Good day, ladies and gentlemen, and thank you for standing by. Welcome to ACADIA Pharmaceuticals' Third Quarter 2025 Financial Results Conference Call. 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, PhD, Executive Vice President, Head of Research and Development, who will provide an update on our pipeline programs; and Mark Schneyer, our Chief Financial Officer, who will review the financial highlights. Catherine will then provide some closing thoughts before we open up the call to your questions. We are using supplemental slides, which are available on our website, Events & Presentations section. Before proceeding, I would like to remind you that during our call today, we will be making several forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, timing of events, future results and 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 three distribution partners are now actively shipping to patients in the EU, Israel, the 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 validate the long-term value of DAYBUE for patients while also creating 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 healthcare 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 healthcare provider 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 healthcare providers, 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 the standard of care for these patients.

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 timeline. 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 LBDP 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 contributions 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 million. 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 with over $1 billion in total revenues, 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 a 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.

That 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 two 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 are a few different factors, I would say, playing into our thinking. So as you think about kind of the new writer base, 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 underlying dynamic that we've seen throughout the year but actually accelerated in Q3, which has given us the confidence to pull forward this investment into Q1 of next year. 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. 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 percentage basis, 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 given the dynamics that we're seeing in that space as well. So long story short, we're investing in both and ensuring 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-H+D 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+D and why we landed there for Alzheimer's disease. So SAPS-H+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. 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 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, so we're looking for roughly a moderate effect size, a 0.4 effect size on SAPS-H+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 are 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 Liz to talk about 204.

Yes. 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. 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 204?

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

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

Congratulations on the quarter. I have a question about study 204. Can you discuss the overall study conduct and your feelings about it? Will there be any assessments of the blinded safety data that could provide insights about QTc prolongation advantage or information regarding risks such as falls or other aspects of the profile you mentioned that might give an early indication?

Overall, I am pleased with the progress of the study regarding the behavior of the sites, investigators, and the patient population we are enrolling. We are focused on ensuring that we select the appropriate patients by verifying their biologically confirmed Alzheimer's diagnosis through biomarkers, which we believe is crucial. From a blinded safety perspective, we have a Data Safety Monitoring Board reviewing the study regularly. They would alert us to any concerning issues, and so far, they have supported continuing the study as planned. We also conduct ongoing medical monitoring. However, I prefer not to comment on data from ongoing blinded trials because the outcomes can be unpredictable across different groups.

Your next question comes from Ash Verma with UBS.

This is So Youn 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 may be a bit hard to hear, but I believe your question was about our comments on the peak potential we discussed at R&D Day and our expectations for the commercial portfolio in that context. Let me outline ACADIA's overall goals. During R&D Day, we stated our aspiration to achieve $12 billion in revenue if all our pipeline programs succeed over the next 2 to 3 years. However, our 101 program did not meet expectations, which reduces that top-line forecast by about $800 million to $1 billion. Therefore, we now aim for total peak sales of approximately $11 billion for our currently discussed portfolio of compounds. Regarding our commercial goals, we mentioned expectations of $1.5 billion to $2 billion for our commercial products, NUPLAZID and DAYBUE. We are fully committed to achieving that and look forward to providing more clarity next year on the prospects for each brand, so you can better understand where we see them in the 2 to 3-year timeframe.

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 supermajority 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 one-time 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 our plan?

Thank you for the question, Malcolm. There's a lot of energy going into our launch readiness planning in Europe. We'll be following the standard process for approvals there, starting in Germany. We're already preparing to ensure our team is ready for that market, with a small group of key account managers and several staff members focused on the medical side actively engaging with prescribers, particularly Rett treaters. Each European market varies significantly from the U.S., but we're ensuring the right infrastructure and focus are in place. I'm pleased to share that we opened our compassionate use program in Germany this quarter and have received several requests from German healthcare professionals to enroll their Rett patients, which we see as a positive sign of interest in our product. We'll make sure that the experience is positive as we approach the launch.

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

Sure. 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. 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.

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 actually new writers, which was over 25% in the quarter. As we look ahead to opportunities for growth, we did a deep dive on what that assessment looks like and where we see the opportunity, and we see a ton of opportunity across a wider group of customers that we've been actually calling on to date. For reference, historically speaking, we've generally called on neurologists, some movement disorder specialists, and some psychiatrists. Looking at that 26% who are new to writing prescriptions for NUPLAZID, a ton of those are now coming from primary care, often nurse practitioners or advanced practitioners that are now writing NUPLAZID. 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 highlighting the benefit that NUPLAZID can offer. As a reminder, our share in terms of NBRx remains in the mid-20% range, so 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. You can 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 overall investment. And we'll just share this 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 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 onboard last year in September, the team had just started their DTC communications, both the unbranded and the branded. 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 in the numbers real traction in terms of carers and their families being made aware of what the symptoms of Parkinson's disease can be beyond motor, and those 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 patients to treat their hallucinations and delusions. All of those metrics have come together. With the important IP win that we had for NUPLAZID, allowing us 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. Tom, can you talk a little bit more about some of those investment decisions?

Yes. I mean, I think Catherine captured it really well. It's really been a story of momentum this year for NUPLAZID, and Q3 in particular has really seen this step change in how we're seeing referrals across the board. Given that momentum, that gave us the opportunity and the lens to really reassess our customer model, especially as we see a number of new prescribers outside of our core target base engaging with this community, which, as a reminder, can be challenging to get time with a neurologist or with a PDP specialist. We think that with this expanded reach, we'll be able to help these patients understand the benefit they can see with NUPLAZID beyond what we're doing today. It's about capitalizing on momentum while ensuring we have the right structure in place for both today and tomorrow 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, insights, and data. Within the new expansion, it's being fueled by analytics, data, and insights, and we'll be using that and AI on top of it to ensure that we efficiently find our patients and target them. 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 wanted to

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

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

Thanks, Jack. We are obviously in the middle of discussions and thinking right now around reimbursement in Europe. We did have a disappointing decision in Canada. Tom, do you want to share how we're thinking about reimbursement in terms of the sequential approach to that in Europe?

Absolutely. As I mentioned, our plan would be to launch first in Germany. And as a reminder, in Germany, as we launch, we have six 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 given the engagement that we've already started with payers and clinicians, we remain confident that our European clinicians and the broader environment are seeing the benefit that DAYBUE can offer. 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, we are 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 speaking on behalf of Paul. I wanted to ask about ACP-204 and if you could explain the exposure response relationship you've observed with pimavanserin and the research conducted on ACP-204. You frequently mention the insights gained from development, including execution and scientific perspectives, and I'm curious why you believe that the increased potency of ACP-204 will lead to greater clinical benefits.

Liz?

All right. I'll try and get all the things that were in there. Starting with the exposure response. Both in the Alzheimer's disease population and in Lewy body, we do have some information from pimavanserin suggesting that with higher levels of exposure, you can achieve higher levels of improvement on the clinical endpoints and that the median exposure we achieved with pimavanserin leaves some of that efficacy on the table. This is sort of midway through that exposure response downward curve. The reason for this, of course, is that, unfortunately, with pimavanserin, there was a tendency towards QT prolongation, which limited the ability to dose range. So we could not dose patients to achieve maximal efficacy. With 204, we don't have that problem. Thus far, our nonclinical and clinical data support the absence of a QT prolongation signal, and overall, our experience suggests we can explore higher levels of efficacy. The higher dose is roughly twice that. So those are the pieces that give us some optimism that we can achieve higher efficacy. Even if we do not reach higher efficacy with higher doses, we believe there are program learnings we can apply. We will evaluate both disease states. We think we have promising data from pimavanserin, but it's a limited number of patients. The Alzheimer's program had a single dedicated study with a subgroup in an overall study. In summary, we're optimistic about ACP-204, which we see as potentially changing our company's trajectory.

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

This is Basma on for Marc. 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 older age group? The reason for 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 an aspect of lack of effect driving greater discontinuations. Could you clarify whether the age of Rett patients, in general, seeking treatment is skewed to the younger age group or if it's basically uniform across the different ages?

Thank you. I think there are 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. Thank you for the question. So going back to the original premise, do we think the reason we are slightly lower penetrated in patients older than 11 years is due to discontinuations? I don't think that that's the case. Essentially, the vast majority of patients treated so far, if we look at penetration by age, are those in the 2 to 4 age bracket. Newly diagnosed patients are easy to identify and generally fall under the focus of the Center of Excellence. 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 we can really begin to penetrate further. Especially with our LOTUS real-world evidence generation, which includes patients as old as 60, we continue to see patients benefiting irrespective of age. This has been part of the strategy as we've extended our reach beyond Centers of Excellence because many of these older patients are within the community setting and may not be under the care of a COE. We want to ensure that they are made aware of DAYBUE, as demonstrated by a patient story we heard yesterday for a patient in Kansas who had never even been made aware of DAYBUE before coming into the center. This highlights that we have more work to do in educating the community about Rett and what to look for and ensuring they understand the benefit DAYBUE delivers to these patients irrespective of 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 agree with everything that Tom said there. I think 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. As Tom said, we've also been tracking these patients in LOTUS as well, and we see evidence of improvement in those patients. It's an increasing body of evidence supporting that DAYBUE does bring benefit to patients in line with the indication, which is not restricted by age.

Yes, I think that's 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 efficacy in specific age groups. That's a big focus for Tom and Allyson and the team as we move into next year, to really ensure that data is shared specifically to encourage physicians unfamiliar with Rett to think about that data for all patients, not just younger patients.

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

This is Poorna 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 it doesn't have competition with other branded agents. We haven't seen a comp like that go through the IRA negotiation. 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 ACP-211 is concerned, 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. The data we have so far supports that, both in animal models suggesting efficacy, as well as lacking sedative impacts or dissociation. 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. We designed this to look at efficacy, but also very importantly, to rule out unacceptable levels of sedation and dissociation. We think there is a potential for a really appealing product here.

Your next question comes from 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 LBDP and the PDP population instead of just focused on Lewy body dementia psychosis specifically?

So Lewy body dementia psychosis is an umbrella term that encapsulates dementia with Lewy bodies, as well as Parkinson's disease dementia psychosis. We are looking at both patient populations to understand any similarities and differences in terms of how they behave to help inform our future studies. When we look at the population in the pimavanserin dataset that is specifically 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 in particular makes us enthused about it.

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

You're investing more in NUPLAZID, and there have been some questions already about that. But we're finally seeing excitement in the Parkinson's market. AbbVie recently announced the sales force expansion on the strength they're seeing for VYALEV and the potential approval for tavapadon. 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. So let's just start by reminding everyone that NUPLAZID is the only branded product approved for Parkinson's disease psychosis. As we see more activity in the overall Parkinson's market, I think history would tell us that once more larger companies are in the market talking about Parkinson's disease more fully with more people, there tends to be an increase in terms of awareness of different elements of the disease. As Tom has already noted, 50% of patients suffer from psychosis or experience hallucinations and delusions at some point during their journey. It wouldn't be surprising to see that rate increase. There is relatively low awareness among families and caregivers of those symptoms, which is why we've put effort behind the unbranded campaign. Those non-motor-related symptoms are generally undiscussed and unfocused on by the physicians and their families. We continue to raise awareness with our patient engagement campaigns, hoping to see that physicians learn more about it themselves. Without us, it won't be a natural topic for them. What would you say on that, Tom?

One thing I would say, Parkinson's is recognized as one of the fastest-growing neurological disease types in the U.S. There are estimated to be about 1 million patients with Parkinson's, and about 40% to 50% of that population are diagnosed with hallucinations and delusions during the course of their disease. By our estimate, there are about 130,000 patients identified as atypical and psychotic during the course of the disease. Patients often focus on movement elements of the disease, and unfortunately, not everyone is educated on hallucinations or delusions that can occur. A key call to action we're driving is that if a patient is experiencing hallucinations or delusions early in their disease course, that is a trigger point to start treatment. This prompts engagement with an HCP, whether it's a neuro or a primary care physician, to discuss the need for action. We believe that NUPLAZID can play a critical role given its profile, safety, and growing body of evidence. Taken together, we see more upside, which is why we decided to invest now in reaching that customer base as we look forward.

Now is the time to make this investment, and that's a great way to end that question. Thank you.

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.