afternoon, everyone. Our second quarter performance reinforces the momentum we're building across all facets of our business from commercial strength to our clinical pipeline and global expansion. We delivered total revenue of $264.6 million this quarter, driven by strong growth across our portfolio. This includes $96.1 million from DAYBUE with patient uptake continuing to grow for the second successive quarter and $168.5 million from NUPLAZID, bolstered by new patient starts and commercial execution.

DAYBUE has now passed stabilization, moved into growth and is entering a new phase, expansion and acceleration. Our investments in patient support, community engagement and field expansion are starting to make a positive impact, as Tom will highlight in more detail.

On NUPLAZID, we're encouraged by continued growth across all leading indicators, bolstered by recent litigation wins enforcing our intellectual property. These victories validate our long-term strategy and reinforce our ability to deliver NUPLAZID to patients through 2038. Our full year revenue guidance reflects this confidence. We are raising the low end of our NUPLAZID guidance based upon a foundation of disciplined execution and momentum delivered by our DTC campaign.

We also hosted our first R&D Day, a milestone event that showcased our exciting and expanding pipeline, with 9 disclosed programs in development and 5 Phase II or Phase III data readouts expected through 2027. The excitement within ACADIA is palpable. Liz will walk you through that shortly. First, let's start with commercial. Over to Tom.

Thanks, Catherine. Let's begin with DAYBUE. Q2 sales were $96.1 million, up 14% from a year ago. We observed steady progress across key performance metrics in the quarter. In Q2, 987 unique patients in the U.S. received paid shipments, increasing from 954 in Q1 and 920 in Q4 2024. The upward trend reflects encouraging signs of growth in both new patient starts and persistency.

Long-term persistency remains a key strength for DAYBUE. Our 12-month persistency rate continues to exceed 50%, and we're now pleased to report that our 18-month persistency rate is above 45%. This trend reflects the growing and stable base of patients who remain on therapy over time. When we look at length of treatment among patients currently on therapy, 70% have been on treatment for at least 12 months, highlighting the sustained benefits that DAYBUE continues to deliver and the durability of our growing patient base.

Notably, we're seeing more new prescriptions from the community setting, signaling progress in broadening reach beyond academic centers, which was a key element of our field force expansion, which is now complete. We finished hiring and training earlier this quarter, and we're already seeing encouraging signs that the new customer model is gaining traction. One of the most promising indicators in the second quarter is a meaningful uptick in our proportion of new referrals coming outside of Centers of Excellence, where a majority of Rett patients receive their primary treatment.

Encouragingly, this increase was underpinned by a further increase in the number of new community-based writers for DAYBUE with 900 total HCPs now having written. Additionally, we launched a direct-to-consumer campaign for DAYBUE in July, and we are already seeing positive signs of early engagement from the Rett community.

During Q2, we welcomed Allyson McMillan-Youngblood as Senior Vice President of our Rare Disease Franchise. Allyson brings a breadth of commercial experience across the U.S. biopharma business, including many launches. Her leadership will help to drive this critical business forward.

As we look ahead with the expanded team now in place, we're continuing to execute against our strategy to drive long-term sustainable growth for DAYBUE. We expect this will translate into an increase in new patient starts towards the back end of the year. At the International Rett Syndrome Foundation meeting in June, our presence as a leader in the Rett therapy field was felt. As Liz will detail, we shared multiple compelling posters that add to the body of evidence for DAYBUE.

Let's now turn our plans to trofinetide outside the U.S. In the EU, where the prevalent population is estimated to be between 9,000 to 12,000 Rett patients, named patient supply as requested by local HCPs is available through Clinigen. We've received requests from multiple countries and are continuing to support patients where regulatory frameworks allow. Named patient supply based upon HCP request is also in place in Israel through Rafa and in selective rest of world countries through FarmaMondo. Overall, we're pleased with the continued momentum of DAYBUE in the U.S. and with the global interest in trofinetide, where we have already started serving patients through these programs.

Now turning to NUPLAZID. Our commercial team delivered another strong quarter with revenue of $168.5 million, up 7% from a year ago, driven primarily by volume. We saw strength across all key metrics in Q2. Referrals were up 17% year-over-year, driven by continued momentum in our direct-to-consumer campaign. As a result, for the first time ever, both referrals and new prescriptions increased sequentially from Q1 to Q2.

Another of the quarter's highlights was shipping the highest number of NUPLAZID bottles since launch, a strong indicator of growing demand as we continue educating both health care providers and patients with PDP about the product's unique and differentiated profile. The DTC campaigns are doing exactly as we intended, sparking meaningful conversations with health care providers and reinforcing our commitment to educating caregivers about the symptoms of hallucinations and delusions related to Parkinson's disease. Visits to nuplazid.com have surged with a 17-fold increase in consumer traffic year-over-year, helping to drive more patients to speak with their physicians. To carry this momentum forward, we're pleased to extend our agreement with Ryan Reynolds and the More to Parkinson's campaign through February of 2026. The campaign continues to drive meaningful awareness of hallucinations and delusions in Parkinson's disease, and we believe a strong push through year-end is essential to build on that success.

This quarter's NUPLAZID results reflect the strong executional focus of our field teams, coupled with the ongoing positive impact of our DTC efforts. Taken together, we expect to see sustained growth through the second half of the year and beyond.

And with that, I'll hand it to Liz to review our pipeline progress.

Thank you, Tom. Let me begin by revisiting the highlights from our inaugural R&D Day held in New York on June 25, where we showcased the strength and breadth of our pipeline. We were pleased with how the event came together, and I want to thank many of you on this call who were able to join us. While we had already disclosed all the programs on this chart, R&D Day gave us a great opportunity to provide more details, particularly for 2 newer molecules. The first is ACP-211, an orally administered, selectively deuterated form of R-norketamine, which we're developing for the potential treatment of major depressive disorder. Data to date support the potential for efficacy without significant sedation or dissociation, a profile we will continue to explore in Phase II and beyond.

The second is ACP-271, a GPR88 agonist with potential applications in tardive dyskinesia and Huntington's disease. This is some of the most novel biology in our pipeline, and we believe it to be the first GPR88 agonist that will enter clinical trials.

If you weren't able to participate in our R&D Day, I highly encourage you to visit our website, where you can access the webcast and the full set of presentation slides. The event was a clear demonstration of the momentum building across our pipeline. We're advancing with purpose and clarity, and the progress is tangible.

Across our 9 disclosed programs, we anticipate initiating 7 Phase II or Phase III studies over the course of 2025 and 2026. Moreover, between 2025 and 2027, we expect 5 Phase II or Phase III readouts. These milestones underscore both the breadth of our pipeline and the strength of our R&D strategy.

Specifically, we have several important trial initiations and data readouts on the horizon. In Q3 2025, we plan to initiate a Phase II study of ACP-204 in Lewy body dementia psychosis. Also in the third quarter, we expect to initiate our Phase III study of trofinetide in patients with Rett syndrome in Japan. In early Q4 2025, we expect to report top line results from the COMPASS PWS Phase III study of ACP-101 in Prader-Willi syndrome following the completion of enrollment in Q2. Also in Q4 2025, we anticipate initiating a Phase II study of ACP-211 in major depressive disorder. Wrapping up the year, we plan to begin a first-in-human study of ACP-271 in healthy volunteers before year-end. And finally, we also continue to progress through the review process with EMA for trofinetide with agency decision expected in the first quarter of 2026.

In addition to these upcoming milestones, we continue to make meaningful contributions to the scientific literature for our marketed and pipeline products. The second quarter was a busy one for ACADIA-relevant medical meetings with major conferences for Rett syndrome, Prader-Willi syndrome and Alzheimer's. First, there were multiple DAYBUE-related presentations at the International Rett Syndrome Foundation meeting, continuing to expand the body of evidence describing DAYBUE's long-term impact in the Rett community.

Several posters focused on caregiver reported outcomes and real-world data, which importantly continue to align with what we have observed in clinical trials. Additionally, there were analyses evaluating treatment utilization in less commonly studied populations such as males and older patients. And finally, ACADIA shared an analysis of our clinical trial data suggesting that most patients who are going to benefit from DAYBUE show a response within 6 months, reinforcing our guidance to providers and caregivers. Together, these data points reflect a growing and maturing evidence base that continues to shape how DAYBUE is understood and used in the real world.

In the pipeline, both ACP-101 and ACP-204 teams had important meetings in the quarter. In Prader-Willi syndrome, the end of June marked the United in Hope meeting, the joining together of 3 separate PWS organizations in a combined meeting. Those of you who tuned in to R&D Day will recall that our PWS panel, in part, was live from United in Hope. As we await data out of our Phase III trial, we nevertheless are contributing to the knowledge and understanding of PWS with posters about the experience of patients and families exploring comorbidities and the associated burden.

In the Alzheimer's space, I'm also pleased to report multiple ACP-204 presentations at the Alzheimer's Association International Conference held last week in Toronto. This meeting represented a significant step in our public disclosure of detailed data from nonclinical and early-stage clinical studies supporting ACP-204's attainment to date of its desired profile. Presented data included the specificity for 5-HT2A and the supportive PK profile, indicating a faster time to steady state, support for daily dosing, the lack of QT prolongation and the ability to dose with and without food. We also shared clinical data, primarily focused on the 60-milligram dose across several Phase I trials with supportive safety and tolerability profiles to date, including in healthy elderly subjects. Collectively, the data provides support for the potential utility of ACP-204 and key aspects of its target profile.

Lastly, I'll touch briefly on ACP-101, where we continue to expect top line results in early Q4. Just as a reminder, this is a 12-week placebo-controlled parallel group study. That design is important because, if successful, it would allow us to clearly describe for physicians and patients what to expect upon initiating therapy in a Prader-Willi syndrome patient population. Should the data be positive, we anticipate being in a position to file in the first quarter of 2026. And we continue to anticipate that this will qualify as a resubmission with the FDA with the associated shorter potential review clock with a potential PDUFA date in the third quarter of 2026.

And now I'll pass over to Mark for a financial overview of the quarter.

Thanks, Liz. Let's now review our second quarter 2025 financial results. The second quarter was strong across the board with $264.6 million in total revenues, up 9% year-over-year. Second quarter DAYBUE net product sales of $96.1 million represented 14% year-over-year growth, including 12% volume growth, primarily reflecting the increase in unique patients receiving shipments in the quarter. The DAYBUE gross to net adjustment for the quarter was 23.3%.

Turning next to NUPLAZID. Second quarter net product sales were $168.5 million, up 7% year-over-year with 5% of that growth attributable to volume. The NUPLAZID gross to net adjustment for the quarter was 24.6%. R&D expenses were $78 million in the second quarter, up slightly from $76.2 million in the second quarter of 2024.

SG&A expenses for the second quarter were $133.5 million, up from $117.1 million in the second quarter of 2024. The increase was primarily driven by increased expenditures for both DAYBUE and NUPLAZID in the U.S., including the planned expansion of the DAYBUE commercial team. We ended the quarter with a cash balance of $762 million, up from $681.6 million at the end of Q1 and $756 million at the end of 2024.

Let's turn to our 2025 guidance. We are raising the low end of our NUPLAZID guidance range, reflecting the strength of the business and its performance to date. We now expect NUPLAZID net product sales for the year to be between $665 million and $690 million. This compares with our prior guidance range of $650 million to $690 million. Accordingly, we are also adjusting our U.S.-only total revenue guidance to reflect this change. As you can see on the slide, we are reiterating all other prior guidance ranges from our Q1 call. We're confident in our ability to execute against these targets and to continue creating value for patients and shareholders.

I'd now like to hand it back to Catherine for closing remarks.

Thanks, Mark. As you've heard, quarter 2 was a quarter of progress and momentum. Our teams are executing with urgency and precision, and we remain focused on accelerating DAYBUE's commercial trajectory, sustaining long-term growth and differentiation for NUPLAZID, advancing a deep pipeline through rigorous clinical development and continuing to build the pipeline through business development and expanding globally to reach more patients in need. The next major milestone is ACP-101's data readout in early Q4, and we're hopeful for what that could mean for families living with Prader-Willi syndrome.

Thanks for joining today's call, and thank you for your continued support of ACADIA. And I'll now open it up for questions. Operator?

[Operator Instructions] Our first question comes from Tess Romero from JPMorgan.

So I actually wanted to ask about ACP-101 today. Liz, maybe could you orient us to the approach you plan to take with your top line? How much detail will you provide? And will this be more qualitative or quantitative in nature? And are there any secondary or other end points that you will think will matter beyond HQCT? And then as a follow-up, where are you really most focused from a clinical trial conduct perspective to manage any key risks?

Thanks, Tess. Great question. So in terms of our approach to top line and for that matter, in terms of our approach to how we're thinking about this trial, first and foremost, is the primary end point and success there. We will be looking at our secondary end points, which are a combination of clinician assessments as well as a responder bar for the HQCT as well. In terms of what we're going to release, certainly, I would anticipate that there would be a focus on the primary end point and sort of key overview of safety and tolerability. And that's what you should anticipate out of our top line announcement.

In terms of the areas that we are focusing on in terms of clinical trial conduct, we have been -- throughout, we have been robustly keeping on top of how the assessments appear to be performed and whether variability was within our expected ranges. So those are the areas that we've been focusing on in terms of conduct and making sure that we have as consistent a behavior as possible across the sites.

Our next question comes from Ritu Baral from TD Cowen.

I wanted to talk a little bit or ask a little bit about the new momentum in DAYBUE. Could you tell us what percentage of patients or new patients specifically came from the community setting? And you mentioned the new number of 900 HCP writers. What percentage or at least movement of those writers were in the community setting on a quantitative basis? And then I have a Prader-Willi follow-up as well.

Thanks, Ritu. We'll take the DAYBUE question first. I'll ask Tom to give you some more details on that.

Perfect. So in terms of your first question regarding the penetration that we've seen as a result of the increase in the sales force, which, as a reminder, that went live kind of through May, so we're kind of fairly early on in terms of seeing the impact, but we're pleased with what we're seeing already. In the quarter, we actually saw that the number of referrals that were coming directly from our non-COE accounts actually grew to about 3/4 of our overall number. So that was up from about 2/3 the quarter before, which I think is a nice increase in terms of being able to penetrate that large group of patients that we know exist that fall outside of our COE. So just as a reminder, roughly 65% of our patients fall outside the direct care of 1 of the COE centers -- 1 of the COE-designated centers.

With regards to your second question as to the additional writers that we saw through Q2, the vast majority of those new writers fell outside of the COEs, which given the fact that we saw this nice uptick in terms of penetration through the quarter, I think, again, it's a nice leading indicator that the new model that we have in place is beginning to pay dividends for us.

Thanks, Tom. Do you want to ask your 101 question, Ritu?

Yes. And just mopping up after Tessa's questions, can you talk to how the conduct, specifically dropouts of the Phase III Prader-Willi have gone? Are they within expectations? And are all the DSMB looks for the trial completed and if the SAP has been finalized with FDA?

So I'm not going to comment on data from a currently ongoing trial aside from to say that, generally speaking, we are continuing to see this trial unfolding in an acceptable way. But obviously, it's blinded, and I'm not going to comment any further on that at this point.

We do have an SAP in place. I do consider that we have the right to continue to modify until before we unblind the trial, but we do have our planned analyses established at this point.

Our next question comes from Sean Laaman from Morgan Stanley.

This is Mike Riad on for Sean. Congratulations on the quarter. So thinking about DAYBUE, the 987 new patient adds suggest a good steady growth rate quarter-over-quarter. How should we be thinking about this trajectory? Like given the relative lower prevalence, is it reasonable to expect that this would ever accelerate and doesn't need to? Or how should we be just thinking about that trajectory?

So it's Tom here. I'll take that one. Thank you for the question. So we're pleased with the steady growth that we've seen over the last 3 quarters. I think as we mentioned in the call, if you look at Q4, we had around 920 patients. That increased to close to 954 in Q1, and we're pleased with the continued growth that we saw through Q2 with 987 active patients on therapy.

Obviously, the plan that we have moving forward is that, that will continue to accelerate as we see the impact of our new customer model. And our goal is to make sure that we have more new patient starts continuing week-over-week and month-over-month and quarter-over-quarter. And I think now we have this very stable and growing group of persistent patients, many of whom have now been on treatment for 12 months or longer, I think, gives us a real sense that we can really continue to grow this brand and take it to new heights.

Our next question comes from Jason Butler from Citizens JMP.

Just one on NUPLAZID. Given that you're seeing a return on investment on, for example, DTC activities and now that you have the greater visibility with intellectual property, are there more investments or longer-term investments that you're considering for the franchise?

Jason, thanks for the question. I think as we think about our strategy with NUPLAZID, I encourage us to sort of bifurcate the commercial strategy that we're putting in place now with the longer-term ability to now maximize the brand. So direct-to-consumer decisions that we're making are sort of relative to the 2038 shorter term. We're seeing impact of the DTC. We would have continued to invest regardless of the outcome of the IP trial because it has a strong momentum for the next sort of 2 to 3 years potentially depending on how long we continue to invest.

Beyond that now, what we have been able to do is think about the longer-term strategy for NUPLAZID. I'm looking forward to sharing a little bit more about that as we head towards the back end of the year in terms of how we now think about the investment longer term. But for right now, the DTC campaign is certainly paying dividends, as you point out, and we're excited about the continued momentum. And indeed, in terms of the More to Parkinson's campaign and raising awareness of hallucinations and delusions, we're delighted that Ryan Reynolds has agreed to continue supporting that campaign because we believe that's been one of the main drivers of increased awareness. And once the caregiver is aware, they're encouraged to go in and talk to their doctors. So it's been a very strong impact to caregivers, and we're excited to continue that.

Our next question comes from Brian Abrahams from RBC Capital Markets.

Congrats on the quarter. Just 2 for me, I guess, just both on DAYBUE. As you've expanded the sales force, can you talk a little bit more, I guess, qualitatively around your learnings from the Rett patients outside of the Centers of Excellence just in terms of physician receptivity, number of prescriptions per physician, any early persistent signals and how well educated the docs are around the titration? And then can you also maybe talk about any hints of changes you may be seeing in overall DAYBUE persistence, both quarter-over-quarter and bigger picture trends and just how much the education around AE management and the efficacy message and importance of staying on therapy is resonating?

Thanks, Brian. I'll let Tom come up with his thoughts on that.

Yes. Thanks for the question. So yes, we've already had a number of learnings as we've expanded beyond kind of the COEs. One of the key things is there is clearly receptivity to DAYBUE outside of the COEs. We know that there are physicians who are treating Rett patients who won't necessarily have been called on yet, and we're appreciating that they require kind of ongoing education to make sure that they fully understand the profile of the product, they fully understand how to utilize the product.

And we're utilizing the full mechanics of the system that we've built to make sure that we can educate all of those prescribers as quickly as possible. So I think one thing that you probably need to be thinking about as you look at modeling is that the buying process, the number of calls may be slightly longer for this group of prescribers versus those that we see for COEs. And that's purely because they just don't see Rett patients as frequently.

As you talk about persistency, I mean, we're really pleased with the persistency that we're seeing. So as I mentioned on the call, 12-month persistency remains well above 50%. And as we also mentioned for the first time, our 18-month persistency, although not yet fully mature, is above 45%. So I think that, that gives us a real good sense that we have a -- we've kind of reached a nice kind of plateau as we go into the longer-term outlook for the product. And that gives us, with this growing group of patients who are now receiving therapy, a sense that we can continue to grow DAYBUE to new heights, as I've mentioned, as we get new patients started.

Our next question comes from Ami Fadia from Needham & Company.

I have 2 quick ones. Firstly, just with regards to NUPLAZID, it continues to remain really strong with the number of shipped bottles that you mentioned. Can you give us some sense of what's driving the strength and maybe give us some color around where the growth is coming from across channels?

And then with regards to DAYBUE, as you see increased adoption outside the COE setting, can you give us a sense of what you saw in your open-label study in terms of persistency out at 12 or 18 months in -- with regards to patients that are being treated outside the COE setting, if you have that?

Ami, thanks. I'm going to let Tom answer both of those and Liz maybe in terms of the longer term in the trial. But Tom?

So in terms of NUPLAZID, yes, I mean, we're seeing a nice uptick in terms of referrals, NBRxs and ongoing TRx volume. I think if you look at the second quarter and kind of the impact that we saw, we were pleased with the fact that our NBRx volume was kind of reflected across all channels. So we saw it both within the community setting, but we also saw nice increases across the LTC setting as well.

As a reminder, the vast majority of our patients do sit within the community setting, where -- the fact that we have a group of patients that sit within long-term care, where we also promote -- showed kind of just continued strength across the breadth of patients that we serve for NUPLAZID. So very pleased with that kind of ongoing uptick and the strength that we have now going into the second half of the year.

In terms of the question around DAYBUE and the real-world data, I think the real-world data that we have, and we had a recent publication, I think, at IRSF that showed that 18 months, we had about a 40% persistency rate. So I think the real-world data that we're now seeing through the latest data with a 45% persistency rate through 18 months I think, really kind of begins to match up with that very, very nicely and I think, again, gives us a real sense that this drug is performing as we've seen in clinical studies and moving forward. We don't expect to see any sign of kind of significant deviation versus this very kind of stable kind of plateau that we're now seeing.

And I'll just add on -- thanks, Tom. I'll just add on that in our actual clinical trial experience, we really only have about 9 months of data that you can kind of count on from a persistency perspective because in the later part of the open-label extension, we had patients going off to marketed drug and so coming off of the program. If you look to that 9-month experience at that point, you've got something like 45% persistency. So I think what we continue to see and what we've seen sort of all along is that actually the real-world persistency is a little bit better than we're seeing in the clinical trials.

Our next question comes from Marc Goodman from Leerink.

Can you talk about discontinuations for DAYBUE and what you saw in the quarter? And was there any inventory changes that were of any significance for either product?

Thanks, Marc. I'll let Tom talk to that.

Yes. Discontinuations, Marc, we were very pleased that we had another quarter where discontinuations remained well below 10%. Again, I think as you think about discontinuations as part of the overall story that we're now telling in terms of DAYBUE, very stable but growing group of active patients, discontinuations remaining relatively low. And I think that this all speaks to the fact that we really now have a very good understanding as to the profile of the product, how we can engage with the patient community and ensuring that as we move forward, again, with a real focus on the efficacy profile of the product, which continues to be strengthened, thanks to the work of Liz and team that we feel very good about the direction of travel for DAYBUE as a whole. I'll ask Mark to ask the -- answer the second question.

Thanks for the question. Yes, there's nothing to report on in-channel inventory. NUPLAZID is consistent quarter-over-quarter. And then just as a reminder, that concept really doesn't exist for DAYBUE as our single specialty pharmacy really only takes control of the inventory for like a nanosecond before it goes directly to patients. So the DAYBUE model has always been really a sell-through model.

Fair enough. Mark, can you also comment on just the tax rate and how to think about it this year and going forward?

Yes. So our tax -- so I guess if you look at our P&L, our book tax rate year-over-year is a little higher because for GAAP accounting, we're not able to account for all the credits and NOLs that we're actually using. For modeling purposes, our cash tax rate remains currently in kind of the mid-teens rate. Long term, we guide more towards mid-20s, and that's before considering anything for OB3, which will start to be implemented, from our standpoint, in the next quarter. And with that, we have about $400 million of kind of U.S.-based activity R&D expense that had been capitalized and that, in the near term, we'll be able to have some accelerating expensing for U.S. tax purposes. So in the next year or 2, our tax rate will actually go down.

OB3 is our internal vernacular for One Big Beautiful Bill just in case.

Our next question comes from Ash Verma from UBS.

So for NUPLAZID, I know like you've outlined that this is a largely Medicare patient population. Roughly by when do you think that it will be eligible for IRA price negotiation and implementation?

And then secondly on the ACP-101, I wanted to ask like is it the same formulation from Ferring that required refrigeration? And do you think that could potentially become a hindrance at all in terms of thrice daily administration for this patient population? And then is there a plan for a room temperature stable variant here?

Thanks, Ash. I'm going to let Mark answer the IRA question and then Liz on 101. And some of that was a little bit unclear. You broke up for a little bit, so you might have to just say your 101 question again for Liz, so she can make sure she answers it correctly. But let's start with the IRA.

Yes. In terms of potential timing for negotiation under the IRA, 2029 will be the first year that NUPLAZID is eligible for negotiation unless there's changes in the legislation like getting rid of the pill penalty. That's probably the year we anticipate we'd potentially be subject to negotiation.

Just to remind you, as a small company, we have a limit on the discount we have to offer. It's in the range of 25% to 34% as outlined in the legislation. And then after that would be subject to negotiation like any other drug. From our standpoint, just due to the launch timing of NUPLAZID, if the pill penalty is removed, that could add another year before negotiation would likely be expected.

Right. And the small company is for 2 year, right, 2 years...

Two years, yes.

And with respect to ACP-101 and the question there, and then obviously tell me if there's anything that I didn't catch about your question that I neglect here. But we are using the same formulation as Levo used. And an important thing to remember is that part of what we're doing here is a resubmission to the complete response letter. And so the intent is to provide the new information that FDA requires, which is an additional study to demonstrate efficacy while changing a few things as possible about the overall initial presentation.

We have seen that to be acceptable and usable in our clinical trials, have not found it to be a concern. In terms of your question about next generation, we're always considering whether there are things that we can do to our products to make them more patient friendly. And so I anticipate that we'll be thinking about that for 101 as well as we do for other things.

Our next question comes from David Hoang from Deutsche Bank.

Congrats on the quarter. I just wanted to ask on ACP-101. Can you comment or say anything on the, I guess, open label extension for the Phase III study, like what you're seeing in terms of rollover rate? And would you ever consider adding a randomized withdrawal portion to the plan that I think was used by a competitor with improved product in the market to get that product approved?

Great questions. So first off, on the OLE, I'm not going to comment too specifically at this point, but I will say that we have seen generally good interest in our open label extension and are continuing to collect information on patients who are enrolling into that.

To the question about the randomized withdrawal, it's an interesting question. At this point, we really are focused on the results of our current parallel arm study that we're looking at those data coming in, in early Q4. And we think a real advantage of that is that that's going to be able to give a clear -- if it's positive and it turns out the way we hope, it's going to give a clear demonstration for regulators, for physicians and for patients and families of what you could expect upon initiation of therapy. A randomized withdrawal study could be something that we might consider in the future, but at this point, we think the most important data set really is this parallel group study that we're currently running and eagerly anticipating the data.

Our next question comes from Uy Ear from Mizuho.

This is Leo on for Uy, and congrats on the quarter. For each of your brands, NUPLAZID and DAYBUE, what is the right way for us to be thinking about 2026 from a growth perspective? What are the key factors and drivers we should be thinking about? And maybe on the heels of the recent R&D Day, excitement is clearly growing in the pipeline. Which pipeline programs is the team most excited about?

Thanks, Leo. I'm going to ask Tom to comment on how to think about growth in '26 for both brands and then Liz to tell us which is her favorite child in her pipeline.

Yes. Thanks for the question. So let me start with DAYBUE. So as we've mentioned during the call, we've seen very nice continued growth for the last 3 quarters in terms of active patients. We do anticipate through the second half of the year that the rate that we are growing that number will accelerate as we see the impact of our new field force model really begin to pull through.

As a reminder, our penetration rate in general across the entire Rett community remains kind of in the low 30%. So we've still got a significant opportunity here for this brand to continue to grow, and that's our goal through 2026 and beyond, is to really make sure that we engage with the Rett patient community in the right way. We really meet patients where they are, which is what we are doing with our new customer model. And we can really make sure that we take DAYBUE to the height that we know it can be. So that's our goal for '26. So it's really a story of continued and we plan for accelerating growth through the year.

As it relates to NUPLAZID, it's a similar story in a way. I think we've seen this year and this quarter, in particular, some very nice numbers in terms of leading metrics. The team in the field continue to execute very well. Our campaigns are working for us very well and are giving us a nice tailwind as we think about the second half of this year. And we believe that, that sets us very nicely up for 2026. So I think the outlook for both brands from a commercial point of view is one of strength, and we really look forward to really capitalizing on that as we head into 2026.

I love that Catherine teed this up as my favorite child because what I was going to say is I would never say who my favorite child is. I think that across our pipeline, we have a nice mix of assets that are relatively derisked from a mechanistic perspective, things like ACP-204, where we are following in learnings that we have from NUPLAZID as well as some areas of really novel biology like ACP-271.

I think that we are excited about the fact that we've got a number of different ways we could potentially serve patients living with rare and neurological diseases. So there's a lot in our pipeline that we're very enthused about, and I'm not going to pick a favorite child today.

Maybe I'll just come on top of that with, I think, what was exciting for us at R&D Day was to be able to share our expectations on the market opportunity that these brands, these new brands potentially, if approved, offer to ACADIA in terms of potential expansion. And we shared at R&D Day that we believe all 5 of the new products could hit blockbuster potential. And we believe 3 of them have the ability to achieve over $2 billion should they be successfully approved.

So we're moving into bigger markets with still high unmet medical need, and we're excited to continue to focus our development on really differentiated assets and ensuring that we're developing a pipeline of valuable innovation that patients from those underserved communities will really feel adds to their opportunity to see more memorable moments with their families. So we're excited for that.

Our next question comes from Tazeen Ahmad from Bank of America.

I wanted to ask about whether the 204 study in Lewy body dementia has started. I think your guidance had been that it's supposed to start soon or this quarter. And then I also wanted to get your thoughts about the ADP data that's expected in the middle of next year. If that's positive, what's your view about the likelihood of the Lewy body study working, knowing that you had -- the company had looked at Lewy body as part of a previous study with pima a few years ago?

Okay. The first easy one, which is we do continue to anticipate that the Lewy body study will get started this quarter, so hasn't gotten the first patient randomized yet, but we are confident we'll get it in the quarter. In terms of ADP and potential for read-through, I guess what I'll say is that I think that the data, while limited in terms of its numbers that we have from NUPLAZID, is pretty supportive of Lewy body. Again, there's a relatively small number of patients in that study, but roughly 20 patients in the active arm and 20 patients in the placebo arm, and there was a marked difference in relapse rate of patients on placebo versus patients who continued on drug. So I think we have some good reason to believe just based on the existing NUPLAZID data set.

A positive ADP data set is certainly going to make me feel better, in particular, because that gives you clear evidence that this particular molecule is active, though we, of course, expect it to be based on all the nonclinical and Phase I work that we've done to date. So certainly, we are anticipating that ADP readout with a great deal of anticipation and feel good about Lewy body and its potential for success.

Our next question comes from Sumant Kulkarni from Canaccord.

Nice to see the progress this quarter. Could you give us some specifics on how ACP-2591 fits into your plans for Rett syndrome relative to your current efforts with DAYBUE?

Thanks for the question. We haven't had a 2591 question for a while, so I'll let Liz answer that.

Yes. As we think about ACP-2591, I mean, I think what originally attracted us to the program was the fact that there are some similarities mechanistically speaking to DAYBUE and so that derisks it with a potential for a differential penetration from a brain perspective. So there's a possibility that you've got a difference on the benefit/risk profile there.

Obviously, that's going to have to play its way out in Rett patients in order to know how that would -- how we would use that in the context of DAYBUE. What we're doing right now on this one is some additional work to verify how -- the information we need to specifically take forward in Rett, and I look forward to providing some additional updates on that at an appropriate time.

Our next question comes from Salveen Richter from Goldman Sachs.

For PWS here beyond HQCT and CGI-S and CGI-C, do you plan to evaluate functional end points such as hyperglycemia control and weight loss in the Phase III trial? And what would be a clinically meaningful bar for success in this study?

In terms of clinically meaningful bar of success, I'll be very pleased if what I see out of this study is similar to the magnitude that was demonstrated with the 3.2 milligram dose in the prior study. That would be -- I think we feel confident that that's going to be a meaningful change, and we feel confident not just from ourselves but from talking to physicians as well as patient advocacy organizations. We think that, that would be a meaningful note.

I mean I will say that the -- I think your other question was about things like waist circumference. We aren't specifically looking at that. We do think that this is a complex interplay of the disease itself as well as the mechanisms that families have put in place to manage their children and their access to food. So that hasn't been a focus here. We are looking at adverse events and typically at blood profiles, and at least based on the data that we saw in the prior study, we have no reason to anticipate that routine monitoring is going to be necessary. That's going to be subject to the data we see in the study, of course.

Our next question comes from Yatin Suneja from Guggenheim.

Question is on 204, ACP-204. Could you just comment on the pharmacology that you think is better addressed with this molecule, which was not addressed with NUPLAZID, specifically as it relates to this ADP population? Just trying to get a sense in terms of how the setup is or how different the setup is into this ADP readout versus the DRP study that's ran with NUPLAZID.

So I think -- so thank you for the question. As I think about the differences with 204, they kind of go into a couple of different categories. There's the molecule differences and then there's program design differences. And I do think both of those play into what we could be looking out of the ADP study.

So on a molecule perspective, just hitting on this really briefly, NUPLAZID does have that QT prolongation. It's not significant -- it's not clinically impactful. But in an elderly and frail patient population, you do need to think about it, but also it limited our ability to dose range. And we do see some differences in the exposure response that suggest that higher levels of exposure could get us to higher efficacy. We think that this is a reason to think that we've got increasing reason to believe with 204 in our ADP program.

And then on the design of the program itself, I think one of the biggest things that we learned from our prior experience was the importance of having our program specifically focused on the disease that we are studying. I don't want to go through the whole history of DRP, but obviously, that was one of the challenges that we had there. So the program that we've designed with ADP is very specifically identifying that patient population. It's specifically looking at a patient population that's a little more severe in their psychosis, which we also found to be more responsive, and we're biomarker confirming that patient population. So if we take all of these things together, we think that we have set up -- we think we have a good setup for ACP-204 to show what it can do and some good reasons to think that it might be more likely to be successful.

Our next question comes from Evan Seigerman from BMO Capital.

Malcolm Hoffman on for Evan. Back to DAYBUE. I noticed an improvement in the percent of active patients who have been on therapy for 12 months or longer from 65% to 70% this quarter. Can you just expand on this a little bit further? Is this more a factor again of just providers handling treatment, becoming more comfortable with the GI profile and how to manage it over time? Just would appreciate any color there.

Yes. I'll take that question. So thank you. I think it's a few different factors. I mean, as I mentioned a few minutes ago, we are learning more about the product as we go. We are clearly educating the -- both the patient community and the caregivers and the HCPs regarding how they should go about utilizing the product.

If you look at the overall kind of usage that we see, I mean, our percentage to dose remains in the 70% range, which I think also just talks to the fact that our user base is just getting more comfortable in terms of titration as well. And I think, over time, as they see the benefits of the product and as we lean in more in terms of the efficacy profile, I think that there is more that we can kind of pull through there as we think about kind of DAYBUE for the long term.

So I think it's a story of continued knowledge. I think we continue to educate in the right way. We make sure that all of the learnings that we have from our COEs are now being amplified into the community as well. And I think that this is all being reinforced with our kind of updated customer model and strategy as we think about DAYBUE moving forward.

And I think just finally, the persistency that we continue to see sort of amplifies that. So the 65% to 70% is really a recognition of everything that Tom has just talked to, just a much more stable base than we were a quarter ago and then we were a year ago. So again, lots of steadiness and now we're driving the momentum into DAYBUE. Thank you for the question.

Our final question comes from Paul Matteis from Stifel.

This is Julian on for Paul. Congrats on the progress. I just want to circle back to something that was mentioned earlier in the Q&A about the SAP for ACP-101 and how you guys "retain the right to modify" SAP while you remain blinded. Just curious what types of modifications could potentially qualify or could be sort of in the realm of possibilities. Just curious if you could expand on that. And I have one quick follow-up as well on DAYBUE.

Yes. No planned modifications. I purely meant that as just from a practical point of view, until you have unblinded your database, you can consider your SAP subject to the possibility to change. But no, there are no planned modifications.

Got it. That's helpful. And then on DAYBUE, it just sounds like things are going well. You're starting to see increased scripts in the community in addition to higher persistence or I guess, greater line of sight to the persistence of your patient population. I guess just thinking about the second half of the year, you've sort of messaged how you expect to see greater growth. Why the decision to not narrow guidance this quarter? It just seems like you'd kind of easily hit if you continue to add the patients that you have this year. Just curious if that's being conservative out of sake for being conservative or if there's anything else to that.

Yes. I wouldn't read anything in the guidance. I think what I would say maybe on the reason why we adjusted NUPLAZID is we started the year with a wider range than we normally do kind of coming into the year not knowing all the puts and takes for the Medicare Part D redesign. So when we looked at the NUPLAZID range, we just thought it was just too wide kind of halfway through the year. As we look at all the other ranges, we left them, including DAYBUE, and we'll revisit those in the third quarter as we would typically -- it would be a typical point to start narrowing.

Thanks, everybody, for the questions, and thank you, operator. We really appreciate everybody joining us today, and we look forward to updating you on our progress next quarter.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

All right. Good morning, everybody, and thank you so much for joining us for Acadia's inaugural R&D Day. Welcome to the people in the room here at our hotel, welcome to everybody online. We're delighted that you took time today to join us. Because today marks an exciting milestone for the company as we open the curtain on the innovation engine driving our future. We're here to share meaningful insights into our pipeline programs. Programs that we believe have the potential to deliver transformational growth for Acadia in the years ahead.

Before we dive into the future, I'll begin with a brief overview of our current commercial businesses, the successes we've achieved to date and our overarching strategy. But let me be clear, the primary focus of today is forward-looking. Accordingly, as noted on our great slide here, these forward-looking statements are based on current information that are inherently subject to change and involve several risks and uncertainties that may cause our results to differ. These factors and other risks associated with our business can be found in our SEC filings. Today, we're here to talk about what's next, what's possible and why we're so energized by the opportunities ahead.

So with that, let me turn to the first slide. I do want to take a moment just to ground us on where Acadia stands today, how we're positioned to drive near-term value for our shareholders. At our core, Acadia exists to advance care for patients with underserved neurological and rare diseases. That mission guides everything we do. And as we look to our future, our growth strategy or the how is anchored in these four key pillars: Precision medicine, data innovation, globalization and patient empowerment.

We begin today's discussion from a position of strength. Acadia really is an exciting place. We have two successful growing brands, each profitable on a stand-alone basis. And for the first time in our history, we expect these brands to generate more than $1 billion in combined revenue this year, which is a remarkable milestone.

Both of our commercial brands share a powerful commonality. They were first to market in their respective indications, addressing high unmet needs and they remain the only approved therapies in those spaces. With NUPLAZID, we recently achieved a significant set of legal milestones with two favorable patent litigation rulings. And in 2025, with a strong focus on growing our market share, we anticipate net sales in the range of $650 million to $690 million representing 7% to 13% year-over-year growth.

Turning to DAYBUE. We're looking to drive incremental growth with new patient starts in the U.S. as well as expanding globally with an anticipated EMA approval in the first quarter of 2026. In 2025, we expect DAYBUE to generate net sales between $380 million and $405 million, reflecting 9% to 16% growth.

Now you'll see from today that we're excited about every program in our pipeline, but we also understand that the time horizons in this room matter to this audience. And that's why Liz and our team will deep dive into our two later-stage assets with top line readouts in 2025 and 2026.

The first is our COMPASS PWS Phase III study evaluating ACP-101 and Prader-Willi Syndrome-related hyperphagia with results expected soon. Second is our Phase II study of ACP-204 and in Alzheimer's disease psychosis with top line data expected by mid-2026.

We are equally excited about the earlier-stage programs we'll be discussing today. These are highly differentiated assets with the potential to deliver meaningful impact for patients in critically-underserved populations. They represent bold science and big opportunity, and we believe they're an essential part of Acadia's future.

So with strong growing brands and meaningful upcoming data readouts, a solid financial position underpinned by positive cash flow and a healthy balance sheet, we're also well positioned to pursue strategic business development opportunities that can further enhance our growth trajectory.

Of course, the focus of today is how we will build on our strong commercial franchises with the new wave of innovation in each of these two core franchises. So let me walk you through our strategy for doing just that. You'll see here within each franchise, we have a core pipeline coming behind each launched brand to build on our current commercial strength and capabilities. Today, Liz and our team will talk you through five of these assets in seven new indications with a focus on why we believe these molecules hit our high bar of unmet medical need, the opportunity to be first-in-class or best-in-class and the ability for Acadia to develop them and commercially successfully launch them.

And that's just the start of building Acadia to become a biotech powerhouse. Looking ahead, we see opportunities to drive our BD focus to expand into adjacent rare disease categories that you see here. These areas, we believe, our internal capabilities align with our rigorous scientific approach, and we can make a real difference.

So now let's turn to where these programs can take Acadia and why we believe our future is so bright. As you look at where Acadia is today and where we aspire to go, it's clear we're building from a position of strength. Our current commercial portfolio consisting of NUPLAZID and DAYBUE is expected to generate, as I've just said, over $1 billion in revenue this year, a milestone that puts us in a select group of biotech companies. But we anticipate over time that their total peak sales could reach between $1.5 billion and $2 billion combined. When we look at the five pipeline molecules we're going to be discussing today, we will be entering larger markets. They have high unmet need and relatively little competition today. So with that favorable backdrop, we estimate that their combined peak sales potential on a risk-adjusted basis represents an incremental $2.5 billion.

Now when we look at the full peak sales potential of the assets we're going to discuss today, so the five assets, if each molecule were to successfully make it to market, we see them having the potential up to $12 billion combined with at least three of them capable of achieving well over $2 billion in peak sales.

Now let me be clear, this is not guidance. As we all know, drug development carries inherent risks, clinical, regulatory, commercial. And not every one of these programs will succeed, although I sincerely hope they do. But the purpose of sharing these figures is to give you a sense of the magnitude of the market opportunity we see in our pipeline. We believe the potential embedded in our current clinical programs are significantly undervalued by the market today. And we understand it's our responsibility to build the case to deliver the data, to execute with discipline and to unlock that potential value.

We are deeply grateful for your continued support as we pursue this mission. Your belief in our vision enables us to push boundaries, take bold steps and stay committed to the patients who are counting on us.

With that, let me turn it to Liz to take us deeper into the science and the strategy that will shape Acadia's next chapter. Liz?

Thank you, Catherine. I am delighted to second Catherine's warm welcome to our first R&D Day. I'm Liz Thompson, and I lead the R&D team here at Acadia. As a scientist and a drug developer, I have found meaning and light in my career by having the great privilege to be part of the journey of many patients and their families.

So when I joined Acadia last year, what drew me was the fundamental resonance with the mission here. Acadians are motivated by the everyday moments that unaffected families can take for granted. And whether that's being able to talk with an aging parent without the fear or suspicion from their delusions, or look mom in the eye, or share a laugh with the sibling. We know that these moments matter, and we wake up every day to try to enable more of them.

Coupled with this deep sense of purpose was the opportunity to be part of charting the next chapter of an organization with a strong foundation. We'll touch fairly lightly on our current marketed medicines today. But you will hear a great deal about how they underpin our growth and diversification strategy for the future.

Now to give you some context, you can see our pipeline here. Throughout the day, we look to give you additional insight into molecules in the pipeline, and in particular, to spend time on programs beyond the later-stage ACP-101 and ACP-204. But of course, you will hear about them as well. We'll be talking about a number of patient populations, including Prader-Willi syndrome, Alzheimer's disease psychosis, Lewy body dementia psychosis, essential tremor, major depressive disorder, tardive dyskinesia and Huntington's disease.

In line with our increasing approach to pipeline risk diversification, you'll see a mix of more established and more novel biology. And in line with the focus that Catherine mentioned on data innovation and precision medicine. You'll also hear a bit about how we're using biomarkers to aid in our development efforts.

By the end of the time you're spending with us today, I hope you'll come away with an appreciation of how Acadia is advancing care for underserved neurological and rare diseases. We have an active pipeline, and it's gathering momentum over the next few years. This includes nine disclosed programs, of which eight are expected to be clinical stage by the end of the year and multiple undisclosed programs.

We have seven Phase II or Phase III studies anticipated to start between now and the end of 2026. And on top of that, we anticipate five study readouts from Phase II or Phase III trials between now and the end of 2027. We are accelerating our potential to bring solutions forward to patients and we'll be delivering on that commitment with this team, portfolio and pipeline.

So here's our agenda for the day. You've just heard Catherine's welcome and introduction and you're now getting close to the end of my opening section. Throughout the rest of the day, we'll be specifically highlighting pipeline assets, including ACP-204, ACP-211, ACP-711, ACP-271 and ACP-101. We'll also be providing an overview on DAYBUE. Towards the end of the day, I'll be covering diseases, including rare epilepsies, our potential expansion areas in rare disease and giving you an overview of our future-looking R&D strategy.

Throughout the day, we are going to have several short breaks for questions. The first of these is going to be after ACP-211. The second will be after ACP-271 in tardive dyskinesia and the final is going to be at the end of the day. So please hold your questions until those times. And I should also note that we anticipate that each Q&A section is going to be short with only time for a few questions. So for those items, we can't get to you today, please contact Al Kildani, our Head of Investor Relations, and he's going to help you get answers to those additional questions. Now without any further ado, let's move on with the day.

So our journey through the pipeline today is going to be an exploration of adjacencies showing you how Acadia's journey has been one of carefully building from areas of success or experience to new frontiers, as we've expanded within neurological diseases and how we plan to continue that approach in the future, now applying our sharp commercial insight to every program we consider.

So today, we'll start with programs that build upon our pod legacy in neuropsych with ACP-204 and ACP-211. The first up here is ACP-204, our new 5-HT2A inverse agonist, which has been built upon learnings from pimavanserin in both molecule and program design. ACP-204 is a molecule with what we believe to be improved properties, reduced likelihood of QT prolongation, greater achievable exposures and faster time to steady state which we hope together can lead to greater efficacy.

And we've selected our clinical spaces and designed programs within those spaces to increase our likelihood of technical and regulatory success, again, grounded in what we've learned with pimavanserin. You'll hear about how we've done that in both Alzheimer's disease psychosis and Lewy body dementia psychosis.

With that, I am pleased to introduce Dr. Sanjeev Pathak. Dr. Pathak is our Head of Clinical Development here at Acadia. He's a psychiatrist and a neuroscientist with nearly 20 years in the industry, following more than a decade in academic medicine. He's contributed to the development and registration of numerous medicines, currently serving patients living with schizophrenia, bipolar disorder and bipolar mania and major depressive disorder. I am delighted to have him here to share with you more of our insights into ACP-204. Sanjeev?

Thank you, Liz. As Liz noted, I'm a neuroscientist and a pediatric and adult psychiatrist, and I head clinical development at Acadia. Today, it is my great pleasure to talk about ACP-204, a novel and highly selective 5-HT2A receptor inverse agonist that we are developing for the treatment of Alzheimer's and Lewy body dementia-associated psychosis.

Firstly, there's a tremendous unmet need for Alzheimer's disease psychosis and Lewy body dementia psychosis as there are no approved therapies. Importantly, off-label therapy that we clinician prescribe, sometimes in desperation, could be potentially ineffective. Moreover, these off-label therapies carry significant side effect burden such as worsening of cognition that is severely debilitating for those living with dementia. These can aggravate motor function and cause sedation resulting in falls.

The physicians and caregivers deserve a treatment that works, is convenient to administer and devoid of these adverse effects. And we think that ACP-204 has the potential to deliver efficacy and an experience that is devoid of these troublesome side effects. Now let's look at the prevalence of the patient population that we are trying to help on the next slide.

Psychosis in the context of Alzheimer's disease, Lewy body dementia as well as Parkinson's disease is highly prevalent with approximately 3 million people living with these symptoms that ACP-204 alongside NUPLAZID could help. This includes approximately 30% of the population with Alzheimer's disease. Approximately 50% to 75% of the population with Lewy body dementia. And this is in addition to the patient population with Parkinson's disease that NUPLAZID is approved for, where approximately 50% experience psychosis.

Alzheimer's involves amyloid and tau-based pathology in the brain. Lewy body dementia involves alpha-synuclein based pathology and includes two subpopulation, of Parkinson's disease dementia and dementia with Lewy bodies.

While the proteinopathies may be different in these disorders, similar brain works are implicated in psychosis in these disorders and ACP-204 is believed to normalize these brain networks by modulation of serotonin signaling.

The high prevalence, the high unmet need motivates us to work really hard to serve this community. And therefore, at Acadia, we have been working for a long time to serve the patient community living with psychosis associated with neurodegenerative conditions in the context of the pimavanserin program, and now with the ACP-204 program. There, we have learned a great deal about what would make a good molecule as well as considerations for what would -- we would like to achieve. And let's look at this on the next slide.

On the left, you see the structural differences between pimavanserin and ACP-204. These differences are to minimize or eliminate the QT prolongation and improve upon the well-characterized and favorable safety profile of NUPLAZID. This is very relevant for a frail and elderly population. Additionally, the lack of a QT signal enables us to investigate higher doses and achieve higher blood exposures. Data from pimavanserin tell us that this has the potential for greater efficacy, and I'll speak more about it on subsequent slides.

We also want to achieve a faster onset of action, and that is possible with ACP-204. We also want to have a program that robustly characterize efficacy and safety and meet regulatory requirements.

Now let's further into the potential of a QT signal on the next slide or lack of a QT signal on the next slide. Shown here our concentration QTc chain graphs. Here, you see why we believe there may be no risk of QTc prolongation even with the higher doses. Pimavanserin is shown in the graph on the left and the ACP-204 is shown in the graph on the right.

The green arrow on the left reflects roughly the concentrations of the marketed dose of pimavanserin. As shown here, the QT change is not clinically significant. However, if the concentration is roughly twice, as high as the marketed dose of NUPLAZID as shown with arrows in red, there is a risk of increasing QTc beyond the threshold of 10. This finding limited the dose of pimavanserin to the therapeutic dose of 34-milligram.

On the right, we have the ACP-204 graph with a similar plot. The slope of this graph is flat or ever so slickly negative. And you'll note that even at double the therapeutic exposures, depicted as a vertical green arrow on the far right, there is no increase in QT. This enables dosing flexibility with room for higher doses, room for higher concentrations to achieve stronger efficacy. Overall, as I've noted before, the ACP-204 program builds upon what we learned from pimavanserin.

Recall that Acadia previously ran a randomized placebo-controlled trial in nursing home patients with Alzheimer's disease psychosis. Results from the trial are shown here. On the left, pimavanserin met its primary endpoint versus placebo at week 6. In the middle, at the same time point, you can see a number of responder analyses suggesting meaningful separation between pimavanserin and placebo at various levels of improvement. While the data package was deemed not sufficient for approval by FDA, it gave us confidence in the relevance of 5-HT2A mechanism of action, especially in the context of potentially better efficacy and potentially faster efficacy.

In regard to Lewy body dementia, we had observed very favorable signal in this population with pimavanserin in the context of dementia-related psychosis randomized withdrawal study. In this study, the Lewy body dementia population was a subgroup. While the sample size was small for the subgroup, we observed very few relapses with pimavanserin and substantially higher relapses on placebo. This further strengthens our conviction in the 5-HT2A mechanism of action.

Another key lesson from pimavanserin is that higher blood levels can achieve higher efficacy. Shown here is an exposure response curve with concentration on the X-axis and efficacy on the Y-axis. In looking at the data, pimavanserin demonstrates positive exposure response, suggesting that higher blood levels yield more efficacy. There are two lines, one showing Alzheimer's disease psychosis and one showing Lewy body dementia psychosis.

You can see here that as the concentration increases, towards the right on the X-axis, the efficacy improves as shown by a decrease on the Y-axis. This is true in both diseases. And importantly, the vertical line represents the median exposure yielded by the currently marketed dose of NUPLAZID, suggesting that additional exposure could yield some additional efficacy.

Now let's look at how ACP-204 concentrations compared with pimavanserin. This is a concentration time curve. In this figure, the concentrations of ACP-204, 60-milligram and pimavanserin, 34-milligram are plotted with time in days on the X-axis and drug levels on the Y-axis. Note that the 60-milligram dose of ACP-204 represents the higher dose currently under clinical exploration. Pimavanserin concentrations are depicted by the dark blue line and the ACP-204 is shown in light blue. The concentrations are modeled for the elderly population. The concentrations achieved with 60-milligram dose of ACP-204 is much higher relative to the marketed dose of pimavanserin and the concentration reaches a steady state faster at approximately 6 days versus roughly 15 days with pimavanserin.

We believe that it has the potential to lead to stronger and faster efficacy for ACP-204. We are also exploring a lower dose of ACP-204 of 30 milligrams, which would achieve concentration similar to pimavanserin's marketed dose, but would do so more quickly. After measuring blood concentrations, we also wanted to estimate the brain concentrations to obtain [ under variable, ] informing the potential for efficacy.

Shown here are concentration time graphs depicting drug concentrations in the CSF of nonhuman primates. As these are nonhuman primates, these data would more readily translate to human CSF levels. Our findings show that ACP-204 results in 5x higher CSF levels relative to pimavanserin when the plasma levels are equivalent, this finding would also suggest that ACP-204 has potential for stronger efficacy.

Next, we'll look at information that supports that ACP-204 can be conveniently dosed. We have learned in our Phase I clinical trials that ACP-204 can be dosed with or without food. The graph on the right shows exposures when given with food as seen in gray or without food as seen in dark blue. As you can see, the lines are on top of each other, demonstrating it can be given with or without food. We also observed a half-life of around 20 hours, which means it can be taken once a day. Importantly, it can be conveniently taken with the usual medicines prescribed for neurodegenerative conditions like Alzheimer's disease and Lewy body dementia.

Now let's look at safety and tolerability. Like pimavanserin, ACP-204 is dopamine sparing that lends itself to having favorable tolerability and safety profile compared with dopamine-blocking atypical antipsychotics. While dopamine-blocking antipsychotics are associated with cognitive side effects and dopamine blockade specifically exacerbates movement disorders, in clinical studies, data demonstrated that pimavanserin did not impact motor function nor cognitive function.

The table on the left shows the ratio of 5-HT2A and D2. The higher numbers mean low or negligible D2 activity. We see that neither pimavanserin nor ACP-204 showed D2 activity with ratios in thousands. As the number for ratios go down, the D2 activity goes up. As a result, we believe that ACP-204 will not contribute to motor side effects, nor it is likely to have cognitive deteriorating side effects that are seen with dopamine-blocking agents. So far, our clinical trial data support this belief.

The forest plot on the right-hand side shows pimavanserin data plotted against data from second-generation dopamine-blocking antipsychotics. The vertical line of 0 represents a level where the drug would be similar to placebo. While we see -- what we see is that for all of the dopamine-blocking agents, the point estimates are on the right. And the confidence interval does not cross 0 when all the antipsychotics are put together, which demonstrates cognitive side effects with these agents. In comparison, pimavanserin's point estimate is on the left-hand side with the confidence interval crossing 0, that means it is a medicine without cognitive side effects. We expect a similar profile from ACP-204 since it is also dopamine sparing.

And next, you will hear from is Ms. Helen Medsger and Ms. Meryl Comer, who are caregivers, and Dr. Jeff Cummings, an internationally renowned expert about how much new and better treatments are needed.

Alzheimer's disease is a progressive neurodegenerative disorder of the brain. It is characterized by the accumulation of two toxic proteins in the brain, one is called amyloid that accumulates into plaques, and one is called tau that accumulates into neurofibrillary tangles. And these pathologies then kill the cells and produce atrophy or shrinkage of the brain.

Alzheimer's disease psychosis is the presence of hallucinations or delusions in an individual with a diagnosis of Alzheimer's disease. So hallucinations are seeing that are not there. So they might see a dog in the room or they might see other people or they might see children in the backseat of the car that are not really there. Delusions are false believes, that are their beliefs usually around people stealing things from them, feelings of abandonment that they believe that their children intend to force them out of the house, they have feelings sometimes of having no money, impoverishment, dilutions of impoverishment. And then in some cases, there are dilutions of infidelity that their spouse is having an affair with someone. And of course, the point is that these are all extremely painful experiences both for the patient and for the care partner.

So my survival strategy, as painful as it was, was to play into his reality. So for example, at night, and that's when there's much more confusion. If he claimed that strange creatures had invaded our bedroom, I would capture them in a pillowcase, run down the steps, open the door, slam the door and only then could calm my husband down enough to get him back into bed. What he began to ask who I was and why was I sleeping in his bed, I had to move to another room. And I put up camera to monitor because night was day, and he was up and moving all the time. It was exhausting and it was terrifying, which is why, quite frankly, I didn't speak about it. I swallowed it.

Lewy body disease is another neurodegenerative disease over the brain. And it differs from Alzheimer's disease in that the protein that accumulates in the cell is called alpha-synuclein. So we had amyloid and tau protein in Alzheimer's disease. Now we have alpha-synuclein accumulating in the cell in Lewy body dementia and the aggregates of the protein are called Lewy bodies. So that's the pathology that occurs, that protein then kills the cell, there is atrophy and the emergence of a very extravagant set of neuropsychiatric symptoms in this disorder.

So hallucinations are one of the core features of Lewy body dementia. And again, these are usually fully formed, visual hallucinations of animals or people but they can also be misinterpretations of flashing lights or other things that occur in the visual environment.

Having had three family members who have gone through the arc of Lewy body dementia and had all the symptoms of the psychosis along the way, I know the impact personally. And I know the broad spectrum of the symptoms and how they affect. I watched my mother be decimated by my father saying, "I don't recognize who you are, and I don't like you." I -- telling other family members, "Well, you know we're divorced." That was heart-wrenching to my mother.

I just ran under crisis management. And by the time my father passed away responding to his needs in the care home, making sure the physicians were on board, trying to mitigate his symptoms, I nearly collapsed from both physical and emotional exhaustion.

With my sister, it was unique. We -- she asked me at the very beginning of her journey, will you walk this path with me, and I told her, "All the way through to the end." No hesitation. But halfway through her journey as I watched her suffer more with this disease, I was at my office one day, and I just stopped cold and said, if I don't get professional help, I can't do this because I was projecting her death. I know what this disease looks like. I know every bit of it physically and emotionally. And I didn't -- stop it, Helen. Stay in the present.

And with my dear brother, he wanted to live in denial. As many families do, they don't want to know how desperate this can become. And so he stayed in the dark until it was so obvious he couldn't. And we just held on and supported him as best we could.

So to all the families out there that I work with, and there have been over 100 caregivers throughout this country that I have cared for and supported, I have seen and heard more stories that literally will break your heart. We desperately need solutions to this psychosis.

There are no approved treatments for the psychosis of Alzheimer's disease or the psychosis of Lewy body dementia. We really need these treatments. These are very distressing symptoms, both to the patient and to the caregiver.

What I would hope for is a medication that is very efficacious, that would have a more effect on reducing dilutions and hallucinations, a medication that was very safe to use in older populations, particularly, for example, no impact on gait [indiscernible] something that would not exacerbate the Parkinsonism of Lewy body dementia because we know that's a common problem with using conventional or atypical antipsychotics. And then we want something that is very convenient for the patient to take. So once a day dosing, for example, would be terrific.

Throughout my journey as a treating physician and a drug development scientist, I'm deeply moved each time I witness or hear the challenges faced by caregivers or individuals with Alzheimer's or Lewy body dementia. I'm sure you all felt the same. And we all heard that there is tremendous unmet need. With this unmet need in mind, I will go into details about our Alzheimer's clinical trial.

This is a global, double-blind, placebo-controlled, parallel group randomized controlled trial, evaluating two doses, 60 milligrams and 30 milligrams. The primary endpoint is SAPS-H and D, which assess hallucinations and delusions in this population. We have a master protocol for three studies that will run in a seamless fashion. Phase II is currently ongoing, and the sites will begin enrolling once Phase II is completed.

We have a different design for Lewy body dementia psychosis, which is on the next slide. Our Lewy body dementia program once again includes a global, double-blind, randomized, placebo-controlled study, where we are testing two doses, 60 milligrams and 30 milligrams versus placebo. We are enrolling patients with Parkinson's disease dementia and patients with dementia with Lewy bodies because these populations share the common alpha-synuclein pathology.

The primary endpoint SAPS-Lewy body dementia psychosis at 6 weeks, which assesses psychosis or hallucinations and delusions in this population. Please note this is the endpoint that is identical to the primary endpoint for the pivotal study with pimavanserin for Parkinson's disease psychosis or PDD -- or PDP.

Now I would like to underscore some key innovations that we have introduced into this program. As I mentioned, we are running a seamless Phase II/III trial in Alzheimer's disease to accelerate development. Specifically, sites can commence enrolling in the Phase III studies once Phase II enrollment is complete.

Importantly, though the Phase II and Phase III studies are statistically separate and can be analyzed and reported separately, we're also using state-of-the-art biomarkers for both programs. This allows us to enroll patients with a confirmed diagnosis of Alzheimer's disease, consistent with the latest biomarker-based diagnostic criteria for this disease state.

For the Lewy body dementia program, the biomarkers will enable us to inform similarities or differences between Parkinson's disease dementia and dementia with Lewy bodies, and support and inform the Phase III population and enrichment strategies. Overall, this will give us greater confidence in the population and in efficacy of ACP-204.

Lastly, we are also working with TREND Community, a digital analytics company to enable faster recruitment.

In the end, I would like to reiterate the key takeaways for ACP-204. Alzheimer's and Lewy body dementia-related psychosis are severe, highly debilitating illnesses. And there are no approved treatments. And the off-label treatments are potentially ineffective and carry significant adverse effects, and ACP-204 could change that.

ACP-204 is highly selective, potent inverse agonist of 5-HT2A receptors and is believed to normalize disregulation in brain networks implicated in psychosis. It has shown that it is not associated with QT prolongation, enabling exploration of higher doses and a wider dose range and has the potential for stronger efficacy in both Alzheimer's and Lewy body dementia-related psychosis. Finally, the program incorporates innovations that enable collection of meaningful information to strengthen Phase III.

Thank you for your attention. Now I will hand the mic back to Dr. Liz Thompson.

Thanks, Sanjeev. In the next section, we'll be sharing information on ACP-211. We first disclosed this program earlier this year. Our vision for ACP-211 is an oral agent with the potential of ketamine-like efficacy with an improved patient experience, specifically, including minimal in-office monitoring requirements. And in this section of the presentation, we're going to share some of the data that make us believe in that potential.

This section should also give you some understanding of our drug development philosophy. In particular, some insight into how we define the criteria by which a molecule earns its right to stay in our pipeline and how we design our experiments to enable disciplined decision-making around those criteria.

Dr. Dragana Bugarski-Kirola is a psychiatrist and neurologist who has been working in the field for almost 30 years. Most of our academic research clinical work has been focused on neurophysiology and sleep, schizophrenia, autism, dementia and effective disorders. Dragana has authored more than 40 papers in high-impact journals and she's a Vice President within our clinical development organization, and I am delighted to welcome her up to join us. Dragana?

Thank you, Liz. Hello. As you heard, my name is Dragana Bugarski-Kirola, and I'm the Vice President of Clinical Development at Acadia. Today, I'd like to share some information about our program in major depressive disorder and treatment-resistant depression. I will tell you a little bit about what ACP-211 is, how it compares to the other compounds in its class, and most importantly, why we are excited about it.

There are depressive episodes in life, but not every episode of low mood is a major depressive disorder. Major depressive disorder is a pervasive feeling of sadness and loss of interest that lasts for more than 2 weeks and is accompanied by disturbances in sleep, appetite, energy and concentration. Low self-worth and hopelessness can oftentimes lead to willingness to hurt oneself. The symptoms have to be so severe that they impact everyday functioning.

Current treatments for major depressive disorder can be limited by the extent and the onset of efficacy, or show quick antidepressant effect, but require clinic administration and protracted clinical monitoring due to serious side effects such as dissociation and sedation.

To illustrate my point, I will give an example of a former patient of mine, a young 30-year-old mother of 2 small children. She was walking with them one day down the street when she suddenly left him on a sidewalk and jumped in front of a moving truck, and it was just by sheer skill of that truck driver that she survived unhurt. Her husband reported that she was not sleeping, that she was not responding. And she sat in front of me severely depressed and completely mute.

In order to get her treatment, she needed, I had to convince her to stay voluntarily in the psychiatric unit with other chronically-ill psychiatric patients and be separated from her children for months. This is because the treatment required the combination of antidepressants that would be given intravenously and would only have an impact after several weeks during which she would remain symptomatic and in high risk of suicide.

As a doctor, I want to have better options for patients like her. She should not have to choose between getting treatment and staying with her kids, being surrounded by her family members as opposed to being with psychiatric patients, which is why I'm excited about this program. ACP-211 is designed as oral therapy with potential for ketamine-like efficacy and targeting minimally required in-clinic monitoring.

Approximately 21 million of the adults in the United States are diagnosed with major depressive disorder. And of those, only 9 million are getting treated. And of those 3 million deemed treatment resistant. Now to put things into perspective, the state of Florida has 21 million people, imagine all of Florida being depressed. Imagine that of 21 million people, less than half are getting treated for it. This is why major depressive disorder is the second highest cause of disability of all the diseases and why the economic burden is so high. Both ketamine and esketamine have efficacy in depression, but with significant side effects.

Ketamine is a mix of two isomers, the R one and the S one, (R,S)-ketamine shows a rapid reduction of depressive symptoms within 2 to 4 hours when given intravenously in low sub-anesthetic doses. And as many of you know, the esketamine or SPRAVATO has been recently approved for treatment-resistant depression.

Now the dissociative anesthetic properties of ketamine and esketamine, namely dissociation and sedation, occur even at low doses shortly after administration. Sedation is observed in SPRAVATO studies, and it can be severe. By that, I mean that people cannot get up from a chair or they may be found unresponsive.

The other side effect is dissociation. Low-grade dissociation has no impact. People may actually report that they are seeing their surroundings a little bit more clearly. More profound dissociation can lead to feelings of the derealization, feeling detached -- being detached from oneself, deep personalization or even identity confusion. This is why protracted clinical monitoring for several hours is needed.

So clearly, a new therapy would ideally have the rapid and robust antidepressant effect of ketamine or SPRAVATO with minimal potential for sedation and dissociation, which brings me to ACP-211, a selectively deuterated form of R-norketamine with potential to have that ketamine efficacy and with lower sedation or dissociation.

So let me explain. The causes of depression are not well understood, but it has been proposed that the impaired glutamatergic signaling may play a significant role in it. In healthy state, you can see that synaptic activity is enabled through rich connectivity or short and long branches of glutamatergic neuron. In depression, there is a decrease in the density and loss of synaptic connectivity that affects brain's ability to regulate mood. Antidepressant treatments like ketamine or ACP-211 increase density again and promote neuroplasticity, which is involved in mood regulation.

Now this process is actually mediated by the inhibition at the NMDA receptor and by the activation and increased expression of AMPA receptors. Both of these are on the glutamatergic synapse.

This is for those of you biologists, a very simplified version of glutamatergic synapse. So in healthy brain, there is a balance between activation and inhibition between glutamate and between GABA, Gamma-aminobutyric acid or the inhibitory neurotransmitter. In depression, there's clearly an imbalance that's leading to decreased synaptic connectivity, favoring inhibition, which can be seen clinically like in my patient, for example.

Ketamine binds to the NMDA receptor, preventing its inhibition but this may not be the only mode or the only way to mediate antidepressant response. Additional mechanisms such as AMPA activation, the activation of AMPA pathway may play a significant role. Thus, what I'm trying to tell you is that compounds like ACP-211 that have lower affinity for an NMDA receptor inhibition can still be clinically effective.

So what happens over here is that glutamate activates the AMPA receptor that leads to the increased release of the brain-derived neurotrophic factor, which is involved in neuroplasticity -- promotes neuroplasticity. And then that process activates the tyrosine kinase receptor, which influences signaling downstream and eventually resource the functioning of the synapse.

So in conclusion for this slide, ACP-211, as you can see over here, uses similar pathways as ketamine to deliver antidepressant efficacy or activity, but because of its propensity to lower affinity for an NMDA receptor, its propensity for sedation and the dissociation is much, much lower.

All right. So in animal models, as you can see, ACP-211 has actually shown comparable efficacy to ketamine. And what do I mean by that? Well, ACP-211, when given up to the animals 24-hour prior to testing, significantly decreases the immobility time, which is a measure of antidepressant activity, a behavioral despair model. And not only that, it actually -- the animals resume swimming which means that their motivation is restored. Their survival instinct is restored. And as you know, lack of motivation is one of the key symptoms of depression.

The other model that we use over here is a decreased preference for sucrose, which is considered as a sign or evidence for anhedonia, loss of the ability to feel pleasure. So in this model, restored sucrose consumption would actually be indicative of antidepressant activity. And as you can see over here, again, when animals are treated 24 hours prior to a test with ACP-211, there is a significant jump, significant increase in sucrose consumption that sustained all the way till the end in stressed animals, but not in non-stressed animals. Again, this shows that the animals show recovered ability to feel pleasure and that is the evidence for antidepressant potential of ACP-211.

Now the second feature of our target product profile is superior safety or no sedation and minimal dissociation. So as you can see over here, ACP-211 shows less motor impairment than ketamine in animal models, specifically rotating rod test. Here shown are animals treated with vehicle, and they're able to resist from falling off of the rotating rod for about 3 minutes. There are no bars for animals pretreated with ketamine because they fall immediately down from the rotating rod.

And then the animals pretreated with 3 different doses of ACP-211 show comparable latency to falling off from the rotating road as the vehicle, meaning no impairment -- no motor impairment, technically no sedation if you really want to translate it into humans.

So let's see how the humans react. ACP-211 has been tested in healthy volunteers because they are more sensitive to the side effects of medications than people -- than patients who have been tried on a variety of different drugs. And as you can see over here, in the graphs, this is a concentration over time of ACP-211 from the single ascending dose study, where doses from 30 all the way to 900 milligrams were tested.

A couple of points over here. First, the peak concentration happens within 2 to 4 hours after dosing. Second, the peak concentration is dose dependent. So the higher the dose, the higher the peak. And remember, the higher risk for side effect sedation and dissociation. And the third point is at the end of day 1, there is nothing in the system. No ACP-211. So there's no accumulation.

From the safety point of view, the data to date or the profile to date seems very reassuring, as you can see from the data from healthy volunteer study. No impairment of consciousness. No sedation. Dissociation was seen only with the highest doses and was mild and transient. There was some impact on the heart rate and on blood pressure where the dizziness was associated with orthostasis and again, mild and transient. So these data really support our next step, which is to proceed testing ACP-211 in patients.

As I said, our next step is really the next stage trial design -- is designed to inform our ability to meet our target product profile on sedation and on dissociation. This is a pretty typical proof-of-concept study. The design is illustrated over here below, but it will be in patients with inadequate response to antidepressant treatment. And what I want to highlight is that the stopping criteria and monitoring for rate of sedation and dissociation are embedded in the study design. The start of the study is planned for the last quarter of this year.

So in summary, these are the key takeaways. Major depressive disorder is a serious mental disorder that affects 21 million people in this country alone. Currently approved treatments, as you can see, are limited by the efficacy and the onset -- either the onset of efficacy or simply the efficacy or inefficiency, or show rapid improvement, but with serious side effects such as dissociation and sedation. ACP-211 is an orally administered, selectively deuterated the form of R-norketamine.

And as you can see from my presentation, data from animal models support ketamine-like efficacy, but also a very benign profile, no sedation. And then finally, when we looked at the healthy volunteer study, they allow us to go high with the doses with minimal dissociation and no sedation. The Phase II MDD study is going to evaluate efficacy and safety, specially ruling out unacceptable rates of dissociation and sedation, as Liz has alluded to.

Finally, I want to close with two points. The first is that my patient was not the only young, depressed mother. There are many others out there that could benefit from rapid improvement that can be compatible with living their daily lives, not staying in the hospitals for days, weeks or months. And second, ACP-211 exemplifies the opportunity to pave the way to new, much better treatment, I think we all deserve. Thank you so much for your attention.

Thank you so much, Dragana. Now we have just a few minutes for questions, and so we can take two or three of the most burning questions that you have regarding ACP-204 or ACP-711. And Alice is walking around with the mic.

Ritu Baral from TD Cowen. I'm going to stick with 211, your deuterated norketamine. Can you talk to how you believe that the deuterated R-norketamine could be different from the IV R-ketamine that was previously investigated like what sort of PK and PD dynamics may give it an advantage versus that drug that failed?

And also, can you talk to -- in that Phase II that you're starting in Q4, can you talk to your definition of MDD with inadequate response versus the TRD definition that was used in SPRAVATO development?

Okay. I'll make a couple of comments, and then I'll invite Dragana to add in a little bit. I think that we see 211 as having a unique profile in a number of ways. Certainly, the convenience of an oral administration, I think, is a positive compared with some of the other agents that have been investigated in the space.

I think that also the data we have to date, and obviously, that's preclinical in Phase I. So we're going to learn more about this as it goes through later stage clinical. But the data we have to date is supportive of seeing the potential for strong onset of efficacy with no sedation and low dissociation, which I think would be a pretty impactful profile if we're able to demonstrate that in Phase II. But thus far, data are supportive in that direction.

And Dragana, would you like to comment -- actually, I am sorry, I forgot what the second half of the question was. The definition of MDD. Would you like to comment a little bit more on how we're defining patient...

Yes. So thank you for the question. And I think this is a very typical question. As many of you know, they are not -- there's not a real consensus in -- among the scientific community when it comes to the TRD. FDA has their own and then community has their own and also for the inadequate response. So for the inadequate response, we actually do have the questionnaire that we're going to use retrospectively for two or more failed studies and that also with -- in the context of the percentage of the response.

For the TRD, the FDA actually does request at least a minimal response less than 25% or 30%. We will use this retrospectively, but within the same -- within one episode that -- ongoing depressive episodes. So those are the criteria for the clinical trials, and there will be a randomization also based on those criteria as much as we can.

Yes. And this Phase II data, of course, is going to help us inform what we would go forward with.

For the indication, yes.

Brian Abrahams, RBC. Maybe shifting to 204. In addition to the differences that you discussed, I believe, that 204 also has some differences in preference for 5-HT2A versus 2C as compared to pimavanserin. And I know it can be tough to predict the impact of some of these subtle differences in receptor profile. But I'm curious if you have any sense as to how this could potentially affect its antipsychotic efficacy, relatively speaking, as well as its safety profile.

Okay. Sanjeev, would you like to address that one?

Yes. Great question. So as we have understood our molecules better and the receptor profile better, what we have concluded that with pimavanserin, there is some 5-HT2C activity, but it is orders of magnitude lower than 5-HT2A, roughly 40x or more. So at the therapeutic or marketed dose of pimavanserin, there is essentially no 5-HT2C activity. So in conclusion, 5-HT2C is not, in our view, contributing to antipsychotic efficacy.

And similarly would be the case for ACP-204 we believe that the activity and the efficacy is a result -- results from 5-HT2A, where ACP-204 is highly selective and very potent and in our functional assays, works as well as pimavanserin, if not better.

All right. I think maybe time for one -- actually, I guess -- we're at time. All right. Hold thoughts. We will have a couple more question periods throughout the day.

Okay. All right. Thank you both. Appreciate it.

So I said earlier that we would be walking you through how we expand our areas of focus in a measured and strategic way. And so in this section, we're going to talk about the next subset of neurological diseases that we focus on. And in specific, that's our neuro-motor programs.

With the first and only approved product for patients living with Parkinson's disease psychosis, neuro-motor is a natural adjacency for us. And it's one with many areas of significant unmet need. You'll be hearing about ACP-711 in this section as well as the first part of the story about ACP-271, with the ACP-271 sequel as we move into the rare disease section of our day.

So starting with ACP-711. This is our GABA alpha-3 specific positive allosteric modulator that we're developing for the treatment of essential tremor.

I am delighted to introduce Dr. Vic Abler, a Vice President within our medical affairs organization. Vic is a neurologist, who was previously the Professor of Neurology at the University of Cincinnati College of Medicine, as well as the attending neurologist at the VA Hospital Medical Center in Cincinnati, Ohio. He has more than 20 years of pharmaceutical experience within medical affairs and has published more than 40 scientific articles in peer-reviewed journals. And today, he's going to share both his professional and also his personal experience with essential tremor. Vic, come up and join.

Thank you, Liz. Appreciate it. So I am really excited to talk to you today about ACP-711. I -- ACP-711, as Liz mentioned, is a positive allosteric modulator for the potential treatment of essential tremor or ET. We are partnering actually with a company called Saniona based in Denmark.

So let's start by asking what is essential tremor? And why is it so important to bring another medication to market to treat ET? So as a neurologist who's practiced for years, I've seen many patients who had essential tremor. It's actually a very unique tremor, it's very different, for example, than a Parkinsonian tremor.

It's described as postural and/or kinetic tremor. So what do I mean by that? Postural tremor is, let's say, you're holding a full glass of water straight out in front of you. You would actually see a tremor there. Kinetic tremor is if you brought that full glass of water closer and closer to your lips, the water would splash around because the tremor would worsen as you got closer to the lips. So that's what I mean by postal and/or kinetic tremor.

Now there is a large unmet need in this space. Current treatments are not always effective and can have really unwanted side effects. We are striving for better treatment options for the patients. ACP-711 is meant to fill that unmet need. It's a selective GABAA-alpha-3 modulator that targets GABA dysfunction within the cerebellum.

We do have Phase I data that supports the potential absence of negative cognition, sedative and sleep effects. It's very common. In fact, it's 10x more common than Parkinson's disease. In the United States, it's estimated that 2.2% of the population suffer from ET, which equates to about 7 million patients. There are 1 million patients who are seeking treatment.

So you may ask yourself, if there are 7 million people that have ET, why will only 1 million be seeking treatment? So in part, the answer is that, especially early on, ET is mild enough not to necessarily warrant treatment.

Now I'm going to share a personal story. My dad actually has severe essential tremor. And this created a roller-coaster ride for us as a family where we started him initially on some oral mitigations that didn't either seem to work or he just couldn't really tolerate them. Let me give you an idea of what was happening. So for example, he could not bring a spoon full of soup to his mouth because the tremor would worsen. He could hardly button his shirt any longer. And he could not write a check. And he stopped playing piano because he couldn't do it because of the tremor, which he loved to do, and found -- this was a way to relax.

Also, ET is an autosomal dominant disorder. What this means is that the child of an effective parent will have a 50% chance of developing ET. So true to the genetic form, I have actually inherited this disorder as well. But I'm one of those who don't yet quite need treatment because it's pretty mild.

So the reason I bring this personal story, it does speak to the larger population, where half the patients who are treated with essential tremor see no benefit. And half of those who actually see that benefit or reach this plateau where there's just no satisfactory improvement. Not surprisingly, 1/3 of the patients will stop their medication. Propranolol, the only approved drug currently in the United States was the FDA approved way back in 1967. Now there are other treatments off-label being used such as benzodiazepines and anticonvulsants like primidone. Most of these off-label treatments were investigated in these small studies with like 28 to 30 patients per treatment arm, and they were done many decades ago. So there's so much room for improvement here.

So now I really want to talk to you about why do we think -- or what causes ET? So I'm going to start with a structure called the cerebellum. That's depicted on the left-hand slide here in the slide -- the left-hand side of the slide in blue. The cerebellum is a neuroanatomic structure that's slightly smaller than the size of the fist. It's tucked in the back of the brain, underneath the occipital cortex adjacent to the brainstem.

Now the cerebellum is a key important structure for balance and motor control. Now within the cerebellum, there are important neurons called Purkinje cells. These Purkinje cells for unknown reasons start to degenerate. Now I'm going to show you the Purkinje cells in this slide. So if you look to the black and white panels, you're going to see Purkinje cells. The two side-by-side in the green panel or in the green box are actually postmortem cells from humans who did not have ET.

Now I want you to look closely at that panel and you're going to see these Purkinje cells that look like healthy trees, full of thick branches and many leaves. Now look to the right side, in the red box. That's a Purkinje cell -- human Purkinje cell, postmortem, in a patient who had ET and look at the difference. It looks like the tree is kind of -- have thinner branches and many of the leaves have been lost.

Now this signifies loss of dendritic spines as pointed out by the dark arrows. This is all due to Purkinje cell degeneration. Now most Purkinje cells release a neurotransmitter called GABA, gamma-aminobutyric acid. GABA is an inhibitory neurotransmitter. So this degeneration of Purkinje cells creates this dysfunction within the GABA system as you see on the right-hand side of the slide.

Now this results in the loss of inhibition that creates this increased pacemaker activity of the neurons that are trying to work overtime in the cerebellum. In turn, there's an increase in thalamo-cortical activity. Now the thalamus is the main relay station of the brain. It receives input from the arms and the legs and the lower extremities and it sends this information up to the cerebral cortex. Now this increase in activity is thought to cause tremor. The brain loves homeostasis. It relies on this nice balance between inhibition and excitation. And when inhibition is lost, excitation takes over.

Now on the next slide, I'm going to dig deeper into the cerebellum itself. Now GABA, that inhibitory neurotransmitter, needs to land on a receptor in order for it to work. These are called GABAA receptors. And actually, there's multiple GABAA receptors in the brain. GABAA receptors are made up of different subunits. These subunits are called alpha-1, alpha-2, alpha-3, alpha-5, for example. Different receptors made up of different subunits can be located in different places in the brain, making this a very complex system and historically difficult to target with precision.

Now as I mentioned before, evidence currently suggests that the cerebellum is the location of the problem. Now let's look at the right-hand side of this slide. What you're looking at is a confocal microscopy of a rat cerebellum. The arrows that you see are pointing to various layers of the cerebellum, such as the Purkinje layer, white matter layer, granular later. Now take a closer look within the green, and you're going to see these bright spots. These bright spots are showing you alpha-3 GABAA receptors. This means that within the cerebellum, there are abundant alpha-3 receptors in all layers of the cerebellum.

Now what I want to do is talk to you about the connection between ACP-711 and these GABAA receptors. So as a recap, Purkinje cells degenerate so they cannot release that inhibitory neurotransmitter. This, in turn, is thought to cause tremor. The GABAA receptor alpha-3 is an abundant and key receptor in the cerebellum as you saw. So what's that connection between ACP-711 and the receptors? Now as I mentioned earlier, ACP-711 is a positive modulator of GABA alpha-3. What you are looking at here in this slide is a study, in-vitro study of cells expressing human recombinant GABA alpha-3, but also alpha-2, alpha-5 and alpha-1.

The line graph is showing you the activity that ACP-711 has on the various receptors. Now you see that there's high activity with the GABA alpha-3 receptors, as shown by the top dark blue line and little to no activity with the other receptors mentioned, alpha-1, alpha-2 and alpha-5, as shown by the other line graphs lower down.

Now this is an important distinction because we know from research that alpha-1, alpha-2 and alpha-5 subdues are implicated in things like anxiety, cognition, memory problems and reward-enhancing issues. On the other hand, alpha-3 receptors are associated with motoric control.

Now what I want to do is let's move on to some evidence of some efficacy with ACP-711. So what I'm going to do in this slide is show you something called a Harmaline model. Harmaline is a chemical that actually originates from a seed from a plant that's indigenous to South America. It's in the alkaloid family. Once Harmaline is injected into an animal, it produces a tremor similar to the frequencies seen in essential tremor in humans. The Harmaline model is considered the standard model for preclinical exploration for efficacy in ET.

Now let's look to -- look at the graph on the slide. Let's look at the left side of the slide, looking at that graph. The Y-axis is pointing towards -- the Y-axis stands for the percent motion power. In other words, how much tremor the animal is -- or how much tremor the animal is experiencing. The X-axis is showing you what was administered to that animal.

So let's start to the left. And on the far left, you see a white bar. This is saline in a normal animal without tremor. The gray bar is vehicle or placebo, that's given to the animal that now has tremor induced by the Harmaline. The dark red bar is propranolol. The three colored blue bars are different doses of ACP-711. Note that propanolol does reduce the tremor significantly compared to the vehicle or placebo as well as a reduction using the higher doses of ACP-711.

Now looking at this, propanolol appears to be more effective in the tremor model. But in this case, the animals were actually all rendered recumbent due to muscle weakness after given propanolol. This was not seen with ACP-711.

Now look to the right bar graph. This is a similar approach, but the difference here was that the animals were given primidone, again, another commonly used drug in ET. Now this graph shows efficacy of ACP-711 in different doses, that significantly reduce tremor versus vehicle as well as primidone. However, drugs used to treat ET like primidone have limiting side effects that cause sedation in humans, for example.

Now what I want to do is let's talk about some human studies on this next slide. I'm going to start with some pharmacokinetics that were done in healthy subjects. The left-hand side of this slide. ACP-711 was given orally to these healthy subjects, and we noted that there was rapid absorption in about 2 hours or less. After ACP-711, the mean half-life was about 10 hours across different doses that supports the possible twice-a-day dosing. Now the most common side effects seen here were headache and some dizziness.

Now let's switch over to brain imaging study. On the right-hand side of the slide, it's called PET scan, PET, positron emission tomography. PET scans can actually show us what kind of occupancy a drug may have on the various receptors. In this case, healthy subjects were given radio-labeled injections. In the first column, they were given radio-labeled flumazenil. Flumazenil is a potent GABAA receptor binding agent. And what you're seeing here is an intense uptake of flumazenil on those GABAA receptors.

Now the middle column are subjects that were given radio-labeled ACP-711. And what's happening here is within 30 minutes of infusion, you see that ACP-711 is actually displacing the flumazenil and occupying those very same receptors. And then third, the last column is 24 hours post-dose ACP-711. And what you're seeing here is that flumazenil receptor occupancy is starting to come back. It's returning.

So in summary on this study, the PET scan showed us that there's an 86% occupancy of GABAA receptors with ACP-711, and we're currently exploring even higher doses as well as the impact of dosing on the elderly. Now this suggests that we'll be able to achieve good target modulation with ACP-711 at the planned clinical doses.

So next what I want to do is talk to you about the effects that ACP-711 have on brain activity versus ACP -- versus other drugs and ACP-711. Now on this slide, what I'm going to show you is the impact that commonly used drugs like benzodiazepines have on essential tremor when it comes to brain wave activity, EEG, electroencephalograms. Now there are various brain wave patterns that we're seeing that are going to be described here, that you're going to see at the right lower side of the slide.

Now I'm going to start with something called delta activity, delta waves. Delta waves are those long undulating waves that are seen during times of sleep and heavy sedation. Next is something called alpha wave activity. Alpha wave is when you're in a deep, meditative, very focused state, relaxed. Last, beta wave activity. These are seen when you're an intense concentration maybe with somebody or maybe you're doing a very complex mathematical equation, beta waves, fast activity.

So healthy volunteers in this case were admitted to an observation unit for 9 days. They were given ACP-711 orally for those days and monitored with EEGs. Now what we've seen in this study was that there was -- with ACP-711 was a decrease in delta activity. This suggests that possibly ACP-711 has no sedation properties. Now with benzodiazepine, you're going to see the opposite. You're going to see an increase in delta wave activity, suggesting drowsiness.

Next, the subjects given ACP-711 experienced an increase in alpha activity. Remember, that alpha activity is that experiencing when you're in a deep meditative focus state. Now with benzodiazepines again, you're going to see the opposite, alpha wave activity decreases.

And last, ACP-711 caused no changes with beta wave activity in the brain. Those waves that are seen with doing a complex mathematical equation, for example. Now interestingly, benzodiazepines will actually increase beta activity, that fast activity. We think it's due to a compensatory mechanism to overcome sedation and normal -- in order to maintain normal behavior.

So now that we know what happens with brain waves, let's go to sleep. What happens in sleep now. So we know that drugs used in ET have a negative impact on sleep by interrupting sleep architecture and sleep patterns while you're sleeping. So let me set the stage here on this slide.

There's various stages of sleep. There's non-REM stages, stage 1, stage 2, stage 3, for example. Now in stage 1 sleep, that's when you go to bed and you're probably like 10 minutes in, very brief. There's no deep sleep here. And you can be easily aroused out of the sleep, but sometimes when you pop out of stage 2, you don't even realize you were sleeping at all. Stage 2 sleep is a little deeper. It's a little longer, 25 minutes in. And you start to get this deeper stage of sleep. And even though you can still be aroused fairly easily, some people will actually feel very refreshed after that period.

Now stage 3 sleep is that deep sleep. That's where I was talking about that delta wave activity on the previous slide, where you get these delta wave activity in very deep stage of sleep, stage 3. It's hard to arouse some people from this stage. And then the last one I want to talk about is something called spindle rate activity. We call this a micro architecture because spindle rate activity occurs within stage 2 sleep. Now this is a very important -- spindle activity is very important in sleep because what it does, it consolidates memory during times of sleep. And obviously, it's important to have this sleep.

Now I want to draw your attention to the graphs on this slide. The blue bars you're seeing on this slide represents various doses of ACP-711 given orally to the healthy volunteers. The red bars are placebo. So what we see here with ACP-711 given over the 9-day period to healthy subjects was that there was no significant change in sleep architecture.

Now you will see sleep variability in anyone during these stages of sleep. But what these bar graphs represent is no significant change in that variability over that 9-day course. This suggests that there's no impact sleep after taking ACP-711. Now this is not the case in research that was done in -- with other drugs in ET such as benzodiazepine, primidone and even propranolol.

So finally, I want to go to what we're going to -- what's going on next with us. We have an elderly multiple ascending dose Phase I study that's currently underway. And we plan a 4-week, randomized, double-blind, placebo-controlled Phase II study, looking at lower doses of ACP-711, higher doses versus placebo over 4 weeks. We're going to be using an endpoint called TETRAS. It's a validated scale used in essential tremor, stands for essential tremor rating scale (sic) [ The Essential Tremor Rating Assessment Scale ].

Now this scale measures the overall severity. But very importantly, it also measures ADLs or activities of daily living. I'm going to bring this back to my dad who has ET. If we have a drug that helps the overall severity, but it doesn't do much for your ADLs like being able to address or write a check, then the quality of life probably just won't be there.

So what I want to do is just go over some of the key takeaways. Essential tremor is the most common movement disorder worldwide. Existing treatment options remain suboptimal, fewer than 50% of the patients experiencing meaningful benefit, and there's no new therapies that's been approved for over 50 years. ACP-711 selectively in affects GABA on the GABAA alpha-3 containing receptors expressed in key brain regions that I described in essential tremor.

ACP-711 improved tremor without sedation in preclinical studies. In Phase I, ACP-711 demonstrate high receptor occupancy with minimal impact on sleep and no evidence of sedation or cognitive impairment. We have a current study evaluating dosing in the elderly cohort in a Phase II trial that's designed to explore dose response, efficacy and safety impact on daily functioning that's being planned for 2026.

I really appreciate your attention. Thank you. Back to you, Liz.

Thanks, Vic. We're now going to turn to some of the most novel biology in our pipeline. ACP-271 is a GPR88 agonist, and we think it has first-in-class potential. We see this as a mechanism with substantial potential, particularly in the neuro-motor space. And we are excited to be taking this oral treatment into first-in-human studies by year-end.

Dr. Rachael Hawtin is Acadia's Vice President of Translational Sciences. She has nearly 3 decades of translational science leadership experience including broad therapeutic area exposure across oncology, autoimmunity and rare diseases, including rare neurologic indications. She is experienced with multiple therapeutic modalities, including small and large molecules, antisense oligonucleotides and gene therapy. She joins us most recently from Ultragenyx, and she is going to introduce you to this exciting program. Please welcome, Rachael.

Thanks, Liz. Hello, everybody. As Liz referenced, GPR88 agonists have considerable potential in several neurologic indications. We're initially focusing our lead molecule, ACP-271 in tardive dyskinesia and Huntington's disease, or TD and HD. Before showcasing our preclinical data in these two indications, we're going to share with you a brief movie that introduces this novel target.

[Presentation]

So we've just shared a little bit about GPR88 as a target and why GPR88 agonists may be beneficial to patients with TD and HD. Being a novel target, we just bombarded you with quite a bit of new information, and we'll be revisiting these themes throughout the next two sessions.

ACP-271 is an orally dosed GPR88 agonist entering first-in-human studies later this year. We also have follow-on assets with differentiated characteristics such as increased potency and brain penetration. And these are currently earlier in preclinical studies. Now I'm going to walk us through an introduction to tardive dyskinesia and share some of the data that support the potential for GPR88 agonists in this indication.

Tardive dyskinesia is a disorder that arises in patients being treated for extended period with dopamine 2 receptor antagonists. It manifests as hyperkinetic, repetitive involuntary movements affecting the face, for example, lip smacking, the trunk, the limbs it can be disabling and disfiguring. And this is on top of the patient having to deal with their underlying mood disorder or psychosis.

Treatment options for these patients are limited. One option is to reduce the dose of the dopamine 2 receptor antagonist. However, this exposes the patient to increased risk of psychotic episodes and will be ineffective in those cases of irreversible TD. Currently approved treatments for TD reduce dopamine availability at the synapse. And these carry side effects of sedation that affect everyday life and also boxed warnings for depression and suicidal behaviors, characteristics that compound the challenge already experienced by the patient dealing with their underlying psychosis or mood disorder. And I'll come to this in a little bit more detail in a few slides.

Our rationale for applying GPR88 agonists in TD is based upon the novel dopamine sparing mechanism that was introduced to you in the movie, and which brings the associated potential to avoid sedative side effects. Our molecules also showed durable activity in preclinical models, which distinguishes them from the currently available treatments, and I'll show you that also in a couple of slides.

The disease burden of TD is high, being experienced in the United States by up to approximately 30% of patients being treated for extended periods with D2 receptor antagonists. And this represents upwards of about 0.5 million people.

So the rationale for GPR88 agonists in TD is elaborated on in this slide. A patient presenting with TD due to extended use of dopamine 2 receptor antagonists may be treated with a VMAT2 inhibitor or vesicular monoamine transporter 2 inhibitor. Inhibiting VMAT2 reduces the availability of dopamine at the synapse. This provides relief from the involuntary hyperkinetic movements. However, a challenge is that reducing dopamine levels can cause sedation. And importantly, as I mentioned, these agents carry boxed warnings for depression and suicidal behaviors.

In contrast, GPR88 agonists do not reduce dopamine levels, but aim to balance D1 and D2 medium spiny neuron signaling from the striatum as described in the video.

By leaving dopamine availability untouched at the synapse, there's the potential to relieve the involuntary movements without causing sedation or carrying the risk of depression and suicidal behaviors.

To explore this potential, we asked ourselves the following three questions in preclinical studies. First, do GPR88 agonists relief involuntary movements in animal models and if so, for how long? Second, does GPR88 agonism interfere with the dopamine 2 receptor antagonist? Bearing in mind, of course, that these patients are already being treated for psychosis or mood disorders, and we need to maintain that therapeutic activity. Thirdly, is there an advantage to the mechanism of action of GPR88 agonists over the currently available VMAT2 inhibitors? And I'm going to walk through these data in the next 4 slides.

To explore whether GPR88 agonism does reduce involuntary movements, we used a rat model of oral dyskinesia. In this model, the animals jaw moves involuntarily for absolutely no reason at all, and these are called vacuous chewing movements or VCM, and this is a standard model for the analysis of involuntary movements in TD. We explored whether vacuous chewing could be relieved by GPR88 agonism, and we compared with tetrabenazine, which is a VMAT2 inhibitor. And we'll be comparing GPR88 agonists with tetrabenazine in the following data slides in this section.

So if we focus initially on the left-hand side, these data show the activity of tetrabenazine in this model. The open bar represents animals treated with nothing at baseline. And as you can see, the green bars, treatment with tetrabenazine significantly reduced the VCM. Similarly, we see on the right-hand side the treatment with a GPR88 agonist reduced the VCM in this model. Therefore, these data support the potential for GPR88 agonism to reduce involuntary movements.

Part B to this question was, how long does this affect last given that the currently available VMAT2 inhibitors need to be administered daily. And the answer to that question is shown here. Here, we're capturing the duration of VCM over time, so time on the X-axis in hours and VCM count on the Y-axis. As you can see, we're comparing ACP-271 with tetrabenazine, both molecules caused an initially rapid reduction in VCM counts.

However, in the case of tetrabenazine, these return to baseline within about 6 hours. In contrast, the effect of ACP-271 extended to about 3 weeks. So now we've established that we do see a reduction in involuntary movements in this model, and we have a protracted pharmacodynamic effect compared to the VMAT2 inhibitor tetrabenazine.

Our next question is does GPR88 agonism interfere with the dopamine 2 receptor antagonists that the patient requires for alleviation of their underlying psychiatric disorder. To explore this, we used a mouse model of induced psychosis in which the effects of the antipsychotic risperidone were evaluated in the presence or absence of tetrabenazine or a GPR88 agonist.

And the results of that experiment are shown here. Here, locomotion is used as a surrogate for psychosis. The open bar shows control animals treated with vehicle and saline and it's walking around in its little cage. The black bar represents the animals in which psychosis was induced, see there's a significant induction of psychotic locomotion.

In the adjacent grey bar, we're looking at the effects of risperidone where we see a significant reduction in psychotic locomotion. The adjacent blue bar evaluates the activity of risperidone in the presence of a GPR88 agonist. And you can see the effect is entirely comparable. There was no effect of the GPR88 agonist on the activity of the antipsychotic.

And when we look at the green bar for tetrabenazine, we see there's a further reduction in locomotion. What we're looking at here is likely the additive effect of reduction in dopamine availability and the sedation associated with the molecules. Comparable results were also captured using other end points, such as the animal rearing up on its hind legs in the cage.

So we've now shown that GPR88 agonism can reduce involuntary movements, has a durable PD effect and does not interfere with the activity of a dopamine 2 receptor antagonist. Our next question is, is there any advantage to GPR88 agonists over the VMAT2 inhibitors. To address this question, we explored the effects of the two mechanisms on wild-type rodents.

Here, we're showing the effects of GPR88 agonism and tetrabenazine on locomotion and motivation to receive a reward. If we focus initially on the left-hand side, here, we're looking at locomotive activity in wild-type mice treated with negative control vehicle, GPR88 agonist or tetrabenazine.

In the blue line, what you can see is that it closely resembles the vehicle control line. Basically, GPR88 agonist did not affect locomotion in these wild-type animals. However, in the green line, the animals treated with tetrabenazine, we see a significant reduction in locomotion, representing the sedative effects of these inhibitors.

Now on the right-hand side, what we're looking at are wild-type animals in a cage where they have to press a lever to get their pellets, which are tastier than the regular chow that's readily available. The graph to the left of this box here is quantifying lever presses and the graph on the right is quantifying pellet intake. The open bar represents animals treated with vehicle control and the blue bars represent animals treated with increasing doses of GPR88 agonist. And what you can see is that the GPR88 agonist had no effect on lever pressing or consumption of the pellets.

In contrast, tetrabenazine was associated with a significant reduction in lever pressing and pellet consumption, suggesting in these wild-type animals that they have a reduced motivation to obtain their reward and reduced ability to press the lever to obtain it.

So combined, these data support the potential advantages of a GPR88 agonist over the currently available VMAT2 inhibitors, which are associated with sedation and depression.

The contrasting mechanisms of the VMAT2 inhibitors and GPR88 agonist as measured by the effects on dopamine metabolism are shown here. What the graph is quantifying is dopamine metabolism in isolated wild-type rat striatum, following dosing with either tetrabenazine or GPR88 agonist. As you can see, increased doses of tetrabenazine are associated with increased metabolism of dopamine, whereas the GPR88 agonist has absolutely no detectable effect.

Now we've reviewed the application of this mechanism in TD and its potential benefits. But the attributes listed here also apply across neurologic indications. That being the potential to avoid sedation and depression and with a durable pharmacodynamic effect. And after the break, we'll come back to this concept in the context of Huntington's disease.

To conclude this section on GPR88 agonists in TD, we've shown that these molecules may ameliorate the involuntary movements with a mechanism that has significant potential advantages over the currently available VMAT2 inhibitors. By restoring the balance of D1 and D2 receptor signaling without removing dopamine availability at the synapse, GPR88 agonists may avoid the sedative effect and boxed warnings of depression and suicide that are associated with the VMAT2 inhibitors. The positive pharmacodynamic effect is also durable, suggesting the possibility that less frequent dosing may be required.

And after the break, we'll return to these concepts with the application of these agonists in the context of Huntington disease. Thank you very much for your attention.

All right. Thank you, Rachael. We have a few more minutes for questions now and then we're going to go into a short break. So again, top two or three maybe questions based on what you've heard about ACP-711 and 271 in TD.

Tazeen Ahmad from Bank of America. Can I just ask one on each, if I may really quickly. For essential tremor, can you talk about the heterogeneity of the patient population. So as you design studies, this current study and future ones, how are you going to think about the best type of patients to enroll? Can you -- from your own experience and what you know about the advancement of the disease, what is the right type of patient profile to enroll to be able to show the biggest effect?

And then secondly, for tardive dyskinesia, how are you thinking about positioning of those products given that there are already approved drugs on the market, which by the time I'm assuming your products could launch could be integrated into a highly generic market. And do you feel like this would be initially used for refractory or could you see it being used for frontline right away?

Okay. I'll make a couple of comments and then maybe invite Vic and Rachael to expand. So certainly, I think one of the things that we heard about in Vic's section is the heterogeneity in terms of degree of severity and what might or might not require treatment. So that's obviously going to be a place that we're going to be focusing in substantially. I don't know if there's anything else you want to expand on there, Vic?

Yes. So we -- as I mentioned, as you get older, it gets worse. So we are kind of looking at some multiple ascending dose studies in the elderly, which is going to be our focus for treatment. And as I mentioned, a lot of times early on, you don't really need treatment. And the focus on more elderly patients would be key to this study.

So that's why a big focus on the elderly cohort right now. And as far as TD is concerned, I think we talked through some of the things we see as potential differentiators from what's currently available in the space.

Obviously, some of this is going to play out over time in terms of what the profile of 271 actually winds up looking like and what benefits we really can deliver. But we do think from a patient experience perspective, being able to get away from something that is heavily sedating, being able to get away from a situation where patients might be having to cut back on the dosing of the therapies that they require in order to treat psychiatric diseases, we think these are potentially some pretty compelling aspects to the story.

You answered it beautifully.

All right. Fantastic. Nothing else to add on that one. I think we've got time for at least one more.

Matt Hershenhorn from Oppenheimer. Really appreciate the question. So we were wondering, I guess, for ET, there was SAGE-324 that failed its Phase IIb study, but that was a GABA, I believe, alpha-1/3, nonspecific to alpha-3 unlike 711. So just curious, I guess, how that confers the higher specificity, potentially better efficacy and safety as an overall benefit risk. And just if there's anything from learnings from Sage's studies that you could apply to your own clinical study. Appreciate it.

Yes. I think Vic touched on this in his presentation. I think what we do know is that the GABA system is immensely complex and is involved in a tremendous number of different activities. We do think that data to date suggests that alpha-3 is what we should be focusing in on, and that's going to give us our best benefit/risk profile that gives you the opportunity potentially to push a dose compared with what you might be able to do with something that has more effect at alpha-1 or other alpha-containing subunits.

So we really do think compared with Sage and other molecules that have been explored historically. This gives our best opportunity to thread through that needle of targeting what we think is going to drive the disease the most, while sparing aspects that might bring additional risk on board.

Time for maybe one more?

One more? Okay.

Sumant Kulkarni from Canaccord Genuity. So given the protracted effect you saw on -- in preclinical margins of 271, what's the potential for developing a long-acting version? And what do you think of eventual dosing frequency?

It's a really good question that I don't think we are ready yet to propose what that's going to look like. We want to take this into humans and see how this PK/PD relationship plays out there. We'll be starting that Phase I first-in-human study towards the latter part of the year. We are encouraged by the fact that there looks like the possibility for a PD effect that could be less frequent dosing, but obviously, we're going to have to see how that plays out.

All right. With that, I think we have time for a 15-minute break, and we'll see everybody back here in -- I'm not going to try to do the math, 15 minutes from now. All right. Thanks.

[Break]

Bonus gift to everyone who's back in the room already as you're going to hear all the content and anyone whose late back from break is going to miss things. So thank you for being back.

So far this morning, we've been focused on more common diseases. And you see that these are and will continue to be an important part of our future. But our next adjacency step has been into rare diseases. And so we're now going to share some of the rationale behind the second half of our ambitions for ACP-271, and I'm going to welcome Rachael back to tell you about the data, underscoring our interest in exploring 271 in Huntington's disease. Rachael.

Hello again, everybody. Now we're going to switch gears and discuss the application of GPR88 agonists in Huntington's disease. Huntington's disease is a rare inherited neurodegenerative autosomal dominant disease, meaning that a person inheriting one copy of a mutant gene will develop the disease.

It's caused by the expansion of a CAG trinucleotide repeat within the Huntington gene, which results in the production of toxic mutant RNA and protein. The disease presents with both motor and psychiatric symptoms. The initial symptoms typically occur around age 45, but they may present quite a bit earlier or later in life.

Motor disturbances are typically the first clinically apparent signs of the disease, possibly with some detectable impairment of executive function. These motor disturbances involve involuntary movements, which are known as Huntington's chorea and loss of coordination. Once those symptoms appear, the disease progresses relentlessly with a devastating effect, including severe psychiatric changes such as aggression, mood swings, depression and dementia on top of significant motor decline.

These manifestations are the result of significant neuronal atrophy, particularly in the medium spiny neurons of the striatum, and death occurs within about 15 to 20 years of symptom onset. There are currently no approved treatments to arrest or prevent Huntington's disease. Approved treatments for the chorea, the involuntary movement seen earlier in the disease include the VMAT2 inhibitors, which we discussed in the previous section, and as we discussed in the previous section, these are associated with box warnings for depression and suicidal behaviors.

Now HD patients are already at risk for depression and suicide as part of the disease course and as part of living with this disease. So these drugs need to be used with caution in the treatment of Huntington's chorea.

In addition, about 50% of patients do not respond to treatment. So the unmet need in this devastating disease is therefore significant. Our rationale for applying GPR88 agonist in HD is based again on that novel dopamine sparing mechanism that was introduced in the movie and that we highlighted in the TD discussion. In the context of HD, this has the potential to relieve psychiatric symptoms of the disease as well as the motor symptoms. And I'll review the rationale in more detail in a couple of slides.

Prevalence of HD is around 4.9 per 100,000 people worldwide. In the United States, there are an estimated 21,000 patients currently diagnosed and almost that number estimated undiagnosed in the U.S.A.

The rationale for GPR88 agonist in HD includes multiple lines of evidence several of which are captured in broad strokes on this slide. Huntington disease patients experienced significant loss of the striatum, which is composed about 95% of medium spiny neurons and it's where GPR88 resides. As shown in the diagram on the upper right, comparing the healthy brain with the Huntington disease brain, and we're calling attention to the caudate nucleus and the putamen, both areas of the striatum and both of which are atrophied in Huntington's disease.

On the lower right, the diagram captures the fact that early in the disease the D1 -- the D2-containing MSNs are preferentially sensitive, resulting in lots of D2 MSMs and the choreatic movements that are seen early in the disease due to the predominance of D1-expressing MSN. As the disease progresses, there is loss of D1-expressing MSNs and the patient experiences bradykinesia or slowness of moving.

In addition to these characteristics, individuals who do not have Huntington disease, but who do have a deleterious mutation in GPR88, show characteristics of Huntington's disease, including choreatic-like movements and learning disabilities. So here, there's a direct association between the loss of GPR88 function and manifestations of Huntington disease like symptoms.

Animal models of Huntington's disease show reduced expression of GPR88, and preclinical models have shown involvement of the target in multiple phenotypic domains, including both motor and psychiatric domains, including impulsivity, motivation and cognition. A GPR88 agonist, therefore, has the potential to ameliorate both the motor and the psychiatric components of Huntington's disease by balancing out that signaling between the D1 and D2 medium spiny neurons. In the next two slides, I'll be showing you the effects of GPR88 agonists in two animal models of Huntington's disease.

The first of this is a Zebrafish model of the disease. So the Zebrafish is very small, and it is a fish. However, it does retain that cortico-striatal-thalamic-cortical loop, the CSTC loop that we were introduced to in the mechanistic video at the very beginning. Therefore, we can explore the effects of perturbation in this loop via GPR88 agonism or VMAT2 inhibition.

So in order to efficiently swim forward, Zebrafish need to effectively coordinate their bodies. We, therefore, measured the motor control of a mutant Huntington Zebrafish in the presence or absence of a GPR88 agonist or tetrabenazine and compared this with wild-type fish.

Focusing initially on the left-hand side, we're looking at locomotive activity. And what you can see is that the wild-type fish is happily swimming along. The mutant Huntington fish shows significant reduction in locomotive activity. The presence of a GPR88 agonist, we see an increase towards the wild-type fish in locomotion. However, animals treated with tetrabenazine show a further reduction in locomotion, probably representative of the sedative effect of these molecules.

If we look on the right-hand side at motor coordination, we see a similar effect, wild-type animals showing a certain level of coordination, significant increase in the mutant Huntington fish towards the wild-type level, tetrabenazine has no or mild effect. These data support potential for a GPR88 agonist to ameliorate the loss of coordination in Huntington's disease.

Now as you'll recall, Huntington disease progresses slowly. It's observed initially through the more readily detectable motor presentation, but psychiatric effects of the disease appear and then become increasingly detectable.

Based upon this disease progression, it's important to measure the effects of potential therapeutics in a representative system that itself develops solely and enables the capture of multiple aspects of the overall disease phenotype. To this end, a mutant Huntington disease mouse known as the Q175 mutant Huntington heterozygous mouse is considered a relatively representative genetic model of the disease. It contains one mutant copy of the Huntington gene. The disease progresses slowly with detectable motor and psychiatric components.

Now in order to capture the multiple aspects of the disease in these animals, a PhenoCube can be used to measure the pheno type based on multiple components of the disease in the presence and absence of potential therapeutics. Because of the dimensional nature of the information obtained using this approach, the data are represented as clouds comprising hundreds of data points collected over time. We can't simply plot them as a line graph or a bar plot. So with that description, I'm now going to show you data that we obtained in this model where we explored the effects of a GPR88 agonist.

So there's a lot of visually unusual information here, and we're going to walk through it slowly to clarify what we're sharing with you. We're looking at data obtained from three treatment groups of mice. Mice treated with -- mutant mice, I'm sorry, treated with a GPR88 agonist; mutant mice treated with vehicle control; or wild-type, non-mutant, vehicle-treated control mice.

Mice in these treatment groups were dosed for either 1 day or 8 days with twice a day dosing, followed by observation and data capture in the PhenoCube for 48 hours. Now as I just mentioned, multiple aspects of their behavior are captured in these data clouds, including both motor and psychiatric indices. Here, we're looking at day 1. And you can see the three data clouds representing the three groups.

This pinky one is representing the mutant mouse treated with vehicle control. The green cloud is representing the mutant mouse treated with a GPR88 agonist. And the blue cloud is representing the wild-type mouse. What you can see here is that there is direct superimposition of the two mutant groups of mice. They're not distinguished by whether or not they receive GPR88 agonist.

However, when we examine the data -- the mice after 8 days of dosing, we see that the green cloud is moving away from the pink mutant mouse data cloud. And towards the wild-type healthy animal cloud. This reflects a trend towards the healthy phenotype and away from the mutant phenotype in animals that have been treated with a GPR88 agonist. And to capture this numerically, we saw approximately 47% normalization of the HD phenotype in this experiment. So these data support the potential for a GPR88 agonist to ameliorate multiple characteristics of Huntington's disease and the cumulative disease presentation.

So to summarize what I've shared with you in this section, multiple lines of evidence support the potential for GPR88 agonists in the treatment of HD. There are no approved treatments to prevent or arrest HD, or to broadly address the motor and psychiatric symptoms. VMAT2 inhibitors are approved for treatment of Huntington's chorea and are only effective in about 50% of patients and need to be used carefully in this population.

GPR88 deletion in non-Huntington patients is associated with features of Huntington's disease. And Huntington disease patients experience loss of their striatum, which is comprised over 95% of medium spiny neurons where GPR88 resides. Animal models support a role for GPR88 in HD symptomology. And now today, we've shared with you some data in animal models that support the potential for GPR88 agonists to relieve the symptoms of both motor and psychiatric effects of Huntington disease.

So in summation, by balancing dopamine 1 and dopamine 2 receptor signaling from the striatum, there's the potential to ameliorate both the motor and psychiatric symptoms of Huntington's disease, sparing the sedative effects and avoiding the box warnings of the VMAT2 inhibitors, which are currently used to treat the chorea.

Next steps for our GPR88 program include filing an IND for ACP-271 and the initiation of our first in-human study later this year. This will be the first time a GPR88 agonist has entered the clinic. So the study will be exploring the safety, tolerability and pharmacokinetics of ACP-271 in healthy volunteers. And in parallel, we're going to continue to advance our follow-on molecules through preclinical studies to maximize the potential that this mechanism has to offer for patients living with neurologic diseases. And thanks again for your attention.

Neuro rare diseases offer an opportunity to apply our expertise in neurological disease while also building a foundation in how to develop and commercialize in rare diseases.

Drug development in rare disease is a passion of mine and has been an important part of my career, and it encourages different and creative thinking at every step along the way. First, in this section, we're going to turn to ACP-101, our investigational product aimed at the hyperphagia associated with Prader-Willi syndrome.

For this section, I'm pleased to invite some friends to join me. First of these is Dr. Shawn McCandless, from the University of Colorado. Dr. McCandless is a Clinical Geneticist with special expertise and interest in inborn errors of metabolism, Prader-Willi syndrome and generally rare genetic diseases. Thank you for joining us, Dr. McCandless.

You're welcome.

Excellent. We have audio. Okay. Joining us live from the United in Hope Conference is Susan Hedstrom, Executive Director of the Foundation for Prader-Willi Research. The United in Hope Conference is the main conference of the year for the Prader-Willi community. And it brings together patients and families, physicians and scientists, all in pursuit of a better future for these families. Susan's son Jayden is living with PWS. She is a fierce and formidable champion for her community. And I know she'll bring home to all of you, the patient perspective that drives us every day. Susan, it is a pleasure as always.

Thanks so much for having me.

Yes, 2 of 2. Okay. And finally, I'm pleased to introduce Dr. Jim Youakim, Vice President of Clinical Development, who is in charge of the ACP-101 program here at Acadia. Dr. Youakim is a psychiatrist by training and he's worked in the pharmaceutical industry for nearly 20 years. In addition to rare disease indications, such as PWS and Rett syndrome, he's worked in clinical development of treatments for schizophrenia, major depressive disorder, Alzheimer's disease and other psychiatric and neurologic indications. He'll be sharing some insight into the historical data set as well as an overview of our ongoing program. And welcome, Jim.

Thank you very much, Liz.

Excellent. All right. Going into interviewer mode over here. So to level set us all for the discussion that we're going to have today, Dr. McCandless, can you start off by giving us an overview of PWS?

Surely, I may have the first slide, please. Prader-Willi Syndrome is a rare genetic disorder but is actually one of the more common -- more commonly diagnosed genetic disorders. It's caused by the absence of products of several genes on chromosome 15. How those specific genes cause the symptoms is not entirely clear. The genes are typically only active when they're inherited from their father. So if you're missing those copies of the genes from your father, you'll have the disorder or if you have got both of your chromosome 15s from your mother, which happens occasionally, you will also have the condition.

It's -- it typically has several stages that we see clinically. The first stage is in the newborn period where the babies are very sleepy. They are very poor feeders. They have difficult gaining weight. Typically require tube feedings and just a very to develop and also very placid babies. And then things sort of normalize in terms of their feeding behaviors. And then over the next few years, we begin to see that they start to gain weight. And it really seems as though their metabolism is slowing down greatly and then they become more and more hungry. So they're acting -- the children that have this are acting like they're starving. Their body is telling them, they're starving, even though we can see from their weight that they're not starving, in fact, they're excessively heavy. And that's a continued theme throughout their lifetime. The low muscle tone that we see in the babies persist through life, although it becomes less of an issue.

Some other symptoms become readily apparent over time. There's a relative deficiency of growth hormone, so short stature and low muscle mass is very common. There are a number of respiratory complications and there are a lot of behavior regulation issues with emotional -- difficulty with emotional regulation, rapidly becoming angry or upset for little or no reason. What really kind of overshadows all of this is this intense hunger that the patients clearly feel. Their -- it seems like their body is telling them that they're starving and they are driven to get food the way any person who's literally starving to death would be. They steal food. They think about food constantly. Anytime there's an opportunity to get food, they will do it and without a second thought.

So that combination of -- they also have mild intellectual disability. So they -- in most cases, although 20% or 30% of people with Prader-Willi Syndrome have functional IQ testing in the normal range. Overall, that complex of behavioral dysregulation, anxiousness and hyperphagia leads to a really, really huge challenges for the family. I'm going to circle back to that in a minute. I do want to go back to the last slide for just a minute to point out that over the past 25 or 30 years, the life expectancy has been shown to be around 30 years of age on average, although we have many patients who are much older than that. The rate of mortality for a wide variety of reasons is really quite high, 3 to 6x higher than we see in other children with developmental disabilities. And so there's -- and there is a -- in spite of that, there is fairly large population of people living in the U.S. Some estimates say 8,000 to 10,000, it could even be a bit higher than that.

The mortality is caused by a variety of things. Early in life, it's typically respiratory symptoms. Later in life, it may be accidental deaths. It may be pulmonary embolism. And in a disturbingly large number of patients, it's actually related to intestinal catastrophes from gorging food and rupture of intestine or stomach. And that's just awful. So if we could go back to the next slide then. I just want to point out a couple of things. So the hyperphagia, that unrelenting pathological hunger and the inability to -- the complete inability to regulate food consumption for the person's self-drives their care. They have to have 24-hour attention to make sure that they are only getting access to the food that they need to gain weight. And because their muscle bulk is low, that's usually about 60% of what another person their size would need to maintain their weight.

Because of the obesity, the hypotonia and everything else that goes along with it, there are significant comorbidities with metabolic conditions like diabetes, right-sided heart failure from secondary to obstructive sleep apnea are extremely common, as you can see here, renal and liver disease and just a wide variety of other problems. Orthopedic problems are very common, both in childhood and adult life because of the obesity, scoliosis, hip dysplasia. Altogether, this is a really difficult condition for both the patient, for their family. And it just is, as I said, a 24-hour a day job to keep the person with Prader-Willi Syndrome safe. So I think as stuff there and you'll hear more about that from Susan.

Thank you so much, Dr. McCandless. I think that gave us a really good grounding. So Susan, tell us a little bit about what your journey has been like with your son, Jayden, what diagnosis was like, what it was like to learn about PWS.

Sure, absolutely. So Jayden was born 16 years ago. We were fortunate enough to be in San Diego, where we have excellent health care. So he was able to be diagnosed pretty quickly. They -- within a day or 2, were whispering Prader-Willi Syndrome and he was diagnosed clinically at only 6 days old, which is pretty early on. Like many people with children with Prader-Willi Syndrome we had no indication that he was going to have any genetic disorder. We were expecting a perfectly neurotypical baby. So when he was born, it was quite a surprise to us when they rushed him to the NICU. And frankly, when they start giving you this diagnosis, for most families it's quite traumatic. You're given a laundry list of things that your child will never be able to do. They will never be able to go to school. They will never be able to live independently. And what's hurtful for a lot of people, they will never be able to have children.

So as a family, you begin to grieve for the life that you thought your child was going to lead. We all have dreams of what our children will do or assumptions even. We assume our children we'll be able to drive a car, go to college, live independently. And those things are all taken away from you in a single diagnosis. So for many of us, that initial journey is quite bleak.

Thank you for sharing that. It sounds incredibly difficult. Dr. McCandless told us a bit about hyperphagia. And as we'll be touching on shortly, that is the primary focus of our ongoing study. Now I think Dr. McCandless did help to address this but I'd really love it, Susan, if people can hear this, I think, and say, "Oh, no big deal, they're a little bit hungry." Can you tell us a little bit about what hyperphagia has meant for you and for your family?

Sure. So oftentimes, when I begin to tell people about my son and hyperphagia, I'll start with he feels hungry all the time. And people very quickly will say, "Oh, well, I'm hungry all the time. Maybe I have Prader-Willi Syndrome." And I have to explain, this is very different from just being hungry or thinking about your next meal. This is all consuming. He is always thinking about food. How much food he is going to get, where he's going to get it. Every minute of his life, he is hungry and thinking about food. We have 2 other children, as you can see in this photo, a 14 year-old and 11-year-old. And Prader-Willi Syndrome absolutely impacts their lives as well as that of our family.

The first thing you'll notice when you come into our home is there is never food accessible or in view. So if you look at countertops, there is nothing on the counter, ever. It's not that we're clean freaks. It is to keep our child safe. Our refrigerator is locked. Our pantry has thumb locks on it, so that the kids can access the food but Jayden cannot. As he is has gotten older, we've had to get more crafty. We cannot leave food in the garbage can. There cannot be food in the sink. He will pick up food from the floor that is not edible, to eat it.

So we really have to be very cautious, eyes have to be on it all times. We have cameras in our house so that he knows we're watching. He wants to be good. He doesn't want to do things that are not socially acceptable. But he has a drive to do it. It is innate and it cannot be taught out of him. Impactful to our family is our ability to go out into the community. I think that is actually the biggest inhibitor of Prader-Willi Syndrome because he's always thinking about food, it leads to anxiety. So if we're going out to a restaurant, he wants to know where we're going, what he's going to eat, what time it's going to be. And if anything changes in those factors, you are facing the potential of a massive public meltdown, which is the biggest fear of our family when we're going out in public.

You can imagine a 3-year-old having a temper tantrum in a restaurant or in a grocery store, it's socially acceptable. Now imagine that same toddler meltdown with a full-sized grown man. And now it's not acceptable anymore. And in fact, it can be dangerous. So we try to avoid that at all costs. And sometimes we simply have to say, it's just not -- going out is not going to work today. Going to the community barbecue is not going to work today. Thanksgiving meals with the family is not going to work today because hyperphagia is just all too present and the anxiety that goes with that.

Thank you. And I think that hopefully helps people get a sense of the importance of this aspect of the disease and why we are so devoted to trying to find something that can help with that. So with this, I'd like to turn and spend a little bit of time talking about the ACP-101 program. So to start off, Jim, can you tell us a little bit about what ACP-101 is? And what the scientific rationale is behind the program.