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 Specialty 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 via the QR code, and we can cover that. But maybe with that, I'll get started. Yeah, maybe Mark, if you can give us a sense on where you are in the story, just recently announced 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 for 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 late-stage asset, ACP-204, we're investigating 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 is cash flow positive. We have almost 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 different dynamics going on. Maybe we start with Nuplazid, actually. So this is interesting. We have seen the IP extension, which was a big positive news for you guys 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 to us where you are in that growth narrative and as you're thinking of expanding the commercial footprint, where can this go ultimately? Yeah, that's a great question, so Nuplazid's been on the market eight, nine 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 rearview 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 visit. So the traditional metrics that you test to say, "All right, our commercialization and marketing dollars meeting 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 five, six years into launch a 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. That is all of that together has led to 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. 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. 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 kind of a 2-3 year investment horizon. 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. Yeah. 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 when does it start to generate the results in terms of most. I think from my—I mean, I've been at the company five years, so we haven't done this direction with Nuplazid, but we have a very experienced commercial team, commercial 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 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, 2-3 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. Right. Both from DTC and sales force expansion standpoint, kind of that type of time frame? Yeah. So I think both. It's a couple of quarters. 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 line. 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 roughly where consensus is at for 2026, like $730 million-ish. Is that sort of looks reasonable given 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 assets. 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, yeah, I know there's an appeals process when that can play out typically. Anything that you're seeing on that front? Yeah. So there's one. So the 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 mg capsule of Nuplazid. That litigation is subject to appeal. The appeal, the 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. Yeah. Great. Awesome. So maybe just switching over to Daybue then. So here, just I think, yeah, I have to say this has seen quite a bit of a turnaround, right? I think back in 2024 or 2023, you're starting to see a little bit of a stagnation, but with more of a focus on the pushes that you're making. You're starting to see more growth coming back. So I think on this same kind of situation that you're expanding the field sales force, right? And then you're starting to look at more commercial opportunity. Have you quantified where is the sales footprint right now for Daybue specifically? And where is the expansion? The number of reps? Yeah. Yeah. 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 as I would say, about two-thirds of Rett patients are treated outside center of excellence, 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 physician 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 Ponni can talk about this better than I can, any physician can prescribe it. And so what we wanted to make sure is that you have pediatric neurologists or even just normal pediatricians 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 this stage of the life cycle of the asset. That's why we expanded the field force earlier this spring or this year. As we reported on our third quarter, we're now starting to see kind of the fruits of that expansion. 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 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, the centers of excellence, the pediatric neurologists. But as you go into the community, they're not, as they get older especially, they're 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. Yeah. I know you focus on these three different kind of buckets in terms of the COEs and high-volume institutions and then private neuro. So where is the most value that you can extract for the next phase of the growth in terms of focusing in the channel? I think right now, we've now really established our relation to COEs, and so we've taken a lot of their learnings, both from an efficacy as well as the tolerability management perspective. We 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 connections and really educate them, and at the same time, really educating the caregivers because many times, especially the older patients, they're not really coming. 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 awareness is increased. Great. And then, yeah, 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, over time, as you're saying, more than 50% of persistency over 12 months and I think like 45% at 18 months. So, is there a room to go up higher than that? And patients that you have been tracking for, let's say, two years, where is that checking out to be in terms of the persistency? Yeah. 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 uplifts those numbers a little bit. 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, our strong persistency rate. So could they improve? You'd need new patients that start today or are on therapy to have greater persistency at that time point. So the whole curve can, over time, as more patients go through it, can shift up and down. But I think as we've seen it over time, we've waited to report those numbers just because you don't want five patients to reach there, right? Because they don't just be like this. So it's really those numbers are just robust and are supported as more and more patients hit those time-off points. Got it. But it seems a lot of the churn in the patient is happening early on. And if it's like 50%, 45% at 12 and 18 months, that means that longer follow-up is not going to be as effective. Right. So So let's say that you can see us in a room, and I guess there are maybe not people on WebEx. 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. Great. Yeah. And then just talking about Europe for Daybue. So I mean, I know you've discussed it, kind of starting in Germany and stuff like that. But yeah, how is the concept of the market different in Europe at all versus the U.S.? I mean, the standard of care, the physicians, how they prescribe for Rett maybe, if there are any differences between the U.S. and Europe? Yeah. So it really varies by country. So let's take Germany, for example, our biggest market. There isn't 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 the 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, they're 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. Yeah, and then just in terms of the pricing, where you might ultimately realize price versus U.S., or what is the likely base case that you're running? So it's a little early to talk about that. As 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 a 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 yeah, 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, particularly a lot of excitement around the R&D day when you outlined big sort of sales potential, but then unfortunately, the Prader-Willi 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're still kind of firmly believe 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 an R&D day that we had 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 bit more specifically about the pipeline in general and what she sees in it. Yeah. So we're very excited about our pipeline. We do think it will be an important engine for growth of the company. The first, more on the clinical, those stages that are in clinical settings 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 from pimavanserin. We're probably one of the experts in the 5-HT2A receptor science. And so based on that, and really trying to improve the profile. And right now, based on the data from our non-clinical 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 an Alzheimer's disease psychosis, as well as a Phase II study that just started in Lewy body dementia. So two very important and huge market opportunities, right? 7 million patients with Alzheimer's disease, of which 30% can develop psychosis, versus an LBDP over 1 million Americans affected, of which 50%-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 we're very excited in the neuropsychiatry space is ACP-211. This is our deuterated norketamine, which we will be studying in major depressive disorder with the Phase II study starting fourth quarter of this year. Interesting. Yeah. I want to ask a few questions about each one of those. So maybe just starting off with Alzheimer's disease psychosis. So this can be a very big opportunity, like you said. And 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 doesn't have the QT prolongation issue that pimavanserin does. So as you're getting to the higher concentration of this molecule, are there any other side effects that might be triggered that Nuplazid does not have with 204? Let me step back first about the molecule. And as you said, based on the early non-clinical 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 mg 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 plasma exposure, we think that'll translate to better efficacy, right? 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. We think that'll also have a shorter onset of action. That'll help translate to this population. Also, it continues to have a convenient, we think, once-daily dosing with or without food intake. Now, with regard to your point, with the higher doses, there could be potentially dose responsiveness in regard to other events. But so far, we have tested single doses up to 180 mg as well as multiple doses at 120 mg, and they've been generally well tolerated. Now, even in our ongoing study, we are testing both 30 and 60 mg. And so far, review of the blinded data is reassuring. Then we also have a data safety monitoring board, which has supported the continuation of the study. For those reasons, we're feeling that the tolerability profile will be very consistent with what we've seen with pimavanserin. That has been a huge advantage for pimavanserin. It's the convenience. Also, it's the safety in the elderly population. Got it. Great. Yeah. I mean, and in this space, there is a fair bit of this focus right now on Cobenfy, right? The Phase III trial reading out. I'm just curious if you have any views on their study kind of as a competitor. It seems that they, I mean, even on the schizo side, have a pretty high discontinuation rate. And for this study, they're using a thrice a day, which in this population can cause even more discontinuation. So just in terms of 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? Yeah. 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. But with ACP-204, as I mentioned, we have a pretty robust target product profile. And so far, what the profile looks like, 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. All right. I was looking at 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, which I think they have NPI-C. So yeah, what is essentially like an FDA-validated endpoint, like a registration endpoint? Or is it kind of that situation that because it's totally new disease state that there's no consensus around it? Yeah. 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 in the harmony with 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 with the change from baseline at week six. Now, the NPI-C is the neuropsychiatric inventory rated by the clinician. Now, we have included that as an exploratory endpoint. But 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 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 to change. With this scale, what's the right clinically meaningful effect size versus placebo for the duration of the time that you're running this study? Yeah. 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 Impression. And so we feel based on this, this will be clinically meaningful for these patients. Great. 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, what's the timeline on that? You said initiation by the end of this quarter. We've actually started enrollment in the trial, and so we're hoping to be able to read out potentially mid-part of next year. Got it. Okay. Perfect. And then yeah, there are a few different early pipeline programs that I was looking at. So 2591 in Rett plus Fragile. So yeah, just kind of how you're thinking about that from a positioning standpoint versus Daybue for Rett. Yeah. So this is a compound that we licensed from Neuren, and this is an IGF-1 analog. And just early work suggests it may have better brain penetrance. And so we're continuing to work on this. Right now, we're very committed to bringing new solutions to the Rett community in addition to, of course, ensuring that Daybue gets to more patients around the globe. So right now, it's in the early stages. For this program, you have the rights for two indications, but Neuren has a right for, I believe, for the rest of them, one of them kind of including Prader-Willi. Just given you have shown excitement around Prader-Willi as an opportunity, is that something that makes a logical step for you to try to secure that piece of the research? As of now, Neuren is investigating 2591 in a number of indications. As kind of the owner of the asset that they've chosen strategically, they want to keep those and invest them on their own. We have Rett and Fragile X. We'll stick with those. It's just the nature of the business relationship that we have with Neuren. Yeah. Is this one of those sort of broad 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 neurodevelopmental disorders, right? At least the mechanism of action of trofinetide, for example, which 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 a neurodevelopmental disorder, so this has given a lot of hope into the other areas and enthusiasm in investing in some of these other neurodevelopmental disorders. Got it. Got it. Okay. And then yeah, I mean, I think you mentioned the ketamine, deuterated ketamine. So yeah, can you talk about that a little bit? I think yeah, what's the angle there? Are you going for which subtype of depression or how fast can you see onset of action with that different approach? Yeah. 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 be less likely to have impact on and cause anesthesia. And also, because of this, it could potentially be dosed at a higher level, which can enhance AMPA activity, which can lead to this impact on depression. At the same time, with oral dosing, and also one of the theses for our target product profile is the ability, because it's not as potent, potentially to be less sedating and also have less dissociation. Now, why is that important? Because in the clinic, then they don't have to be there longer being monitored. So it'll be convenient. But at the same time, of course, the focus on efficacy. Great. And then just on 271, so this is yeah, going after Austedo, Ingrezza, and a very, very underpenetrated market. So yeah, I mean, I'm just curious, yeah, 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? Yeah. It's in the very, very early stages right now. But it does have a very interesting scientific hypothesis, right? It works on the GPR88, and it's an agonist there. And so we do think that it may have some potential in Huntington's disease, both on the chorea and 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 be the main indication and tardive is secondary? Is that? It's very early. We're hoping both, but yeah, 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. Yeah. This was great. Thank you very much. We enjoyed it as well. Yes. Thank you.