Thank you for joining us for this next session. My name is Nevin Varghese with RBC Capital Markets. I'm here joined by ACADIA Pharmaceuticals, Mark Schneyer, Tom Garner, and Sanjeev Pathak. Yeah, let's get right into it. I know a lot of these conversations usually start out with looking at the commercial trajectory of NUPLAZID and DAYBUE, and I promise we'll get to that as well. I think the key focus on a lot of investor minds recently has been remlifanserin. I'd love to start with that. Maybe you can talk about some of the preclinical differences that you've seen in remlifanserin versus pimavanserin, and some of the properties there that could enable this next generation to potentially show some efficacy in ADP, as well as what you've seen from the prior pimav trials that give you that confidence as well. Okay, great question, first of all. The biggest difference between remlifanserin and pimavanserin is that we have been able to eliminate or mitigate the QTc prolongation issue. We have seen that in our non-clinical data, in vitro studies, and now we are seeing it in the clinic as well. What it allows us to do is increase the dose, increase the exposures, and what we have learned in our pimavanserin program is that if we can deliver higher levels of exposures on an average basis, it lends itself to better efficacy. That is the key non-clinical distinction. Overall, otherwise, the potency as well as the functional potency is generally similar, if not slightly better, but the distinction is on the QTc. Now, what we have learned with the pimavanserin program is many things. Four in particular. One is that for a program in ADP, we need a dedicated program with several studies. What we had with pimavanserin was a singular study in ADP in nursing home patients. We are taking care of that. What we have also learned is that if we enrich the patient population with more severe psychosis, we get a better effect size. We are enrolling such a patient population in our program. The third thing that we have learned is that it is best to have a highly sensitive endpoint. We have used several in our pimavanserin program. Now we are using the SAPS-H+D, which we have found that it performs well across sites, across studies. They're sensitive to change and also sensitive to differential change versus placebo. Finally, the point that I initially stated is that what we have seen in our exposure response, ClinPharm modeling is that in patients who achieve a higher blood level with pimavanserin, the efficacy is higher. On an average level, if we can draw the exposures to a higher level, we feel that it will also result in better efficacy, and we are able to do that. We have two doses in our remlifanserin program. A 30mg dose, which is equivalent to the pimavanserin, 34mg or NUPLAZID dose. Then we have 60mg dose, which should offer double the efficacy. This is all that will contribute to higher probability of technical as well as regulatory success we think. There are other advantages as well. The half-life of remlifanserin is shorter, and we reach steady state in around five days or six days in the elderly, relative to 12 days to 14 days or 15 days in the elderly for pimavanserin. There is potential for reaching efficacy earlier as well. Got it. Got it. Within these trials, can you talk about the trial conduct, how the trial has been enrolling so far, as well as some of the strategies that you've taken to mitigate some of the placebo responses that we might see? Yes. Placebo response is important as well as the conduct of the trial is critical. We have seasoned staff who ran the pimavanserin program, we know we are good at site selection and the conduct as well as training the staff, investigators, et cetera. What we are doing is not only training them rigorously on endpoints, patient selection, but also monitoring in a blinded fashion and interacting with them in a constant basis. We are feeling confident about the sites we have. Now, in terms of placebo response, what we have learned is that if we enroll a confirmed group of patients with Alzheimer's disease psychosis using biomarkers, if we reduce the heterogeneity, if we are able to convincingly exclude patients who may have what we used to clinicians, physicians like me used to call pseudodementia. It looks like ADP, it is not a neurodegenerative condition. It may be because of other psychiatric symptoms. It, our placebo response would be lower, as well as the signal detection is likely going to be higher. We are doing all that. What we are doing it, achieving it is through biomarkers. We confirming a diagnosis of AD, and then very rigorous training of the investigators. It is much tighter relative to the pimavanserin program Got it. Got it. Yeah, then can you remind us about what the powering for the trial is and what you think would constitute a meaningful difference on the primary endpoint of [SAPS-H+D]? Then I guess a separate question kind of, you know, assuming this moves forward into phase IIIs, typically in larger phase IIIs, we see a compression of the delta. So what do you think you might need to show in the upcoming phase II in order to kind of give you confidence that a larger phase III and a potential compression of efficacy might still yield stat sig and clinically meaningful? Very thoughtful, multi-pronged question. Thank you. Let me take them one at a time. The study is powered at 80% for a moderate effect size of Cohen's d or standardized effect size of 0.4. What we are trying to learn from this trial is have data that can inform us to optimize, enrich, phase III so that we are feeling confident about our investments going into phase III. Now, you're absolutely right that the delta or effect size tends to get compressed going from phase II to phase III. Of course, ADP does not have any information because we haven't had programs in ADP. The closest proxy or example could be psychosis in schizophrenia, where there was a meta-analysis done in 2017, and if someone is interested, the primary author was Stefan Leucht. What they showed was that there was an attenuation of effect size by around 19% or 20% going from phase II to phase III. If we take a very conservative view, the attrition or diminution could be around 30%. Now, these studies with schizophrenia, when they were conducted, they had replicated almost exactly phase II to phase III. What we could do, and there are anecdotes where lessons from phase II are utilized to enrich phase III, then the diminution may not happen. ADP is a new field where this will apply much more so. We are thinking that we would be able to find a way a patient population, as also fine-tune the biomarkers, tighten them, to enable a similar effect size going from phase II to phase III. It'll all, of course, be dependent on the data. Okay. Makes a lot of sense. Then just wondering how you're thinking about the potential read-throughs from some of the other competitor programs. I know BMS was running their COBENFY trials. We might see some of the ADEPT data later on this year or early next. How are you thinking about read-throughs from that trial? You know, we'll have the remlifanserin data at that point, I know this is kind of a theoretical exercise, how are you kind of thinking about that just given the different mechanism. Yeah. It's absolutely tempting to do a cross-study comparison. I do wanna mention that there are limitations to across study comparisons. Even the same compound. Across studies may show different effect size. For instance, COBENFY may have several ADP studies. The effect size may be different. In other programs that have read out, some studies have been successful and some not, for instance, [ANAVEX] study with agitation, etc. With this consideration in mind of these limitations, the way we think about it is that when we look at efficacy, we have to understand the differences in the patient population, how the enrichment was done, how the conduct was done, whether there are biomarkers or not. Eventually, when the results, we have results in hand and our other sponsors have results in hand, we will be able to look and compare and contrast. We are feeling good about our program, especially because we are leveraging lessons from pimavanserin, which we have extensive experience with. Got it. Okay. Excellent. I know as I promised earlier, we'll get to NUPLAZID and DAYBUE as well. I guess, moving to the commercial franchise, you've recently expanded your sales force for NUPLAZID. Can you talk about how that expansion has resulted in changes in kind of the volume trends, script growth? What kind of early metrics, either on prescriber, outreach, new scripts per rep, you know, any kind of color that you might be able to provide there? Sure. We executed the expansion of our sales team in Q1 of this year. We increased the overall reach by about 30%. Our primary focus remains on neuros. Of the 10,000 customers that we're now covering, about 45% of that remains neurologists who remain kind of the mainstay of treatment of neuro Parkinson's disease, psychosis, et cetera. However, we have seen a real evolution in the mix of writers over the last two years, especially as we've employed our direct consumer campaigns, both direct consumer in terms of patients, but also amplifying our reach into the HCP community as well. If we look at Q1 in isolation, about 25% of our total writers were actually new to brand writers. You know, a nice proof point that the expansion that we're putting into place is working for us. That was one of the reasons that we had decided to expand our reach in the first place, is clearly NUPLAZID is now being written by a different group of customers to where it had been written historically. In terms of your question as to kind of impact to the sales force, I would say it's still early, to be honest. I mean, we only really had the team fully trained in the field kind of middle of Q1. We are seeing a nice uptick in total call volume. As we kind of move through the journey now in terms of getting the team up to speed with their new targets, obviously, they get more proficient in kind of just being able to talk and sell NUPLAZID. We would anticipate that the impact's gonna be more back end of the year loaded. We're anticipating a six-month to nine-month ramp in terms of kind of true efficiency of the increased model. I know we saw some delays with the script refills in the first quarter. Are there any additional insights into that yet you've been able to glean since, or was this just a blip? Y- You know, shouldn't really be? Yeah. We've looked into it in detail, as you would imagine. We're not identifying any specific issue that we saw. It was just that we had a group of patients that were late returning. Slightly large group of patients that were late returning in this quarter one versus prior quarters. Remember, NUPLAZID has very, very high Medicare exposure. We're kind of in the 80% range of our patients are actually Medicare patients. They are the group that as January 1st hits, everything resets. They have to go through re-verification. They may well go onto a different plan. It just takes a while to get them, you know, back into kind of status quo. Nothing that we're anticipating kind of having, you know, a continued drag through the rest of the year. Got it. Then moving on to DAYBUE. How has patient persistence discontinuation kind of looked between the community centers and specialty centers, especially as you've expanded more so into the community centers of late? How has that level of patient and physician education kind of, you know, differed either between the community or specialty centers? Yeah. Compliance, persistence been? Yeah. As a reminder, you know, we took a decision last year to actually move beyond just being focused primarily on Centers of Excellence to now reaching more patients within the community. As a reminder, about 2/3 of Rett patients actually fall outside the direct care of a Center of Excellence. Significant opportunity. As it stands today, we're actually fairly under-penetrated in that specific segment. We're kind of in the late 20% range now. Significant headroom for growth, that's why we did take the decision last year to expand our focus into the community. In terms of your question regarding persistence and compliance, what we're seeing for both COEs and non-COEs is as we have more patients kind of going through 12 months, going through 18 months, we continue just to see this growing group of persistent patients. We are actually seeing that the shape of the curve is really beginning to shallow now. I think we said during the last earnings call that our 12-month persistence rate across all cohorts is now north of 50%. In fact, it's close to 55%. Our 18-month persistence is now in the 50% range. Again, we feel good about that, and we do believe that now we have both the liquid formulation and with the recent launch of DAYBUE STIX, that we actually have an additional opportunity to potentially unlock even more growth and help keep patients on longer still. Yeah. Wondering if you could talk a little bit about that, about the STIX launch as well. You know, I think you've mentioned that there's about 30% of naive and returning patients who've initiated on STIX. How do you see that, you know, potentially more patients coming off the sidelines to initiate on DAYBUE STIX? Are you seeing early signs of the STIX formulation potentially resulting in better compliance, lower GI issues potentially? Is there kind of just I guess, what has the patient and physician feedback been so far? Yeah. So as a reminder, we launched DAYBUE STIX in Q1 of this year. Again, that launch was primarily centered on Centers of Excellence. We wanted to ensure that they had the experience, they got the hands-on kind of touch and feel for how to prescribe, and making sure patients understood how to reformulate the product 'cause this is a, it's a powder that you can mix with any liquid that's non-dairy based. Quite honestly, we've been just very pleased with the initial demand that we've seen. It's been across a mixture of naive patients, returning patients, but also patients who are maybe saying, "Well, now DAYBUE STIX is available, I may consider moving over from the liquid". We've kind of got those three distinct streams. I think the initial feedback that we're hearing both from caregivers and from HCPs has been positive. I think they appreciate the fact that ACADIA really leaned in and listened to the feedback that they had provided around liquid. As a reminder, the STIX formulation, highly portable, no refrigeration needed. We've taken out a ton of the excipients that patients were concerned about, especially in a very fragile patient population like those living with Rett, because a number of these kids are on keto diets, as an example, 'cause it helps with seizure control. I think all of that taken together has resonated well. I think we've actually been kind of very pleased with the initial uptake that we're seeing both across naive, but even more importantly across those who are returning back to DAYBUE, to your question. We're seeing patients who are actually returning back from the very early stages of the launch. They may have received the product in, you know, late 2023 into 2024 as we first launched, and now they are coming back, which I think again demonstrates DAYBUE is recognized as the standard of care. I think the recent Delphi paper kind of recognized that. With STIX, I think we have an opportunity now to reengage with those patients in a way that we weren't able to do with just the liquid formulation. Are those patients who are returning to DAYBUE or to STIX in this case, are they coming to their doctors of their own volition? Were their doctors reaching out to them and saying, "Hey, listen, there's a new formulation available. Would you like to try this?" Has the company been reaching out since, you know, maybe those contacts were established? How has that been? We actually, we actually amplified our direct consumer efforts at the beginning of April once we were through the initial focus launch, and we were going into the community talking about STIX. I think that that's certainly resonating. We are seeing doctor requests coming through as well. To your question, we do have a team of what we call Family Support Educators who remain in very close contact with every DAYBUE family, whether they are on therapy or they've decided to discontinue. We've been reengaging with patients who we know may have discontinued due to formulation concerns to say that we now have DAYBUE STIX available. I think that that approach is clearly resonating. Got it. Then can we talk about what the strategy might be with the IP for STIX? Is this potentially something that could enable- extended IP beyond just DAYBUE or is that, you know, is that something that you guys are considering looking into? The IP as it stands today is on trofinetide use in Rett. The same IP estate covers, you know, both liquid and STIX formulation. Okay. That's how it stands today. Got it. Shifting to DAYBUE in the European Union, I know there, I think the reanalysis of the data was recently submitted to the CHMP. What does the timelines look like there for potential SAG meeting and what the decision, what the timelines to a decision might look like? Yes. The, as, you're aware that this reexamination process is a highly structured and time-bound process. We expect it to conclude by the end of June. It involves a lot of steps, and which includes us submitting our intent to request reexamination. Rapporteurs have been assigned. We also have submitted our grounds for reexamination. We are preparing for the SAG, which is the Scientific Advisory Group, as well as preparing for an oral reexamination. As I said, it should wrap up by the end of June. Shifting to some of the other pipeline products, how are you thinking about ACP-271 in neurological disease? It's a GPR88 agonist. How de-risked is this particular target, and what are you hoping to learn from the phase I trial to inform go, no-go decisions for further evaluation? We are really excited about the ACP-271 program, which is, as you said, a GPR88 agonist. GPR88 is an orphan receptor, which by definition means that the endogenous ligand has not been identified yet. We are working on that, though. GPR88 is highly abundant in the motor areas of the brain, the basal ganglia, et cetera, as well as in areas of the brain involved in higher cognitive function. Though the density is somewhat lower. What we expect is, and hypothesize is that it should be able to ameliorate some of the movement disorders that we are going after, plus the associated neuropsychiatric symptoms associated with it. What gets us excited is the consistency of benefit in what we have seen in non-clinical data. As you may be aware that the tardive dyskinesia animal models are highly replicable, where we have seen enduring benefit, as well as not seeing the typical safety findings seen with the approved therapies, which is sedation, et cetera. They are the approved therapies tend to be dopamine as well as monoamine depleters, so lend themselves to depression, et cetera. We are hoping that or hypothesizing that this GPR88 agonist will not have those burdens. In fact, because of the presence in the higher cognitive areas, that it may be actually able to ameliorate some of the associated psychiatric symptoms. Got it. Okay. I know in the last minute, just want to ask about updated thoughts on BD. I think the company has talked about kind of a barbell approach. Is that still- Yeah. I mean, that- ...where your thinking is? That's exactly how we think about it. We'll still look to invest both on the neurological side and the rare disease side of the business. As you mentioned, kind of as we've talked about barbell, you know, can we bring in things that are late stage that could be launching in the next, you know, few handful of years? Then on the opposite side, kind of of our robust kind of mid-stage pipeline, bring in assets that are earlier to supplement the early stage portfolio. Great. Thank you all so much. Thank you, Tom, Sanjeev, and Mark. Thank you. I hope this has been helpful for everyone here. Thank you. Thank you. Thank you, Nevin. Very good. Thank you.