ACADIA Pharmaceuticals Inc. Stock

Good morning, ladies and gentlemen, and welcome to the ACADIA Pharmaceuticals conference call to discuss the RADIANT Phase II top line results evaluating Remlifanserin for the treatment of Alzheimer's disease psychosis. My name is Christa, and I will be your coordinator for today.

I would now like to turn the presentation over to Al Kildani, Senior Vice President of Investor Relations and Corporate Communications.

Please go ahead.

Thank you, Christa. Good morning, and thank you for joining us on today's call to discuss the top line results from the Phase II portion of our ongoing RADIANT clinical trial program evaluating Remlifanserin for the treatment of hallucinations and delusions associated with Alzheimer's disease psychosis or ADP.

On today's call, Catherine Owen Adams, our Chief Executive Officer, will provide opening remarks. Following Catherine, Liz Thompson, PhD, Executive Vice President and Head of Research and Development, will review the study design and discuss the Phase II top line efficacy, safety and tolerability results from RADIANT. Catherine will then provide closing remarks before we open the call for your questions. I would also like to point out that we are using supplementary slides, which are available in the Events and Presentations section of our website.

Before we proceed, I would like to remind you that during today's call, we will be making a number of 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, development time lines, regulatory activities, future study outcomes, commercialization opportunities and future results are based on current information, assumptions and expectations that are inherently subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially.

These factors and other risks associated with our business can be found in our filings 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.

I'll now turn the call over to Catherine Owen Adams.

Thank you, Albert. Good morning, everybody. Thank you very much for joining us today. We are very pleased to share the top line results from our Phase II portion of the RADIANT clinical trial program evaluating Remlifanserin for the treatment of Alzheimer's disease psychosis are Phase III-enabling. Importantly, these Phase II results demonstrated meaningful and consistent efficacy trends across endpoints.

The 60-milligram dose narrowly missed statistical significance on the primary endpoint of change from baseline in SAPS-H+D total score at week 6 and demonstrated nominal statistical significance on the key secondary endpoint of change from baseline in CGI-S-ADP. Remlifanserin across both doses also demonstrated a favorable safety and tolerability profile with no new safety signals identified. Taken together, we are excited that the efficacy and safety results support the further development of Remlifanserin in the 2 Phase III ADP trials currently underway.

I'll now turn the call over to Liz to review the Phase II study design and results in greater detail, after which I will return with some closing remarks.

Liz?

Thank you, Catherine. I'd like to begin by thanking the patients, caregivers, investigators, study coordinators and of course, the dedicated internal ACADIA team whose dedication made this study possible. RADIANT is a global, randomized, double-blind, placebo-controlled, operationally seamless Phase II and Phase III program evaluating Remlifanserin in Alzheimer's disease psychosis.

The Phase II portion of the study was designed to evaluate the efficacy and safety of 2 doses, 30 milligrams and 60 milligrams given once daily and to inform the dose and patient population for the Phase III program. The results provide clear and important information to support the continued development of Remlifanserin, including the selection of dose and considerations on how we could refine the patient population for Phase III.

In RADIANT, patients were randomized in a 1:1:1 ratio to receive 60 milligrams of Remlifanserin, 30 milligrams of Remlifanserin or Placebo once daily for 6 weeks. The primary endpoint was change from baseline in the SAPS-H+D total score at week 6. And the key secondary endpoint was the change from baseline in a clinician global assessment of severity called the CGI-S-ADP at week 6.

Our prespecified population for our efficacy analysis was the modified full analysis set, which is referred to in these slides as the mFAS. This comprised 326 patients who received at least 1 dose of study drug, had a baseline SAPS-H+D total score of at least 10 and had at least 1 post-baseline SAPS-H+D assessment. In the mFAS population, 109 patients were assigned to the 60-milligram dose, 110 to the 30-milligram dose and 107 to Placebo.

Demographic and baseline characteristics were generally well balanced across treatment groups. The mean age was about 75 years old and approximately 2/3 of patients were female. Baseline SAPS-H+D and CGI-S-ADP scores were also generally similar across the treatment groups, supporting the interpretability of the results.

Going to the next slide. Turning to the efficacy results. The 60-milligram dose of Remlifanserin narrowly exceeded the prespecified threshold for statistical significance on the primary endpoint. At week 6, the 60-milligram dose demonstrated an effect size of 0.26 on the SAPS-H+D total score with p-value of 0.0603. For the key secondary endpoint, the effect size was 0.37 with a nominal p-value of 0.0077. This corresponded to reductions from baseline of 12.4 versus 10.4 for SAPS-H+D and 1.3 versus 0.9 for CGI-S. A dose effect was observed as the 30-milligram dose showed minimal improvement relative to Placebo with effect sizes of 0.05 and 0.11 across the primary and key secondary endpoints.

Now as we have discussed this topic previously, I want to make a quick note about the NPIC. As you will recall, we added this as an exploratory endpoint and collected it only in patients who were enrolled later in the study. So we are early in our analysis of this endpoint. But to date, it appears that a small numerical improvement in NPIC was also seen in the 60-milligram arm.

Now returning to SAPS-H+D. On this slide, we show the performance over time, where the data suggests increasing separation through week 6. In totality, the efficacy data, combined with safety data that support either dose, which I will review later in the presentation, gave us confidence in selecting the 60-milligram once-daily dose of Remlifanserin for further development.

The next question we turned our minds to was whether there were any modifications to the inclusion criteria that hold the potential to improve Phase III outcomes. We used prespecified subgroups to guide us regarding the potential impact on both efficacy and patient eligibility of several criteria modifications. One promising area with the potential to further improve efficacy in Phase III while maintaining the significant majority of the trial population is further refining the enrollment criteria for modestly higher baseline psychosis.

On this slide, you can see the impact of one potential version of this refinement when applied to the Phase II trial. First, 80% of patients in the trial would still have qualified for participation. Second, the effect sizes in the resulting population increased for both the primary and key secondary endpoint. For the primary endpoint, the resulting effect size was 0.33 and for the key secondary, it was 0.43. Interestingly, on the later enrolled patients where we collected NPIC H+D data, there was a similar suggestion of improved effect in this population.

And again, I must emphasize that the data are limited based on the timing of adding the endpoint to the study. We are considering whether this refinement to modestly higher baseline psychosis or similar refinements would be beneficial to the overall profile of Remlifanserin.

Turning now to safety and tolerability. The overall safety profile observed in this study was favorable and supported continued development of Remlifanserin. Now recall that one of our main goals with Remlifanserin was to avoid the QT prolongation signal that had prevented our evaluating higher doses of Pimavanserin. Preclinical and Phase I data has supported our desired profile for Remlifanserin, and we were pleased to see that in this data set, there was no signal of QT prolongation compared with the Placebo group.

Expanding to the safety profile more broadly, rates of adverse events, serious adverse events and discontinuations due to adverse events were all seen at similar rates to Placebo. There were no deaths in either Remlifanserin treatment group compared with two deaths in the Placebo arm. Rates of individual adverse events were also low. In fact, no individual adverse event was reported in more than 5% of patients receiving 60 milligrams once daily Remlifanserin. Somnolence at 3.2% and nausea at 2.4% were the only adverse events reported in more than 2% of patients receiving 60 milligrams that occurred at a numerically higher rate than Placebo.

Finally, I've talked previously about our target profile for Remlifanserin and what aspects could yield an important treatment option for patients. I was pleased to see that this data set suggested no negative impact on motor function or motor symptoms or cognition. Taken together, the safety and tolerability findings were consistent with our hopes for the molecule and support continued evaluation of Remlifanserin in the ongoing Phase III studies.

Now looking ahead, we plan to present additional efficacy and safety results from the Phase II study at the Clinical Trials on Alzheimer's Disease or CTAD conference, which takes place November 16 through 19 in Boston. The Phase III program continues while we implement protocol amendments, including removing the 30-milligram dosage arm. And with that, I turn the call back to Catherine.

Thanks so much, Liz. So with these results providing us valuable information needed to continue the development of Remlifanserin, I'd like to put the opportunity ahead in context, beginning with the significant unmet need, it may address, if successfully developed and approved.

Alzheimer's disease psychosis is characterized by hallucinations and delusions occurring in patients with Alzheimer's disease. According to the Alzheimer's Association, more than 7 million people in the U.S. are currently living with Alzheimer's disease, and approximately 30% of these patients are estimated to experience psychosis, commonly consisting of hallucinations and delusions.

These symptoms can be frequent, severe and highly distressing for both patients and caregivers. They're also associated with worse clinical outcomes, including increased likelihood of institutionalization, greater disease severity and increased morbidity and mortality.

Despite the substantial burden of disease, there are no currently FDA-approved therapies specifically indicated for hallucinations and delusions associated with Alzheimer's disease psychosis. We believe there remains a significant and important need for new treatment options, and today's findings reinforce our confidence in Remlifanserin's potential to address this underserved patient population.

Additionally, and importantly, we also continue evaluating Remlifanserin in an ongoing Phase II study in Lewy body dementia psychosis. Lewy body dementia is a progressive brain disorder affecting thinking, movement, mood and behavior. More than 1 million people in the U.S. may be living with LBD and an estimated 50% to 75% experience psychosis. There are no therapies approved for Lewy body dementia psychosis, underscoring the significant need for new treatment options. Approximately 200,000 patients with Lewy body dementia psychosis are currently treated with antipsychotics, further illustrating the need for an effective and well-tolerated therapy, specifically developed for this population.

Looking ahead, we expect our existing products to generate meaningful near-term growth with projected global net sales of approximately $1.7 billion through 2028. Over the long term, we have several attractive pipeline assets with strong commercial potential in areas of significant unmet need. Collectively, we estimate these programs could represent approximately $11 billion in unadjusted global peak sales potential, including $4 billion for Remlifanserin across both Alzheimer's disease psychosis and Lewy body dementia psychosis.

While these estimates are not financial guidance and drug development carries inherent risk, they illustrate the substantial opportunity we see across both our existing portfolio and pipeline.

More broadly, Remlifanserin is part of a robust pipeline with multiple ongoing and planned programs across neurological and rare diseases. We expect to announce a further 3 Phase II or Phase III study readouts through 2027 with additional development and regulatory milestones across the pipeline. Today's RADIANT Phase II results reflect ACADIA's continued commitment to developing innovative therapies for patients with serious neurological conditions where effective treatment options remain limited.

I would like once again to thank the patients, caregivers, investigators and study personnel who participated in the study as well as our employees and collaborators whose hard work and dedication has made today's milestone possible. We look forward to presenting additional Phase II findings at our CTAD meeting in November and providing updates on our continued progress.

And with that, operator, we're now ready to open the call for questions.

[Operator Instructions] And your first question comes from Ritu Baral with TD Cowen.

So many questions. We'll start with the NPI. I think, Liz, you mentioned that you're seeing something. Are you seeing an effect size similar to the CGI and the SAPS-H+D? And have you sort of done the correlation analysis that we've spoken about that would really validate the SAPS-H+D. I guess I'm wondering, is the SAPS-H+D in your mind, still the appropriate endpoint? And do you have to talk to FDA before making any changes to the F3 -- I'm sorry, the Phase III around powering?

Excellent questions, Ritu. A couple of thoughts. First, I do want to say these are top line results. We've had these data for a very short period of time. So we've done initial analyses. There is more that we have yet to do, but there are some comments that I can make for now. The first of these, as we have discussed before, one of the things with the NPIC was we did move it late. And so there is a relatively limited proportion of the population that actually do have these data available.

If you look at the overall population there, again, going back to my remarks earlier, it is a relatively small numerical improvement that you see with the 60-milligram arm. When you get into the enriched population that I showed an example of what it could look like, you do see an effect size that is more similar to the effect size that you see with the SAPS-H+D. But again, this is very preliminary at this point. We absolutely have not, at this point, done the kind of validation analyses that we would need to do to support primary endpoint dossier.

That is stuff we will do now that we have the Phase II data in our hot little hands, but that is part of our intent. In terms of talking with FDA, we don't believe that we need to, for example, discuss with them to get their conclusion on dropping the 30-milligram dose arm. I think that that's very clear and the data support it, and we are planning to go forward with that as quickly as possible. Were we to make a change to the primary endpoint in the Phase III eventually, I would want to discuss that with FDA. At this point, we're not proposing that.

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

I had a few on basically related to Slide 11. So first of all, you mentioned, Liz, that this is one of the exploratory analysis you did. Is this the most likely course of action with regard to a change to the Phase II population? Or are there other slices that you might enumerate that would be of interest with regard to enriching for a higher responding group?

Secondly, could you comment at all with respect to whether the efficacy was more enriched on the H, the hallucination versus the D, delusion with regard to the primary endpoint. Just wondering how that shook out? And then my last question is regarding the 30 milligram, I know it didn't hit, but I'm just curious if you did the analysis on Slide 11 for the 30 to potentially show that there may have been a little bit of a separation there, if you enriched for the high baseline psychosis even at the 30, which would give you more confidence in that subgroup?

Okay. Quite a few things there. Hopefully, I got them all jotted down. So we are evaluating various possible options of what we might do in terms of minor modifications to the patient population. It's always a trade-off in terms of the proportion of your population that remains relevant and the potential bump in efficacy that you could see.

I will say that I think that focusing in on a little bit more higher baseline psychosis severity, I think, is a promising area. And that is where I am most enthused, but we are thinking about what the appropriate way of doing that would be. But I do think Slide 11, we gave that as an example because we think that this is a strong contender that really does balance the -- keeping the broadest possible eligible patient population for the trials while also somewhat increasing potentially the efficacy that we might expect or at least were -- would have seen in Phase II with that application.

We are keeping high level at this point in terms of data. So I'm not really going to comment on the breakdown between hallucinations and delusions. But I will say that across endpoints, we did see impact on both. And in terms of we did also look at the 30-milligram dose Slide 11 type analysis as well as other versions of that. And we did see some increase, though it is consistently not in the realm of the 60-milligram arm. So again, we feel very confident that 60-milligram is the right dosage arm to take forward.

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

Catherine, Liz, as you saw these results and thought about the pushes and pulls of moving Remlifanserin forward, what ultimately made you decide that moving this program forward was worth the investment for ACADIA relative to all of the other initiatives at the company? And then as a follow-up, what additional analyses are you working through that we can expect to see at CTAD here in a couple of months that may be supporting your view?

Thanks, Tess. I'll start and give Liz a quick break. In terms of balancing investment choices at ACADIA right now, we're in a fortunate position that we don't have to make those trade-offs specifically for any of our programs. We have, as you know, a strong balance sheet and a strong investment focus on our R&D portfolio, we were very encouraged by the results we've seen. We are continuing to look at how to enrich the population for further enhancement through Phase III.

And we believe with the high unmet medical need in this population, the efficacy that we've seen so far that Liz has described, and we will continue to describe as we move forward in the next few months, as well as the safety and tolerability profile that this molecule offers the potential for patients with Alzheimer's disease psychosis, and it is absolutely worth our investment to move this forward into the Phase III trial.

Absolutely echo all of that. It is good to be in a position where what we -- the choices we are making is, is this worth taking forward versus which thing can't we take forward. So we're pleased to be in that position, and we feel good about the fact that this is a program that has the potential to meet a real, real meaningful unmet need for patients.

In terms of CTAD, we're having only gotten this data very recently, we're very early in putting together what our actual presentation for CTAD would look like. And obviously, we're going to have to work with investigators on what the most appropriate things to put forward are. But certainly, you should anticipate that you're going to see some additional endpoints beyond this, some additional description of safety. And if there are things that we think are especially meaningful in terms of ways that we could refine the patient population, we likely would address that as well.

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

Given the safety you've seen so far, could a dose higher than 60 mg be added? And is there any merit in considering later time points beyond week 6? And if you look at dementia with Lewy bodies, that tends to have higher rates of psychosis versus Alzheimer's disease psychosis. So do you expect any different types of behavior of this product in that patient population as you consider the Phase II trial there?

I'm not sure that I grabbed all of those. So I'll comment on the ones that definitely stuck with me and then somebody around the table will prompt me for what I forgot. So I'll say, certainly, it's an interesting question. We really did feel like we had -- we were targeting an exposure that was going to be associated with near maximal efficacy. I will say that one of the things that we'll be continuing to think about is exposure response analysis to see whether there's a reason to believe that going even higher might be helpful.

All that said, we think 60 milligrams represents a based on the profile seen to date, recognizing we would -- we have to do the Phase III trials and are, we think that 60 milligrams represents a profile that is potentially an approvable medication, if the Phase III were to look like we are thinking that it could based on this information that we have about how to refine the Phase III program.

So I think we don't believe we have to go to a higher dose, and we're looking for the exposure response to see if there could be any benefit to this. But for now, we really do think 60 milligrams is an important treatment option.

As far as a longer time point, patients do roll into an open-label -- into open label here. Obviously, there are always [indiscernible] that you need to think about in terms of comparing open-label to double-blinded data. We think that week 6 gives us a good demonstration of the efficacy. The shape of the curve, particularly if you look at SAPS-H+D, does suggest that maybe you could get a little bit more if you look a little bit further out, but we want to focus in on week 6 as a place that can demonstrate the efficacy and where we have an understanding of both how our drug works as well as the Placebo arm. So we do anticipate maintaining the week 6 time point as our primary endpoint for the Phase III program.

As far as DLB, we continue to be -- or Lewy body, we continue to be very enthused about the potential profile there. I have always thought that the efficacy, while in limited numbers of patients with Pimavanserin was striking. So this suffice it to say nothing about these data have decreased our enthusiasm about that. So we really are looking forward to those results.

We do have to run the study in Lewy body because exactly as you note, it is a distinct patient population that can have distinct reactions to medication and sort of a distinct profile in terms of how sensitive they are to safety. So we look forward to understanding the application of Remlifanserin in Lewy body, but we think this is certainly supportive of that and feels good. So I think that was all the questions.

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

I wanted to understand the enrichment for more severe patients that you've talked about. So I know you mentioned that this Phase II Radiant is enriched already with 80% of these patients have modestly higher baseline psychosis. But you're also saying that you will try for modestly higher baseline in the Phase III. So what would that look like? And then just on the same topic, maybe like when you compare the psychosis level in this Phase II RADIANT, how did that compare to the prior study '19?

Thank you so much for giving me an opportunity to clarify something that I may not have said very clearly. So that example that we gave of an enriched population, when I was saying 80%, that was actually indicating that 80% of our currently existent population would fit under this new definition. So that's just to be clear on what that meant.

So we do think that, obviously, sort of -- that does mean that there is a potential to nudge our population such that everybody fits within the future study. We are considering it. We have not landed on this as the absolute way that we're going to go forward, but that is what we are thinking of because it does appear that there's a possibility of increasing the efficacy that we could see out of it.

In terms of comparisons with the prior study, what I will say, and again, you'll see more granular data on this, I think, at CTAD. But what I will say, generally speaking, is that we had indeed enriched our Phase II program compared with the '019, the Phase II study with pimavanserin to try to move patients -- try to move the general population to a somewhat more severe psychosis phenotype.

And we were successful there. We had increased the severity here compared with the '019 study. That said, we do think that there could be some benefit potentially to increasing that just a little more, a modest increase there, and that is what we're focused on as one very promising potential area for refinement of the population.

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

This is Nevin on for Brian. Just wondering if you could talk a little bit more about what you think might be clinically meaningful delta for the SAPS-H+D, just given that the 60 mg arm showed around a 2.2 point delta. How do you kind of interpret this in the context of the current regulatory landscape, particularly given kind of the high unmet need that we've seen?

Fantastic question. I think a lot of this, we do need to ground in the significant amount of unmet need that I think Catherine eloquently covered in the presentation. And given that, I think that we do believe that these results colloquially, we believe that these results are clinically meaningful and would represent -- could represent a clinically meaningful treatment option for patients.

From a technical perspective, some of the analyses that we are going to be doing is demonstrating that for purposes of regulatory consideration in terms of what degree of change is clinically meaningful to meet a regulatory bar. But certainly, based on conversations running into this readout and very, very limited conversations since, we think that this represents a potentially clinically meaningful profile especially one, in the context of what thus far is a very supportive safety profile; and two, in a patient population with truly significant unmet need and at least at this moment, no approved treatment options.

Your next question comes from the line of Malcolm Hoffman with BMO Capital Markets.

I wanted to ask why you guys think that there wasn't as much activity in the 30-milligram arm. Do you think this is a receptor occupancy issue? Or what else could be potentially driving this? And then thinking about the Phase III, are you thinking about increasing the actual enrollment size for the 60-milligram arm, given that you're going to be dropping out the 30-milligram arm? I appreciate your thoughts here.

Malcolm Thank you. So about the 30-milligram dose, I guess I'm going to take a step back and say a couple of things. We designed our Phase II program based on learnings from Pimavanserin. And the good part is now we have the opportunity to design our Phase III based on learnings from Remlifanserin. That said, we did always anticipate that increasing exposure was going to be helpful in this. And I think that the behavior -- the relative behaviors of the 30 and 60 milligram really just bear that out of the exposure -- increasing exposure here does seem to be important.

I think we've talked before about the -- it is hard to draw a direct line to what we know about receptor occupancy because our studies, by and large, have been in healthy young male volunteers. And so that receptor occupancy information is maybe not as directly translatable. But certainly, data with PIM suggested that getting to higher exposures would be helpful. And while we have not yet been able to do the exposure response analysis on Remlifanserin and certainly looking at the behavior of the 2 dosage arms does seem to suggest that exposure is important here as well.

In terms of enrollment size, what I can say is that originally, we were anticipating we were going to need 3 arms. Now we think we're only going to need 2 arms. So that should be helpful from that perspective. We are going to need to -- we do need to consider what other modifications we might be making, including around the target population, and that could have impacts. But at this point, I'm not in a position to really say that.

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

This is Julian on for Paul. Would you guys mind stating like what is the actual threshold for this modestly higher baseline psychosis population that you're citing on Slide 11. Is that a specific SAPS-H+D score? If you could share it, that would be really helpful. And then can you also confirm that this was prespecified? And were there any other prespecified analyses that you're planning on sharing today?

And then just one other question is just like given effect sizes tend to regress in Phase II to Phase III in neuropsych, as you guys know, how do you balance in the Phase III powering this for success while still trying to achieve a result that's clinically meaningful?

Sorry, I was madly writing, and I'm 100% sure I missed one. So again, somebody will prompt. So we are not going to share right now what the specific threshold is that we're -- this example on Slide 11 is. And there are two reasons for that.

Reason number one is this is an example. We did look at a number, not an infinite number. We're not trying to data dredge here, but we did look at a number of different potential subgroups to inform us. So that's reason number one. But reason number two is that we also do want to be careful about how -- about certain specifics that we put out publicly because it does have the potential to impact Placebo response rates in future studies based on if people are trying to target a certain level that they are trying to achieve to get into a study.

So we likely will continue to take the approach we've taken historically, which is that we are not overly specific around what our inclusion criteria is from a point of view of those measures that could impact our overall Placebo response rate. We did have a number of -- a relatively limited number of prespecified subgroups that we've looked at. We are not planning to share any additional ones today other than -- we're not planning to share any additional subgroups today other than the one that we have already shared.

And the -- there often is a change in effect size going from Phase II to Phase III. And that is one of the considerations that we are looking at here as we think about ways to increase the effect -- to potentially increase the effect size we might be able to see in Phase III so as to balance exactly what you say, the practicalities of making sure that we have something clinically meaningful and enrollable while also reflecting what we think the likely profile of the drug could be.

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

Sorry, apologies. I was just looking for the mute button. Just a few from our end. On the receptor response analysis, I'm just curious, it sounds like that work is still ongoing. Could we get that data at CTAD? Or do you have any timeline as it relates to when we could get that receptor response analysis?

And then the other one we had briefly was on the Phase III and this modestly higher baseline psychosis potential modification. I know you're still considering whether to implement that, but any high-level thoughts as it relates to how that would impact trial timelines would be helpful as well.

Thanks, Jack. I'm not going to give specifics on when we expect the dose response analysis at this point. If we have something meaningful out of it that is by the time of CTAD, we will include it, but we may or may not have that by that time.

In terms of the Phase III potential modification and whether that could have an impact on overall trial timelines, there's obviously kind of a complicated interplay here of the -- what that does to your potential effect size and what it does to the size of your potentially enrollable patient population. So right now, I'm not prepared to say what that could be.

Again, I would say, if nothing else, it's probably useful to keep in mind the fact that certainly compared with a 3-arm study, we would be looking at a smaller study here, comparatively speaking. But the exact impact is kind of going to depend on the specifics of which flavor of refinement we pursue.

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

A couple of questions. So what specific factors do you believe prevented the study from reaching stat sig? How much of the shortfall was attributable to Placebo response versus treatment effect size? And are you able to share the overall average baseline SAPS-H+D score in the study?

Working backwards, I believe the SAPS-H+D baseline score is in the -- in one of the slides.

It's on Slide 8. The median, the min and max, yes...

In terms of specific factors that prevented us from meeting statistical significance, it's always hard to pull out exactly what it was. A very small number of additional patients hypothetically could have gotten us there. A minutely smaller Placebo response could have gotten there, slightly decreased variability. So I think it's the normal sort of contributors here. I do take it again as a -- our goal with this Phase II was to get the information that would help us design our Phase III program.

And I think that from that perspective, this has done what we needed it to do. It has clearly helped us identify the dose, and it has given us the information that we need to consider what refinements we might make to the patient population.

Yes. I just want to underscore that. This is a highly Phase III enabling set of data. And again, to Liz's point, we've been joining the dots between Pimavanserin and Remlifanserin for a while now. And now we're able to really look at Remlifanserin as its own molecule and really understand that from a different perspective in patients who will potentially be treating in the future.

And that ability now to allow us to do that is going to give us the confidence to design a Phase III trial that we believe has the ability to hit technical and regulatory success, and that's what we're doing right now. And we look forward to continuing to share that as we move forward in the next few weeks and months.

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

This is Sam on for David. Just on the topic of population refinement in terms of potential enrichment for modestly higher baseline psychosis. I wanted to ask how you think about the balance between increasing treatment effect versus any potential commercial impact in terms of broad applicability or any potential labeling considerations if there are any when you weigh these Phase III enrollment requirements.

That is an excellent question. And as you can imagine, it is one that we have discussed internally as we've been thinking about this. I make a couple of general comments there, which is I think that there are -- thus far, there do not seem to be a lot of precedents within the neuropsychiatric space of populations being restricted, for example, to moderate or severe versions of disease like you may see in other more common diseases.

So there don't seem to be a lot of regulatory precedent that suggests likelihood of significant restriction. And I think that it is important to say that as we look through the data that we have, there is indication of impact even in the patients that are somewhat lower than the thresholds that we are looking at here. There's just greater impact in the higher thresholds. And so while it would be subject to eventual label negotiation with the agency, and I suppose, for that matter, also subject to seeing data in Phase III that looks similar to what we saw in Phase II, we think that it is reasonably likely that we would not be looking at restrictions based on this kind of relatively modest refinement that we're talking about.

And just to sort of underscore that commercially, it is a modest refinement. Liz has already said that within the Phase II trial, it would have included 80% of the patients. You can see the mean, the medians and the maxes of SAPS-H+D and CGI-S on the demographic slide, so you can kind of work out from there what sort of patient population we would be looking at.

And from a commercial point of view, we still believe this includes a lot of patients with hallucinations and delusions and represents beyond the commercial opportunity, a huge opportunity with patients in terms of the unmet need for a treatment that balances efficacy and safety. And we haven't had that many questions about the safety profile. But I do encourage you to look at that because it is very positive data, and we look forward to continuing to monitor that as we move through the Phase III.

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

This is Basma on for Mark. Just a few from us. I was wondering if you could comment on the Placebo response, the magnitude of the effect. Just looking at the previous trials using the same endpoint, it seems like there is a stronger effect here in the Placebo arm. Just wondering if you have any thoughts around that. And secondly, if you could comment on the baseline SAPS-H+D threshold that you're targeting for the Lewy body dementia study?

All right. In terms of Placebo response, I guess I'd say a couple of things. First is there aren't a whole heck of a lot of data sets out there in the ADP population with this endpoint. So that was one of the things that we did, when we were originally designing the Phase II trial, we were doing a certain degree of extrapolation from different studies, different endpoints and in some cases, a little bit different populations.

What I'll say is the Placebo response that we saw here in terms of its magnitude and its variability was within the range of things that we considered as a possible outcome. Obviously, we are always focused on and we'll continue to focus in Phase III on whether there are things we can do to try to minimize that Placebo response. That is always a beneficial thing. But this wasn't outside of our range of expectations of what we could see in the trial.

I'm not going to comment too specifically on the inclusion criteria around disease severity that we apply in our trials for sort of the same reason I talked about earlier about we don't want to potentially inflate our Placebo response by giving -- by very publicly giving people a target that they should be working to of what you need to get into our studies.

But I will comment that we are looking similarly in the Lewy body population to how we had approached the original Phase II of ADP with ensuring that we have adequate disease severity to be able to distinguish a signal if there is one to distinguish and then we'll take those Phase II data and use that to inform our Phase III program there, should it be enabling similarly.

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

So given that RADIANT is 80% power for 0.4 effect size, I know it's still early. Can you maybe provide additional color how you think about the powering assumption for Phase III based on current data and potential change of the protocol? And just to confirm, do you need positive data from both Phase III studies to support approval?

So in terms of Phase III powering, I guess I'll kind of reiterate the -- it's going to depend on a few factors. It's going to depend on the powering level that we look at as well as the approach that we take in terms of what further refinement we might make. We are going to be basing our Phase III powering based on the information we have from Remlifanserin rather than what we went in starting with. So I think that, that's going to be a more informed view of powering, and we look forward to sharing that with you as we land on what we're looking at from a population perspective.

Both studies?

Well, we need both studies. Thank you. My notes are terrible, and I couldn't even read it. I will say that particularly in the world of neuropsych, there's ample precedent for approvals that don't have -- that have -- that do not have two positive Phase III trials.

Certainly, we are designed for success across our program and what will eventually be acceptable to regulatory agencies does remain to be seen and is going to be data dependent. But if you look across the neuropsychiatric field, there are a number of examples of assets with one or more failed Phase IIIs that nevertheless get approved.

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

Based on some of your comments before, would it be fair to assume that they're unlikely to narrow the inclusion criteria beyond that 80% subgroup that you showed on Slide 11. And if you could lay out what might be some of the next steps in terms of really figuring out what might be the various changes you make? And then are there other changes beyond the inclusion criteria that are being considered and leading up to sort of finalizing the protocol for Phase III?

So thank you. Starting with the latter, the easy one that we know for sure, we're doing and we're going to do as quickly as we possibly can is the removal of the 30-milligram arm. We are not anticipating broad changes beyond that at this point.

And actually, yes, I think that was what I wanted to say on the protocol amendment front. Are we likely to narrow the population further than the 80% that we talked about? I think it's relatively unlikely that we're going to do something that cuts into our eligible -- our trial eligible patient population too much more than that. We really are trying to get that balance between something that is -- doesn't have a meaningful impact on enrollment, but does have an opportunity to increase our overall -- our overall potential Phase III efficacy.

So something in that vicinity is probably about as significant of a refinement as we would anticipate making.

I think within Ami's question, she was also asking about the FDA kind of interactions that might come with some of those discussions. So maybe you could talk about the Phase II, Phase III situation and that would entail?

Yes, absolutely. So this is an operationally seamless Phase II, Phase III program. I think probably everybody has heard me say about 1 million times at this point. And so our Phase III is currently going. In terms of being able to remove that 30-milligram dose, again, we're going to be doing that as quickly as possible, and we do not believe that we need any FDA discussion around that. We think it's a fairly clear story, a fairly clear and justifiable decision.

In terms of FDA engagement, we -- one of the questions earlier on was whether there was any potential to consider other endpoint hierarchies. If we were to do that, we would anticipate having an FDA engagement. But in terms of being able to solidify our dosing and potentially even one of these more modest refinements of the population, we do not believe those are things that are going to require FDA discussion.

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

This is Eddie on for Yatin. Just a follow-up on what you just said, with that Phase III currently enrolling, will you have two separate populations to analyze? And sort of how will those be handled in the primary analysis, pre and post amendments?

It's a great question. I will say that, I mean, preliminarily, there will be a limited number of patients who were randomized to the 30-milligram arm before this amendment went in place. And I would anticipate that those patients will be -- if they choose to and are eligible for other reasons, they would be eligible to go into the open-label extension where they would receive 60 milligrams and could contribute to our overall safety database.

I don't think that we would need to handle that. We would need to handle it analytically any differently from that perspective. Depending on the nature of the refinement we applied, we would think about what the appropriate statistical handling of that would be. But I anticipate that it could be -- I anticipate that it would likely be of the vicinity of having our future modified full analysis that population be specific to those patients that met that criteria would be the most likely outcome.

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

This is Srinath on for Salveen. A couple of quick ones. One, based on the Phase II data that you've seen, the top line, any updated thoughts on the commercial outlook versus the emerging muscarinics given Bristol will also be having data sometime early next year?

And the second is acknowledging that this is very early data, did you also assess impact on any of the related symptoms like agitation? And can we expect any commentary on that in the near term?

So let me just address the commercial outlook versus the muscarinics. I think we remain confident that, first of all, this is a very large population. There are no currently FDA-approved drugs. And in most neuro psych spaces, there's more than one option for patients, which is highly appropriate and positive for those patients.

So regardless of however Bristol turns out with the outcomes for their trials, there are a lot of patients with high unmet medical need in this Alzheimer's disease psychosis population. Within our own trial data, as we've already said, I hope and reiterated, we now feel very positive about the possibilities for Remlifanserin in this patient population, not only for the efficacy and the refinements that we are looking to put into place, but also the safety profile.

This is a once-daily dose. As we've said in the press release, and you've now seen the safety and tolerability profile is very similar to Placebo. We haven't seen any QT prolongation issues. That was something that the team had designed into Remlifanserin, and we're now very pleased to see that has not come to fruition to date. And obviously, we continue to monitor that. So overall, the package we believe we're putting together for Remlifanserin is very compelling for both patients and clinicians, and we look forward to ensuring that our Phase III trial has technical and regulatory success. So we can actually get this product launched to patients who need it.

Beyond that, I'll let Liz take it.

Yes. We are -- we did, as exploratory, collect a number of different associated symptoms. You'll see those data in due course. But what I will emphasize is that, of course, this is in the patient population with psychosis. And that really is what Remlifanserin, we think is most suited to impact. And so you would be looking at agitation or whatever else within the context of patients whose psychosis was a significant portion of their presentation.

And that concludes our question-and-answer session. I would now like to turn it back over to management for closing comments.

We'd just like to say thank you all for joining us today for our presentation of the RADIANT results. We appreciate your participation, and we look forward to continuing the development of Remlifanserin for both Alzheimer's disease psychosis and Lewy body dementia psychosis, and we'll speak to you all soon. Have a great day.

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

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

And 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 second 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 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 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'd 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 that ACADIA delivered an outstanding second quarter, demonstrating strong commercial execution across both DAYBUE and NUPLAZID. We also continue to make important progress across our pipeline, led by remlifanserin in Alzheimer's disease psychosis.

Let me start with our financial performance. We achieved total revenues of $308 million in the second quarter, representing 17% year-over-year growth on an adjusted basis. This performance reflects strong execution and continued demand for DAYBUE and NUPLAZID.

Turning to DAYBUE. The brand delivered net sales of $125 million in the second quarter, representing 30% year-over-year growth. This strong performance was driven by meaningful uptake of DAYBUE STIX, our recently launched powder for oral solution, which is resonating with patients and caregivers in the U.S.

The strong early adoption of DAYBUE STIX reinforces our confidence in this differentiated delivery option and supports the brand's continued growth trajectory. Based on these strong results, we are raising our 2026 guidance range for DAYBUE to $480 million to $510 million.

I'm also delighted that we recently received a positive opinion from the CHMP following a re-examination process. This outcome represents a significant win for patients with Rett syndrome across Europe and reaffirms the value of DAYBUE as a foundational therapy.

We're grateful to the CHMP for its thorough review and pleased to be moving closer to the opportunity to bring this therapy to patients in Europe. This positive opinion, along with strong DAYBUE STIX performance, reinforces our confidence to achieve our ambition of $700 million in DAYBUE sales in 2028.

For NUPLAZID, the brand delivered net sales of $183 million in the second quarter, up 10% year-over-year on an adjusted basis. The underlying business remains strong, supported by continued demand growth, disciplined execution and impact from our expanded field force. We remain confident in our path to deliver approximately $1 billion in NUPLAZID net sales in 2028.

Looking ahead, our most important near-term pipeline milestone is the upcoming Phase II readout for remlifanserin in Alzheimer's disease psychosis. We now expect to report top line results from this study in September to October of this year. If successful, remlifanserin has the potential to be transformational for ACADIA with peak sales potential of estimated $4 billion across Alzheimer's disease psychosis and Lewy body dementia psychosis.

With that overview, let me now turn the call over to Tom to provide more detail on our commercial performance.

Thank you, Catherine, and good afternoon, everyone.

I'm excited to report another strong quarter for DAYBUE, which generated $125 million in net sales in the second quarter, representing 30% year-over-year growth, driven almost entirely by volume.

Performance was led by continued strength in the U.S. business with additional contributions from our named patient supply programs. DAYBUE continues to strengthen its position as the foundational standard of care for Rett syndrome, and our second quarter results reflect what we believe to be the growing confidence that physicians, patients and caregivers have in the therapy.

Demand trends accelerated during the quarter as we expanded the launch of DAYBUE STIX beyond center of excellence, which is engaging new patients and bringing previously discontinued patients back to therapy.

Importantly, the number of patients returning to DAYBUE reached a record level during the second quarter. Of note, approximately 40% of all U.S. DAYBUE patients were receiving STIX by the end of the quarter. This rapid uptake highlights the significant value STIX is providing to patients and caregivers and reinforces its role as an important growth driver for the DAYBUE franchise.

Turning to DAYBUE outside the United States. We achieved a major regulatory milestone late in the quarter with the receipt of positive CHMP opinion for the treatment of Rett syndrome, and we have already begun preparations for commercialization in the European Union following expected approval of DAYBUE by the European Commission. We've assembled a highly experienced team and remain on track to launch in Germany in early Q4.

In parallel, we expect to submit pricing and market access submissions in our planned launch markets this year, positioning us for broader expansion across Europe as we work to secure reimbursement approvals. In addition, our named patient supply programs are expected to remain a meaningful contributor to growth through 2026, driven by increasing awareness of DAYBUE globally. Taken together, these trends reinforce our confidence in DAYBUE's increased guidance.

And with that, let me turn to NUPLAZID. NUPLAZID delivered another strong quarter, generating $183 million in net sales, representing 10% year-over-year growth on an adjusted basis, driven primarily by volume. We were particularly encouraged by the continued momentum in new patient prescriptions, which have increased 20% year-over-year, representing the highest quarterly volume since the first quarter of 2018.

Turning to our expanded field force. Execution remains on track, and we are beginning to see the early benefits of that investment emerge, consistent with the 6- to 9-month ramp period we anticipated. Since expanding the team, we have seen a significant increase in call activity and improve the depth and frequency of engagement with our highest priority customer segments.

As a result, we have now reached over 12,000 priority health care providers since February, significantly expanding our presence across the clinicians who care for patients living with Parkinson's disease psychosis. Our direct-to-consumer investments continue to be a meaningful driver of awareness, patient identification and activation.

During Parkinson's awareness month in April, our NUPLAZID branded campaign, Mind Your Mind and the refreshed More to Parkinson's initiative delivered record audience reach and generated strong engagement across digital and social channels.

More importantly, these efforts are translating into action as reflected in substantial sequential increases in both branded and unbranded patient conversion, reinforcing our ability to connect patients and caregivers with information about Parkinson's disease psychosis and the treatment options available to them.

As we pair these awareness building efforts with our expanded field force, we are increasing both physician and patient recognition of NUPLAZID and further strengthening the foundation for sustainable growth. The leading indicators we are seeing across the market, including growing disease awareness, increased patient engagement and rising new prescriptions gives us confidence in the near- and long-term trajectory for NUPLAZID.

And with that, I'll turn the call over to Liz.

Thank you, Tom, and good afternoon, everyone.

Today, I'll provide a few brief updates across our clinical stage programs. Let me start with remlifanserin, which, as Catherine said, represents a potentially transformational opportunity for ACADIA.

We recently announced several updates to this program. First and foremost, we have recently completed enrollment in the Phase II portion of our Alzheimer's disease psychosis program. And with this, we've tightened our range for top-line results, which we now expect to report in September to October.

At the same time, we announced receipt of Fast Track designation from the FDA. This designation underscores the substantial unmet need in Alzheimer's disease psychosis, and we believe remlifanserin has the potential to become an important treatment option for patients and caregivers.

Now that Phase II enrollment is complete, consistent with our operationally seamless Phase II, Phase III program design, we have commenced screening and enrollment in the Phase III studies.

Beyond remlifanserin in Alzheimer's disease psychosis, our pipeline is robust and active with multiple studies underway today and several additional trial starts and data readouts expected over the next 18 months.

Starting with the programs currently underway. First is our Phase III study of trofinetide ongoing in Japan. We continue to expect a readout between September and November. We're planning a regulatory submission in 2027, and we'll share more details about our potential filing strategy after we've selected our commercialization partner for the Japanese market.

Now for other clinical programs. For remlifanserin, we also have a Phase II study underway in Lewy body dementia psychosis. And as mentioned, the 2 Phase III studies in Alzheimer's disease psychosis are now open for enrollment. We're also advancing ACP-211 in a Phase II study in major depressive disorder and ACP-711 and ACP-271 are progressing through their respective Phase I programs.

Beyond this, by the end of 2027, we expect to have initiated 3 additional Phase II or Phase III studies. We also expect 4 Phase II or Phase III readouts over that same period. Of those, the readouts we have disclosed include the upcoming Phase II RADIANT results in Alzheimer's disease psychosis and trofinetide in Japan as well as ACP-211 in major depressive disorder. Together, this cadence of trial starts and readouts represents potential meaningful momentum across our pipeline.

One final note before I hand over to Mark. We were very pleased to have achieved a positive CHMP opinion in the EU for trofinetide following the reexamination process. This represents a significant win for patients with Rett syndrome across the EU and brings us one step closer to making this foundational therapy available to patients in Europe. We anticipate a final decision from the European Commission later in Q3, and I'd like to thank the dedicated Acadian who worked so hard to achieve this outcome.

In summary, our R&D organization is executing at a high level across multiple programs, positioning us to deliver important milestones that have the potential to create value for both patients and shareholders over the long term.

And with that, I'll turn the call over to Mark to review our financial results.

Thank you, Liz, and good afternoon, everyone.

I'm pleased to report strong financial results for the second quarter of 2026 that reflect the robust commercial execution Tom and Catherine described earlier.

Total revenues for the second quarter were $308 million, representing 17% year-over-year growth on an adjusted basis. DAYBUE delivered net sales of $125 million in the second quarter, up 30% year-over-year, of which 27% came from volume. This exceptional volume growth was primarily driven by the strong uptake of the newly launched DAYBUE STIX formulation in the U.S. The gross to net adjustment for DAYBUE was 24.4% in the quarter.

NUPLAZID generated net sales of $183 million in the second quarter, up 10% compared to the same period last year on an adjusted basis, driven by 8% volume growth, reflecting strong underlying demand for this important therapy. Our gross to net adjustment for NUPLAZID in the quarter was 23.9%.

Turning to operating expenses. Our investments continue to be focused on advancing our pipeline and supporting our commercial growth. Research and development expenses for the quarter were $82 million compared to $78 million a year ago.

SG&A expenses were $160 million for the quarter compared to $134 million a year ago. This increase reflects our investments to expand both the NUPLAZID and DAYBUE field forces and increased marketing investments supporting both brands.

We ended the quarter with a cash position of $956 million. This healthy cash balance provides us with the financial flexibility to execute on our commercial plans, advance our pipeline and pursue business development opportunities that align with our strategic objectives.

Turning to our full year 2026 guidance. We're raising our DAYBUE net sales outlook to $480 million to $510 million, up from $460 million to $490 million. This outlook reflects our strong performance in the first half of the year and includes all forms of trofinetide available globally, including our expectation for initial EU commercial sales in Q4.

Our NUPLAZID net sales guidance remains unchanged at $760 million to $790 million. Taken together, we now expect total 2026 revenue of $1.24 billion to $1.3 billion.

As we look to the rest of the year, let me provide a bit more color on expectation for each brand. For DAYBUE, we expect similar year-over-year growth rates for Q3 and Q4. And for NUPLAZID, we expect stronger year-over-year growth in Q4 relative to Q3 due to the greater impact of the expanded field force expected later in the year. Also for DAYBUE, we are slightly increasing the guidance range for gross to net to 23% to 25%.

Lastly, on guidance, we are lowering our spend guidance for R&D and now expect R&D expenses in the range of $355 million to $380 million compared to the prior guidance range of $385 million to $410 million. The reduction to R&D guidance is primarily attributable to the shifting of a BD milestone to 2027 and selected portfolio prioritization decisions. All other guidance ranges for fiscal year 2026 are unchanged.

With that financial overview, I'll turn the call back to Catherine for closing remarks.

Thank you, Mark.

As we close, I want to reinforce why ACADIA is positioned for its next phase of growth, anchored by proven commercial execution, a transformational near-term pipeline opportunity and multiple value-driving milestones ahead.

Turning first to commercial execution. Performance remains strong across both brands. We delivered an excellent second quarter led by DAYBUE. These results have led us to raise our DAYBUE guidance.

Looking ahead, the upcoming European Commission decision represents another meaningful opportunity as we prepare to bring this foundational therapy to patients, beginning with our planned launch in Germany in the fourth quarter.

NUPLAZID also continues to perform well, and we are beginning to see the benefits of our expanded field force as the team ramps and reaches more health care practitioners across specialties.

Building on our commercial momentum, remlifanserin remains our most important near-term pipeline catalyst with Phase II data in Alzheimer's disease psychosis expected in the September to October time frame. Beyond remlifanserin, we're advancing ACP-211 and our broader pipeline with additional catalysts ahead, including top line Phase III trofinetide data from Japan later this year.

Finally, we remain guided by our mission to turn scientific promise into meaningful innovation for underserved communities. Our second quarter performance and the milestones ahead reflect the progress we are making and reinforce our confidence in ACADIA's next phase of growth.

Thank you all for your continued support of ACADIA. And with that, we're happy to take your questions. Operator?

[Operator Instructions] And our first question comes from the line of Tess Romero with JPMorgan.

So Liz, actually a question for you. Thinking through the outcome of the Phase II RADIANT trial, how should we think about scenarios around effect size here around your primary endpoint of the SAPS-H+D? And how should we think about the lower bounds of what could still have a path forward into Phase III? Or put another way, how much room do you think you have in your data to be able to execute on a Phase III plan that is derisked enough in ADP?

It's a great question, Tess, and obviously, one we've been giving a great deal of thought to of what would be really Phase III enabling data. And so I'll make a few comments there. First off, as I'm sure everyone on this call knows by now, we are 80% powered for a moderate effect size, 0.4 effect size on our SAPS-H+D. There is probably a little bit of flexibility around that in terms of what would still be a supportable and Phase III progressable asset. There is a lower level beyond which you start worrying about whether you'd be able to replicate the effect. But I think we've got a ways there.

In general, we're going to be looking certainly at the impact on SAPS-H+D, but that's not going to be the only thing we're going to look for at an effect size perspective. We're going to look at responder analyses on SAPS-H+D. There are a number of other endpoints that we're considering as well.

But broadly speaking, we're looking to see that we've got something that we think continues to align with what we think would be a meaningful drug in this space. And that's something that's going to be easy for patients to take, something they can take once a day with or without food, something that has evidence of efficacy, a supportive safety profile and some of the stuff we won't definitively answer in Phase II, of course.

But we are going to want to feel good about the fact that we don't have negative cognitive impact or negative impact on motor, things like that. So there's a number of different considerations we're going to be looking at, but that hopefully gives you a little bit of a flavor for the thinking.

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

Two questions. One is actually a follow-up to Tess's and specifically, Liz, around the CGI-S. We had previously talked about how you intended to anchor the SAPS-H+D to the CGI-S. Can you talk to like what the NCID for CGI-S is and if you're going to release that data and if there's going to be sort of a correlative analysis with the top line data to the -- with your data announcement?

And second, could you speak a little more to some of the presentations that I saw -- that our team saw at IRSF around from the Delphi consensus. They talked a fair bit about improved tolerability, I believe it's an independent group, but improved tolerability with STIX and improved DAYBUE tolerability with new titration regimens and how what they presented at IRSF is making an impact on DAYBUE commercially?

So I'll take a shot at the first part, certainly, and then probably we'll do some tag teaming on the second.

So with respect to some of the CGI-S and how we may use that, first and foremost, this is our key secondary endpoint. I will say, I guess we should start with level setting with expectations around what's actually going to be put out at the time that we do our initial press release. I think it's probably to think in terms of what's going to be there for sure is going to be our primary efficacy endpoint and a comment on safety.

Additional information, we're going to determine whether that is necessary and helpful at that time and some things we will certainly wait for future medical meetings. I would not anticipate that you're going to see any kind of correlation analyses between CGI-S and SAPS-H+D.

I think when I referred to the anchoring before, what I was talking about is in the context of an eventual dossier to support the applicability of an endpoint for regulatory purposes, we do anticipate we would need to have a full dossier explaining the behavior of the instrument, the appropriateness of it, et cetera. And so that is one path that we could take to help support that is through an anchoring with the CGI-S.

Generally speaking, it is considered that a change on CGI-S or CGI-I that those in and of themselves are clinically meaningful. And so that's helpful as you're trying to define meaningful change on another instrument. I think that covered everything around the CGI-S.

With respect to some of the presentations at IRSF, taking the tolerability or the tolerability with titration piece first. What I will say is some of the information that we have from Lotus has suggested over time that there -- in patients who titrate that you certainly don't see onset of diarrhea with the same kind of rate.

And so that can give an opportunity for patients and families to kind of get accustomed to the drug in context of many other tools that are in the toolbox, things that physicians are -- that we have encouraged physicians to make more use of is use of fiber, adequate water intake, making sure that they are discontinuing the antidiarrheals, et cetera. So there are a number of different tools that can help from a tolerability perspective.

And I guess, Tom, I'll let you comment on how that is impacting physician use.

Sure. So just a couple of things I would say. So first off, in terms of the Delphi consensus research that you mentioned, and yes, we did present a number of papers at IRSF. As a reminder, the Delphi consensus was actually conducted prior to the launch of STIX. So all of the information that you were seeing there relates to the oral solution.

As it relates to STIX and the other experience that we're seeing, what we would say is -- at the moment, it seems to be on par with what we've seen historically with oral solution in terms of tolerability. Obviously, we're learning more as we go, this has only been the first full quarter where it's been in the hands of patients and caregivers beyond COEs. But what I would say is we've been very, very encouraged by the early start that we've made with STIX and have been pleased with the momentum that we're seeing across both COEs and non-COEs as we've moved into the community.

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

I've got 2 on ADP as well. Maybe just on the Phase II, the effect size that you're shooting for the 0.4 that you mentioned about the powering. Just help us understand like the prior Study 19 pimavanserin data had shown a 0.2 that was using a different NPI scale, but in RADIANT, you are using SAPS-H+D. So, is that effectively comparable and not the effect size is?

And then secondly, I saw that you've started the Phase III screening and enrolling the patients already, but we are waiting the data from Phase II. So if you are having to dose patients in the Phase III before we get the Phase II data, which dose would you be inclined to?

I'll just keep going. Okay. So with ADP, so just to ground a little bit in the pimavanserin data. So Study 19 was the Phase II study of pimavanserin in ADP. It was, as you rightly note, using a different endpoint. There are other differences from a population perspective. In our current study, we are, of course, requiring biomarker confirmation.

But I will say on balance, we expect that most patients who were in the 019 study probably would have been biomarker positive as they were fairly advanced in their disease course, but we don't actually have biomarkers to be able to confirm that.

And then probably another important thing to keep in mind is One of the things that we have seen in the data set is that there does appear to be a more significant impact in patients with greater baseline psychosis. And so, in the RADIANT trial, we are looking to move that patient population on balance to a somewhat more severe psychosis population than was in Study 019.

And so with that context, yes, the Phase II of pimavanserin did have an effect size of about 0.32. We did power for remlifanserin for 0.4 for a couple of reasons. One, of course, is the endpoint where we've changed to something that we think is more sensitive to change, but also the fact that we have enriched for that more severe psychosis population, which if you look in Study 19, actually, if you look at the more severe psychosis population, your effect size goes up to more like 0.6.

So we think that 0.4 is a defensible and appropriate powering assumption. And we think that if we meet that or in that vicinity, what we have is an agent that potentially could be meaningful for patients.

And then I think the second piece was about Phase III. So yes, the design of our study is operationally seamless. And so what that does mean is that once enrollment completed in the Phase II portion, which we did announce recently, sites we're able to start screening and then enrolling for the Phase III portion.

Right now, our Phase IIIs are designed very similarly to the Phase II study. The fact that these are statistically separate does mean we have the opportunity to analyze those data, which we are going to do in the September to October time frame and share those data, but also make modifications to the Phase III as needed.

Right now, we are enrolling for both dosing arms, so there would be placebo, 30 and 60. There is a possible future where one of those dosing arms doesn't need to be taken care or need to be taken forward. But for now, we are continuing on with that.

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

Yes. So now that it looks like DAYBUE Europe is going to happen, can you help quantify that opportunity for us? And you mentioned Germany in the fourth quarter. What other countries are you expecting to launch? And just give us a sense of how fast you think that ramp can be.

Sure. I'll take that one, Marc. So thanks for the question. So I mean, first off, it goes without saying that we are very pleased that we've been able to turn around a negative opinion into a positive outcome for patients in Europe. And as I mentioned in the preparatory remarks, the team are geared up and ready to go. So we anticipate EC decision by the end of Q3, as Liz mentioned, and the team is going to be pretty quickly ready to go thereafter.

Germany will be the launch market as we get out of the gates and you would then follow the normal cadence that you'd expect to see in terms of other early launch markets in the EU, which tends to be kind of Nordics and then others that we're working through Austria tends to be pretty quickly after Germany at the same time.

In terms of the commercial opportunity, I mean, I go back to what we shared previously, which is as you look at the $700 million guidance for 2028, we estimate somewhere less than 15% of that number to come from Europe.

So as you think about kind of cadence of the launch, it will be somewhat gradual through the end of Q4 as the patients who are receiving free drug today in Germany transition to paid treatment, and then you'll see it consistently come online through next year.

So more information to come, but we are excited by the opportunity. I think as you think about the 3 pillars of growth for DAYBUE into the future, international expansion in Europe is certainly one, and we're really looking forward to pulling that through.

And just to sort of put a name on that, Marc, as you know, it takes years for countries to come online in Europe. So we will continue to follow the path that Tom laid out. But also in the meantime, where we can supply physician demand through our named patient programs, we will be honoring that as well. So both of those things will be happening depending on the country and what's going on and what the legal system allows. So just to continue that.

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

To clarify, do you expect the discontinuation rate to change with the STIX formulations? And then secondly, on pricing in Europe for DAYBUE, on average, what percent discount do you think you'll have to take in the major European countries over time?

Thanks, Tazeen. I'll let Tom talk about STIX and the discontinuation rate.

Sure. So I think as we've been monitoring kind of the STIX performance out of the gate, to date, as I mentioned earlier on, from the early data that we're seeing, it seems to be performing fairly similarly to what we have seen with the oral solution historically.

Obviously, what's been very different, though, with the STIX launch is that we are now able to reengage patients who had previously discontinued the oral solution now that we have the new therapy. And it's clear that patients and caregivers, caregivers in particular, are willing to come back to DAYBUE given the efficacy that the brand offers.

So we're continuing to monitor closely. What I would say overall, as you think about discontinuation rates, although we don't talk about them publicly as much as we did before, is they are largely in line with what we've shared in prior quarters. They remain under double digits, it remains very, very consistent. And as we see more patients move to the STIX therapy, and we're seeing that happen, that adoption happen somewhat quicker than we anticipated, we'll be sharing additional information on that.

In terms of pricing in Europe, I think for now, we're not guiding or giving any indication to prices in Europe. We will keep you updated as we move through those discussions with the individual national reimbursement authorities starting with Germany. And as you know, free pricing in Germany is for the first 6 months. And after that, we'll start our negotiation. So it won't be until the middle of next year that we start talking about that.

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

Actually, just one more on pricing. You just mentioned the free pricing for the first 6 months. After that, what happens? Is there an accrual period where you estimate the expected negotiated price? And then once you get that price, then you move to the set price.

And then with regard, again, back to the ADP readout, I'm wondering if you could just speak to the statistical test. I know I think for the prior study for pimavanserin in ADP, it was a T-test and -- but there was also in the PDP trial used MMRM. I'm just wondering if you could speak to those details.

I'll get Tom to talk about the discussion and Liz can move on.

Yes. So thanks for the question, Yigal. So vis-a-vis Germany, we will be -- as soon as we have the approval, obviously, we'll be launching in Germany, as we said. During that free pricing period, essentially per the legislation that exists in Germany, we have the ability to price as we wish.

At the same point, we will be working with AMNOG directly because we'll have submitted our pricing reimbursement dossier and that actually begins the process of negotiating what the price then becomes post that 6-month repricing period, at which point that becomes the price that's recognized on a GTM basis.

So essentially for that first 6 months, we recognize the revenue at full price, whatever it may be set at. And then post that 6-month moratorium, that's when we start recognizing a different price from the publicly available price. SO, we will see.

We haven't talked a lot about the statistical considerations in terms of the Phase II study. But what I can say is that it is an MMRM analysis, and we are controlling for multiplicity as you would anticipate with a prespecified hierarchy.

And our next question comes from the line of Malcolm Hoffman with BMO Capital Markets.

Congrats on the quarter. I was wondering if you could provide any color on whether you have seen a normalization of typical refill rates for NUPLAZID. I know you had mentioned new patient starts are really strong, but I just wanted to get a sense whether the scripts are back on track.

And then for remlifanserin, can you comment on whether you have had to correct for any rate or drift throughout the study? I know maintaining the consistency of the rating throughout the trials is pretty critical here.

I'll let Tom start on NUPLAZID.

Sure. So yes, NUPLAZID referral and restart rates are exactly where we expected them to be. In fact, if we look at Q2 of '26 versus Q2 of '25 in historical years, that's actually been a particularly good rebound versus prior year.

So, I think the phenomenon that we saw in Q1 of this year clearly does seem to have been a one-off. Obviously, we'll be monitoring very closely as we end 2026. But everything as it relates to demand and pull-through and patients returning is exactly where we anticipated it to be.

And as far as commenting on rater evaluation, potential for rater drift, et cetera, we have tried to be mindful of that. We have a rigorous process back in the day for our site and our rater selection, including proven experience in these kinds of trials and psychosis assessments, have extensive training calibration exercises and standardized scoring protocols.

But probably most relevant to your question, we are on an ongoing basis, looking at blinded data and having sort of booster training of raters based on review of blinded data on an as-needed basis.

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

On DAYBUE STIX, so clearly an acceleration there. But can you quantify how much of the recent demand reflects entirely new patients versus improved compliance, persistence or conversion from the oral formulation? And where do you estimate the current treated patient population penetration stands in the U.S.? And how much untreated or underdiagnosed opportunity remains?

Sean, it's Tom. So, thank you for the question. So let me just provide a little more color on kind of the dynamics that we saw in the quarter.

So, if you look at kind of our overall mix in the quarter, both across STIX and the oral solution, around 60% of our referrals were coming from naive patients 40% were returning patients. And as we think about, again, future growth potential for the brand, obviously, naive will remain a focus. I think with STIX, we now have this additional opportunity to engage patients who have previously just discontinued.

When we look at STIX in isolation, it's interesting there that we saw 55% of our existing patients on were switching from oral solution, 45% were either new or returning. So, kind of that gives you a little more flavor.

We've also been particularly encouraged by just the momentum that we've seen through the quarter. So if we take June in isolation and we look across the entire business, 60% of all of our referrals in June alone for the STIX formulation.

So I think that, that gives you a very clear direction of travel as we think about just the uptake of STIX the positive reaction that we've seen from both the clinical community and the patient community. We had a very strong IRSF meeting. And I think the momentum that we're building gives us a real sense of confidence that we can finish this year strong and really build further as we think about 2027.

Next question.

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

This is Nevin on for Brian. So maybe just one on the DAYBUE opportunity in Japan. Can you remind us maybe what the Phase III trial design is there and what efficacy endpoints those regulators might require? And then just what the addressable Rett syndrome population is in Japan?

We'll start with the addressable and then we'll move to Liz just to give her an opportunity to take a breath.

So Japan, we're looking to commercialize after we get our registrational study completed, which Liz can give you details on. The epidemiology of Rett around the world is similar. It's 1 in 10,000 to 1 in 15,000 live female births. We believe there's around 1,000 patients in Japan who have Rett syndrome, various different sources give slightly different numbers, but it's around that. And we're looking forward to our Phase III trial, which Liz can give you a little bit of a description.

It is a bit atypical as Phase IIIs go. I think it's important to think of this in the context of through discussions with PMDA. The primary support for an eventual indication should we get there, is going to be our LAVENDER data. The Phase III study that we're running in Japan is primarily to give some experience in Japanese patients. It is a very small trial, I think on the order of 20-ish patients.

There is a placebo control, but obviously, it is in a very small number, again. We're looking at week 12 endpoints. We are looking at the same kinds of endpoints that we looked at in the trofinetide global program. Here, though, it is CGI-I as the primary with RSBQ as a key secondary endpoint. But again, the intent here is more to get experience in the Japanese population. There's no expectation that we would be able to hit a p-value, for example, with this kind of trial.

So that's -- it will give us some sense of how the drug behaves there, and we think will be hopefully supportive for what is primarily going to be a LAVENDER-based package.

And our next question comes from the line of Sumant Kulkarni with Canaccord Genuity.

I have 2, one on remlifanserin and one on peak sales potential. So it looks like Bristol's enrollment for ADEPT for ADP is going somewhat slower than that company initially expected. So given your experience with the ongoing ADP trial, do you think that space is something specific to their program? Or does it have wider implications for other ADP programs, including yours?

Probably should be careful on how much I'm speculating on somebody else's program. But I guess what I'd comment on there is essentially we took a while in enrollment because we were looking to make sure we were enrolling the right patient population.

And so I think that anybody who is considering trials in this space should be thoughtful about how they are enrolling their patient population and ensuring that they have the patients enrolled that they're looking to. And so one of our versions there, of course, is the biomarker confirmation. But overall, we are being careful in that.

Got it. And given where you are today with your solid performance on NUPLAZID and you have now European approval for DAYBUE, do you have anything to add relative to your earlier $1.7 billion in peak global net sales in 2028 for those products?

I think we're talking about our confidence now of hitting those numbers as we move through the end of this year and we look at the continued uptake of STIX and we see how NUPLAZID ends the year, we will revisit that at that time. But for right now, both for the $1 billion on NUPLAZID and the $700 million on DAYBUE, we are confident that we will achieve those numbers during 2028.

And our next question comes from the line of Rudy Li with Wolfe Research.

Congrats on a strong quarter for DAYBUE. Maybe just a quick follow-up to the patient dynamic for the STIX formulation. Can you maybe talk about the trend moving into July and August across different patient segments?

And another question is based on your recent market research and physician feedback. How should we think about the market dynamic for Rett syndrome with potential gene therapies in the coming years?

Yes. I'm going to ask Tom to talk about July and August and then talk about our view on gene therapy.

Yes. So a few things that I would say, and thanks for the question is as you look at kind of the momentum that we saw during Q2, and as I mentioned, 60% of our prescriptions at the end of June, we're already for STIX. And we are really now beginning to focus our team's efforts beyond the COEs as we think about pushing STIX more broadly.

We feel pretty confident that the momentum that we saw during Q2 is going to continue into Q3. Early signs are indicating that way in addition to all of the additional programs that we have outside of the U.S. for inbound request name patient sales as well.

So I think as you take that together, this gives us confidence in the guidance that we shared. Obviously, we have lifted both the bottom and the top as we think about the end of this year, and we feel good about where we're situated as we think about the remaining 5 months of 2026.

And in terms of gene therapy, just as a top line, we don't see any impact to our commercial forecast either in the short or long term with the potential introduction of a gene therapy, while we welcome any new option for patients with Rett syndrome. We believe that DAYBUE will remain the standard of care for patients with Rett syndrome, both in the U.S. and globally.

Tom, I don't know if you want to talk any more about that.

Yes. I mean I think, obviously, we're watching with a keen interest these first-generation gene therapies. I think there's optimism amongst certain patient types and certain members of the treating community.

But again, we believe in the foundational standard of care that DAYBUE offers. Obviously, it can be used either pre or post gene therapy. And we think that, that inherent flexibility and the fact that you can use DAYBUE is completely reversible. We know the profile of the treatment very closely that DAYBUE will remain an important treatment for Rett syndrome moving forward. And I think the advent of DAYBUE STIX actually just makes us even more confident in that.

Next question.

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

Congrats on the quarter. I want to ask about the development of remlifanserin in ADP versus Lewy body. Is there any reason to think the probability of success would be different between those 2 indications?

And then on the commercial side, I know you've talked about the $4 billion peak sales number there for remlifanserin across indications. Directionally, how should we think about how that might break out between ADP and Lewy body?

All right. I'll let Liz start on that one. I'll come up behind.

I was so busy writing things down. I may have missed the second part of the question. So broadly speaking, we are enthused about both the possibility in Alzheimer's as well as in Lewy body. These are both areas with tremendous unmet need and really nothing available for these patients.

In broad terms, I don't think we see the probability as wildly different across the 2. We have more data in Alzheimer's with pimavanserin certainly, but the data that we do have in Lewy body, though in a smaller number of patients is pretty striking in its magnitude. So we're looking forward to the first readout coming in September to October. And while we haven't disclosed the Lewy body readout, we are looking forward to that in the future as well.

I think in terms of the commercial opportunity we've described before and so many others, the size of these markets, which are both considerable in the U.S. and beyond. I think in terms of how we see the $4 billion split out I would say it's roughly 60% ADP, 40% Lewy body. Obviously, that highly depends on the data, the competitive frame and who else is also on the market at the same time. So I would say we're sort of roughly around 60-40, but that will evolve as we get there. And let's cross the data threshold first.

And with that, we'll take the next question.

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

This is Chris on for Jack. Just turning back to DAYBUE. Regarding the STIX uptake, I heard you just mentioned that 45% of STIX users were either new or returning. Can you provide what percentage of that 45% were new -- and then are you seeing higher rates of uptake in a certain patient demographic age, for example? And if so, do you see that changing over time?

Yes. So as you think about kind of the 45% that I mentioned, so if you kind of zoom in on STIX, it's roughly 60% were new, 40% were returning that we saw in the quarter. Again, as we go further into community, we anticipate that those dynamics may shift. I mean it's notable that we actually saw a very significant shift in Q2 to community prescriptions versus what we saw in Q1, which you'd expect because obviously, that's when we were actually talking to STIX more broadly beyond just the center of excellence.

In terms of returning patients, I mean, we are seeing a very diverse mix. One of the things that has been different to what we had assumed before we launched is that it would primarily be patients who have discontinued due to formulation concerns that we return to the brand.

We're actually seeing that a far broader group of patients are willing to return, which, again, I think just talks to the community's interest in trying DAYBUE again based upon the efficacy that they know that patients can see with this treatment. And I think the new formulation will potentially give us an avenue to unlock that opportunity further.

And our next question comes from the line of Ananda Ghosh with H.C. Wainwright.

Congrats on the quarter. I have 2 questions on ADP. The first one is where do enroll patients of RADIANT compared to prior trials, as mentioned, like the Ballard et al paper? And what instrument was chosen on that criteria?

The second follow-up question is, we noted that Study 19 was using NPI-NH, both for screening as well as on the endpoint determination. But the RADIANT, I think the screening tool is different than the endpoint. And what's the rationale behind that?

So Anand, the first part of your question was a little bit unclear. So maybe we'll get to start the Study 19 response and then you can reask it so that we can answer the right question.

Sure. So what I'll say is on the screening criteria that we used -- well, let me phrase this carefully. So when we are considering patients that we're including in the analysis, we're taking into account both the NPI-NH values as well as the SAPS-H+D values in terms of who qualifies for the primary analysis.

So we are actually including a component of the endpoint as well as another criterion. And again, the goal here is to sort of edge up that overall population level psychosis severity because we do think that slightly more severe patient population does seem to have a greater effect size that's shown.

The first part of the question was around enrolled patients, but perhaps you could just ask it again so we can understand it properly.

Yes. No, that was helpful. So I think this answers a part of that question. My question was, given that one of the ideas from the Study 19 was that you need to have much more severe patients. So given the baseline of RADIANT, where do they sit with respect to the overall Study 19 population? That was the question.

So we're not, at this point, disclosing what baseline characteristics of the population look like. So what I can say is we did have enrollment criteria that should be consistent with edging up that overall population level of severity, but we're not currently disclosing what the actual baseline values are.

And our next question comes from the line of Uy Ear with Mizuho.

Congrats on the quarter. Just going back to the RADIANT study. I was wondering if you can provide a little more color in terms of the number of patients enrolled and whether all the patients have been dosed? And what are the gating factors, I guess, to getting the data in September versus October?

And my second question is, are you able to share for which program the milestone payment in R&D was shifted to 2027?

Sure. So again, hopefully, I got all my notes down here. In terms of complete enrollment in the RADIANT program, in particular, in the Phase II portion of it, that was 363 patients that were enrolled.

The main gating factor between September and October is going to be the 30-day safety follow-up if patients don't roll over. The study is still -- it is still ongoing. Everybody has gotten past randomization, but there are still patients on study. So I cannot answer today whether all patients are going to go into the open-label extension or whether we may need that 30-day follow-up, which would move us out later.

In terms of the milestone question, so sorry. So as we have been -- as we've been progressing 711 forward, one of the things that we've been pleased actually is from both a -- from a nonclinical perspective, we found that we both have the ability from a tox perspective and also the potential benefit of higher dosing. And so accordingly, we added in some additional higher dosing that we're going to be exploring in Phase I before we go into Phase II. That did shift out our timing a little bit such that the milestone is not going to hit this year.

I do look forward to updating more with some specifics around time lines and study impact as we get through that Phase I dosing, but we wanted to reflect reality of when we thought milestone would hit.

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

This is Julian on for Paul. In thinking about DAYBUE STIX with the reversal of the CHMP opinion, you sort of set this like 15% threshold for contribution. Just thinking about like the peak opportunity, I guess, is that a reasonable sort of like benchmark? Or do you have any analogs that you can point to in the rare disease space that can sort of set expectations to what contribution ex U.S. that DAYBUE could potentially have to your franchise?

And then one quick question also on remlifanserin. There have been some studies published out there that -- from independent authors that suggest that pimavanserin at approved doses can get to 90% receptor occupancy after only a couple of weeks of dosing. I guess just with the improvements to your molecule, what do you think is -- is it fair to expect that it's going to be driving greater efficacy due to receptor occupancy? Or is it going to be elucidating an effect due to the improvements you made to the clinical trial?

Thanks, Julian. I'll just make a quick comment around the peak opportunity for DAYBUE outside the U.S. As we talked about already, we've guided to $700 million in 2028. That is definitely not the peak opportunity that we see. That is the 2028 number, just to be clear about that. And right now, we're talking about around 15% of those sales to be from outside the U.S.

That's obviously highly dependent on the reimbursement decisions that we get as we move through the reimbursement discussions that we've already sort of talked about. I would say that's an average analog for other rare disease opportunities. As we progress through the reimbursement discussions and we get those decisions and we get the first view of prices in the EU, we will be better able to articulate what percentage of our 2028 sales as well as further future peak opportunities would be.

But I think for right now, that's a fairly normal analog for rare disease. But as rare disease is very heterogeneous. There is really not a normal analog. So it's one that we are sticking with for right now, and we will update you as we go through.

And I'm going to hand the other question back to Liz.

Yes. Briefly, I suspect that the data that you were referring to is in young healthy volunteers because that's where most of the receptor occupancy information is.

And I'll say that, that is true that we get to near full receptor occupancy even with pimavanserin at marketed doses. It is our expectation and belief that in elderly and diseased patients, this is a bit of a different animal and higher levels are going to be necessary to get to the same receptor occupancy.

And to sort of support this, I would point again to the exposure response analyses that we've done out of prior data sets in both Alzheimer's and Lewy body that do suggest that levels that are higher than what you can get to with the marketed dose of pimavanserin on average do seem to be associated with higher efficacy. So again, I think that, that is a strong reason to believe there's a potential for greater efficacy.

But I will say that even if the degree of efficacy we saw with remlifanserin winds up being more similar to what we've seen with pimavanserin, we're structuring our programs in such a way by being focused on the individual diseases and properly powered such that I think that we have an increased likelihood of technical and regulatory success even if the effect were to be similar to the pimavanserin in terms of its scope.

Ladies and gentlemen, that concludes our question-and-answer session. I will now turn the conference back over to Catherine Owen Adams for closing remarks.

I'd just like to thank you all for your questions and continued support of ACADIA and look forward to reporting on our next quarter where we will have an exciting set of results for remlifanserin. Thank you all for your attention today.

This concludes today's call, and we thank you for your participation. You may now disconnect.

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.