Acadia at Needham Conference: Strategic Growth and Challenges

On Monday, 07 April 2025, Acadia Pharmaceuticals (NASDAQ: ACAD) presented at the 24th Annual Needham Virtual Healthcare Conference, outlining a strategic roadmap for growth. Despite facing potential challenges from tariffs and regulatory changes, Acadia remains optimistic about its financial outlook, targeting over $1 billion in revenue from its key products, NUPLAZID and Debut, in 2025.

Key Takeaways

• Acadia projects over $1 billion in combined revenue from NUPLAZID and Debut by 2025.
• The company plans a 30% expansion of its field force to boost Debut sales, particularly outside Centers of Excellence.
• European market entry for Debut is anticipated in early 2026, pending regulatory approval.
• Clinical trials for ACP-101, ACP-204, and ACP-711 are progressing, with significant milestones expected in the coming years.

Financial Results

• Revenue Guidance: Acadia expects to exceed $1 billion in revenue from NUPLAZID and Debut in 2025.

• Debut Sales and Penetration:

- 30-35% of Rett syndrome patients are treated within Centers of Excellence.

- Debut penetration is 50% within COEs and 25% outside.

• Q1 2025 Expectations:

- A sequential decline in net sales is anticipated due to a $3.5 million pull-forward into Q4 2024, typical seasonality, and Medicare Part D changes.

Operational Updates

• Field Force Expansion: Acadia is increasing its field force by 30% to enhance physician interactions, aiming for 6-8 calls per year to support Debut's adoption outside COEs.
• Tariff Mitigation: With API manufacturing in Switzerland and Italy, Acadia has secured at least two years of inventory in the US.
• European Market Entry: Regulatory approval for Debut in Europe is expected around Q1 2026, with managed access programs planned for key markets.

Future Outlook

• ACP-101 (Prader-Willi Syndrome): Phase 3 trial enrollment is expected to complete by the end of 2025, with data anticipated in early 2026.
• ACP-204 (Alzheimer's Disease Psychosis): Phase 2 trial enrollment is projected to finish by Q1 2026, with results in mid-2026. A Lewy body dementia study will start later this year.
• ACP-711 (Essential Tremor): Phase 2 trial initiation is planned for next year.
• R&D Day: Acadia will host an R&D Day on June 25th in New York to share pipeline developments.

Q&A Highlights

• FDA Changes: Acadia is closely monitoring regulatory shifts, with no immediate impact on its trials.
• Physician Support for Debut: Outside COEs, physicians require more data, clinical evidence, and guidance on managing side effects and patient nutrition.
• European Opportunity: The prevalent population of Rett syndrome patients in Europe is estimated at 9-12,000, presenting a significant market opportunity.

For a detailed overview, readers are encouraged to refer to the full conference call transcript.

Full transcript - 24th Annual Needham Virtual Healthcare Conference:

Ami Fadia, Senior Biotech Analyst, Needham: Good morning, everyone, again. Welcome to the next session, of, the, Needham twenty fourth year health care conference. I'm Ami Fadia, senior biotech analyst here at Needham, and it's my pleasure to be hosting Acadia for this next session. Good morning, team. Thank you for being here, for this fireside chat.

Maybe if I could just turn it over to Catherine to just kick us off with some opening remarks and just priorities for the company for this year.

Catherine Owen, Unidentified Role, Acadia: Yes. No, absolutely. Thanks, Ami, for having us. I'm joined by Mark Schneider, our CFO and Liz Thompson, our Head of R and D, and we're looking forward to taking the questions. So just to sort of set the scene for Acadia in 2025, we're really excited that for the first time we're guiding to over a billion dollars for our two commercial products in total.

So that's NUPLAZID for the treatment of hallucinations and dilutions of Parkinson's disease, and Debut for the treatment of Rett syndrome. So for the first time, they'll come in over £1,000,000,000 which is an exciting landmark for us at Acadia. As well as that, we've got two late stage programs coming through. We have ACP101 for Prader Willi syndrome, which is late phase three and looking forward to completing that enrollment towards the end of this year. And then ACP204, which is our phase two, three clinical trial for the treatment of Alzheimer's disease psychosis, and also initiating a Lewy body dementia psychosis study later this year.

So very excited about both of those readouts, which will come in 2026. And then finally, we have a newer product into our pipeline, ACP seven eleven for essential tremor, which is fairly early stage, phase one now, but starting phase two next year. And we're really excited to hold our first ever R and D Day in June of this year, June '20 fifth, in New York, and Liz and her team will be sharing much more about our pipeline. So those are the headlines for Academia.

Ami Fadia, Senior Biotech Analyst, Needham: Excellent. Great. Thank you for giving us that overview. Perhaps maybe just before we jump into some of the detailed questions on Acadia, I wanted to just maybe ask you around two topics. Firstly, maybe just the recent changes that we've been seeing with the FDA.

Can you comment on kind of how you as, you know, one of the industry representatives are kind of thinking about this changing environment at the FDA? And any comments you could provide would be helpful.

Catherine Owen, Unidentified Role, Acadia: Yes. I mean, I think we're amongst the many biotech companies that are watching very carefully. The situation, as we all know, is fairly fluid right now with the changes at HHS, yeah, in leadership and now at the FDA. You know, we're all watching. We're fortunate that we have a very strong industry group with Bio led by John Crowley and his team, and they keep us abreast.

And more importantly, they represent us on the hill and ensure that our voice is heard in terms of any concerns about changes that we're hearing. In terms of effects on anything that's happening within Acadia, for right now we haven't seen anything in terms of any effect on any of our trials. But we watch with bated breath like everybody else, and are hoping that we can get through the the next few months of maybe relative uncertainty and come out the other side with with more of an idea. But beyond that, I mean, really a lot to say right now.

Ami Fadia, Senior Biotech Analyst, Needham: Fair. That's fair. Just separately with regards to the tariffs, which are also front and center for everyone. Yeah. Would you like to provide any color on, you know, where the companies in market drugs are manufactured and, you know, what investors should keep in mind as they think about the implications, for Acadia?

Catherine Owen, Unidentified Role, Acadia: I'm gonna let Mark take that because he leads our, he leads our supply chain group. So, Mark, why don't

Mark Schneider, CFO, Acadia: you Yeah. I'm happy to jump in. I think for the first thing I would say obviously, there's another topic that we're paying close attention to and evaluate what the potential implications may be for the company. I think the first thing I would say for for both New Plaza and Debut, we have, like, at least a couple of years of inventory in The US today. So that gives us some flexibility to let see how this plays out without expecting any immediate financial consequences on the company if there are any.

And then I think if we look at that to your question of, you know, historically, tariffs have flowed with API for pharmaceutical companies. So today, NUPLAZID API or pimavanserin API is manufactured in Switzerland, and trofinetide API is manufactured in Italy. And so we do have alternative sources. Those things can be changed over time. They can't be changed immediately, so that's where it sits today.

And then the one other thing I'd point out for investors, if location of IP plays into comes into play here, our PIVVANTORN IP is located in Switzerland and all other IP for the company, pipeline and, etrafinatide resides in use.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. That's super helpful. Thank you. Okay. And just as a quick reminder to our listeners, if there are any questions you wanna send along, feel free to use the dashboard.

So maybe let's switch gears and talk about Debut.

Catherine Owen, Unidentified Role, Acadia: Sure.

Ami Fadia, Senior Biotech Analyst, Needham: Talk about sort of the current penetration of debut in key segments, you know, centers of excellence and high volume institutions and community practices. And, also, remind us how the treated patients are split across these settings.

Catherine Owen, Unidentified Role, Acadia: Yeah. So let's start with that, actually. So about thirty to thirty five percent of our rep patients are treated inside our centers of excellence. And that means, obviously, correspondingly, sixty five percent outside. And those outside centers are really sort of larger hospitals, but also can be down to sort of small community neurologists.

So there's a very variable treatment setting outside of the centers of excellence. In terms of the penetration army, we have in our centers of excellence, there's 21 of those, about 50% penetration of debut. So obviously there's still quite a lot of room to grow there. But outside the centers of excellence, where the sixty five percent of patients are treated right now, we have a relatively lower penetration around twenty five percent. And so that's why we're we're restructuring our field force and also feel very good about the opportunity to grow the brand, and I'm happy to share a little bit more detail around that.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. Yeah. I mean, I I I guess so maybe we could sort of just focus on the noncenter of excellence for now. Yeah. And maybe talk about where you have that 25% market share coming from, perhaps qualitatively?

And how are you thinking about approaching kind of building upon that?

Catherine Owen, Unidentified Role, Acadia: Yeah. No. Absolutely. So it comes from all over, all different types of settings. We're sort of two years nearly exactly into launch now.

And those physicians who have seen and treat rep families outside of the centres of excellence are quite often calling their centers of excellence for advice. So there's lot of phoning in and double checking on how to treat. What we've realised is that these doctors outside of the COEs need more rep time, they need more MSLs and they need more education. So as a result right now we're increasing our field force by about 30% so that we can actually get to those physicians and really support them through the prescribing of Debut. And so we are now putting that into place in the market.

And so we'll be to see those physicians much more frequently and really ensure that they're educated and comfortable about initiating debut and helping the families through the first few months. So that's a really important point. But obviously with only 25% penetration, it really gives us confidence that once we get those people in place and they're and they're active and supporting our physicians, we've got quite a lot of headroom to grow debut beyond where we are now just in The US.

Ami Fadia, Senior Biotech Analyst, Needham: Could you sort of clarify? So, you know, how of the total reps, how many are going to be focused on COEs versus non COEs? And what does this expansion really mean in terms of, you know, the frequency with which they can sort of call on the non COEs?

Catherine Owen, Unidentified Role, Acadia: Yeah. So the way we structure our territories is that the reps are geographically based, so they may or may not have a center of excellence on their territory. But if they do, they will also cover other positions. So they're geographically oriented. So what we're now able to do is have a higher smaller territories and therefore a higher reach and frequency over the year.

And what we do know is that doctors need about six to eight calls from either an MSL and a representative, so combined a total of six to eight calls. So now we have the capacity to achieve that. And so our focus right now is to really still educate within the centres of excellence. We're not losing our focus there, but also now expand beyond and really ensure that those patients that are treated have the right education and support. So that's the strategy.

We're getting those teams in place right now. And which is why when we guided on our first call earlier this year, we're talking about seeing the impact of that towards the second half of this year after the team are embedded and after they've started making their calls. Then we expect that growth to start really climbing towards the back end of the year.

Ami Fadia, Senior Biotech Analyst, Needham: Can you qualitatively give us some color on what exactly do the physicians need the most amount of sort of time Yeah. And kind of discussion? Is it sort of managing the GI symptoms to to the does the office need support with kind of the reimbursement process? So maybe just color there.

Catherine Owen, Unidentified Role, Acadia: Yeah. No. Absolutely. So if you can think about the physician that we're talking about, they're generally a neurologist or a pediatric neurologist, and they're not expert in Rett. They may have one or two patients.

And so actually initially there's some real support around the data, the clinical evidence, the confidence in prescribing, the clinical trials and how they've worked. And also updating on the real world evidence that we now have after two years of market to help them understand the patient types and really give them confidence to initiate that script. And then to your point, once they've initiated, we have family service managers who are out in the field to help support the family. And that's really from the managing the GI side effects side, but also our MSLs are educating our physicians on how to use Debut with all the evidence we now have And understand what they can and can't do around titration. And importantly managing additional focus on ensuring that the patient's nutrition is good so that they are taking their fibre.

They're also thinking through managing their anti constipation meds and titrating those down. So there's a lot of things that the physicians need to think about. And then the back office, we have reimbursement teams now who are able to support the back end and getting the patient on to debut. But it's a real team effort that we now have really going very well in our field force. And every doctor is different, but that's pretty much how it works.

Ami Fadia, Senior Biotech Analyst, Needham: And how is the persistency level different in the COE versus non COE so far?

Catherine Owen, Unidentified Role, Acadia: Actually, you know, what we're seeing is is relatively similar across all settings. We're seeing, as you know, that our persistency rates at twelve months are about just above fifty percent. And we're seeing that it's important to manage the patients in the first three months, but we're not seeing a difference in persistency across the COEs versus the other physician settings. So that's actually great because it means that our physicians are well educated and supported, and we're not seeing one better than the other.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. You had indicated at, the most recent earnings call that there was sort of a step up in the average dose, that was being utilized in the real world setting. I think previously, it was more closer to seventy percent. Mhmm. Now it seems to be inching up towards seventy five percent.

What's really driving that? Are there specific types of patients or treatment centers, or is it just, you know, maybe maybe sort of talk about where what might be driving that and whether it may be driven by center of excellence or non center of excellence?

Catherine Owen, Unidentified Role, Acadia: Yeah. So let's get clarity on that. I think when we when we guided and talked about q four in particular, we did talk about a dynamic that we saw which was pulling forward some prescriptions from patients into Q4 from Q1. And that's sort of a normal dynamic that we see when patients want to have enough bottles on hand for getting through the holidays, making sure there's no new year situations with pharmacy. And so we had this pull through.

And so that sort of automatically shows an increase as an increase in utilization. So that is really the explanation for the 70% to the seventy five percent. We continue to monitor the 70% to 75%. It does fluctuate a little bit, but really we're not expecting that sort of continue to change through the year. Now that we have a fairly stable and very stable patient base, we're really seeing that settling in.

We continue to educate doctors about titration and getting patients up to the right dose, but it seems to be hovering around that seventy percent mark. So that that seventy five was more of a q four dynamic.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. That's helpful. So maybe just, you know, stepping back, you mentioned earlier that you expect a lot of the impact of the Salesforce or field force expansion to come through in the second half of the year. You know, just sort of to set investor expectations, maybe, you know, what are some of the metrics that they should follow, you know, or or what metrics will you share with us through the course of the year?

Catherine Owen, Unidentified Role, Acadia: No. We'll continue to share an update as we see the field force coming online. So just to get specific, coming online now. And as we guided, we expect them to be fully embedded after two to three months. They need to get out there, make their relationships, make their core plans, etcetera.

And so from July onwards, we're expecting the impact of that field force. And if you think about what we're expecting, we're expecting more scripts in in the top of what we would refer to the funnel. So we will continue to update you on the metrics associated with that. But actually the key metric, if you like, is what we report every quarter, which is the active patients on debut. So obviously if more patients are starting there should be more active patients.

So that I believe is the key metric that the analysts should be looking and watching for. As I say again, we expect that to start ticking up towards q three and q four. No. I just realized that

Mark Schneider, CFO, Acadia: to that, Amit, I'd add one thing is think what we've said and what Catherine just reiterated is the kind of operational metrics we expect improvement in the second half. If people are focused on their models of what the kind of the sequence of revenue or net sales is gonna be quarter over quarter since we do expect, you know, seasonality in the first quarter, for and have a decline a sequential decline in net sales, we set we expect kind of the growth trajectory of net sales to be more even over the course of the year as kind of q two will be a normal quarter versus q one, and then q and '3 and '4 will have the expected operational benefits that Catherine mentioned.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. I wanna come back to sort of how we should think about growth in COEs in a second. But since you touched upon first quarter dynamics a little bit, maybe if you could sort of close that topic. Can you can we sort of lay out what are the factors that we should think about as we model first quarter? You talked about some of the pull through of volume Yes.

Mark Schneider, CFO, Acadia: So Catharine so Catharine mentioned, right, the kind of the pull forward of of bottles as patients kind of would get in in front of their, you know, holiday period and, you know, insurance reauthorization process. So that on our fourth quarter call, we quantified about at at three and a half million dollars of net sales. So if you just unwind that, you know, like for like, that's a $7,000,000 reduction quarter over quarter. And then in addition to that, we just expect typical seasonality across our metrics, which are tend to be lower in the first quarter, so that can impact volume further in the fourth quarter. And we do expect a sequential decline in net price, which is primarily related to the changes in Medicare part d as part of the inflation reduction act because trofinetide was launched after the, you know, the date cutoff for us to qualify as a small company manufacturer for debut.

We do for New Plaza, but we don't for debut. So there'll be some increased rebates associated with that, which will impact, net price in 2025, but certainly a sequential decline from, q four to q one. So all that taken together will impact our net sales in q one, which we discussed on our last call. Okay.

Ami Fadia, Senior Biotech Analyst, Needham: Maybe just going back to the penetration and COE setting. Catherine, you mentioned it's about 50% currently. How should we think about the growth potential there or deepening of that market share over time?

Catherine Owen, Unidentified Role, Acadia: Yeah. I mean, we we feel very confident that that we can grow that. Obviously, there's there's a there's a delta there that is is fairly significant, not as significant as outside of the centers of excellence, but definitely there. And just to think about the 21, they're not all the same. So we've got some that are relatively highly penetrated up in the 80s, and we've got some that are lower.

So the median is 50, but we're definitely not the same across all of them. So again, we continue to focus on them. And importantly, their experiences are very influential outside of their immediate COE. There tends to be a regional influence of those physicians. And so as I said before, other neurologists will call in and get advice.

So as well as generating prescriptions, they actually have a positive effect on the confidence of other neurologists in the area. So very, very important part of our focus and continued part of our focus as we move forward.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. Let's switch gears and think about Europe. And, you know, you you have an application under review there with the EMA. Can you share some details on where you are with the review and what the next steps might be? And, you are there some countries where you can make the drug available even prior to approval?

Catherine Owen, Unidentified Role, Acadia: Yeah. So let's talk to that. So we filed in in Europe in the February. And so in terms of the way we have clock stops and responses to questions, etcetera, expect our approval to be around about q one of next year if everything goes towards a normal clock and a normal kind of a number of days in between the clock stops, which it usually does. So we feel fairly confident about that.

As you rightly say, there is the ability in Europe to do a managed access program or a named patient program, depending on the different country. They have a different vernacular. They all have different regulatory approaches to this, but we are partnering with a third party to help us support anybody in Europe that has a country system that allows them to legally ask for debut before it's approved. And so we are launching that in the next few months in some of the main countries. So just as an example, Germany has a program.

Italy has a program, France has a program. So we will be supplying that demand as we get it. But that's generated by key opinion leaders or physicians in the countries, and it's specific to a named patient.

Ami Fadia, Senior Biotech Analyst, Needham: K. What's the opportunity for the product in Europe relative to The US? And how should we think about kind of where patients get treated, you know, and how that could look like relative to The US?

Catherine Owen, Unidentified Role, Acadia: Yeah. So the the the opportunity is fairly substantial. It's a a larger prevalent population at nine to twelve thousand patients with Rett syndrome across Europe. And it's proportionate to the size of the countries because as you know, genetic and it's one in ten thousand to fifteen thousand live births. So there's not one country that has any more or less than the other.

So it's purely population based. So obviously therefore Germany would have the largest population of patients. As you know, each country tends to have a very different approach to treating their population, and the same is true for Rett syndrome. Just as an example, Germany is actually a very diffuse system. They treat them at social centres across Germany, and so there's no really centres of excellence in Germany, just about 100 or so treating facilities.

Contrast that to France where we probably have about five or six centres of excellence across the whole country, a very, very focused treating pattern. So we're approaching each country differently in terms of how we're setting up and how we're actually getting to these physicians. But we have our MSL team out there now gathering information and also working with patient advocacy groups to understand the specific needs of patients in Europe.

Ami Fadia, Senior Biotech Analyst, Needham: And, you know, as we think about pricing and, you know, we are aware of the difference in the pricing dynamics in Europe relative to The US and, the general sort of back of the hand way of thinking about it is somewhere in the 30 to 40% of The US price. Is that a fair way to think about that? This is

Catherine Owen, Unidentified Role, Acadia: We'll be we'll be as specific as we can as we get the first reactions to our dossiers. And, you obviously there are analogues and you can find an analogue that's 20%, you can find one that's 80% and everything in between. So we're focused actually on generating the right evidence for each health care system and each dossiers being developed specific to those needs. We have a very strong team in Europe. We have a team now full time in Switzerland that's managing all of that.

And so we'll as soon as we get the sort of the reactions from each of the countries, we will guide and give an idea. But we are fairly hopeful that we'll get a strong price for for debut in Europe.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. Why don't we switch gears to ACP two zero four? Yes. Can you maybe just give us a sense of where you're at with the studies, and maybe we kick off from there?

Catherine Owen, Unidentified Role, Acadia: I'm going to let Liz take over. Liz?

Liz Thompson, Head of R and D, Acadia: All right. Thanks so much. I will go ahead and start with a very brief introduction to ACP-two zero four, and then talk a little bit more about the studies and where we're going. So first off, two zero four is our new five HT2A inverse agonist. And we built this based on learning from pimavanserin.

And briefly, the things we were looking to improve there were to reduce or eliminate QT prolongation, to enable dose ranging, in particular to let us go up to higher doses because we believe that higher exposures may lead to greater efficacy. And finally, to get a faster time to steady state, which, while not for sure, gives at least the potential for faster time to onset of effect. And thus far, the data that we have does support that we've been able to hit all three of these things. We've been publishing non clinical, and we'll be publishing phase one data to give the outside community some sense of the reality of this. But so far, we think that two zero four is meeting the profile we're looking for.

Now, what we're doing with two zero four. Our first program is in Alzheimer's disease psychosis. And this is in a phase two trial, a master protocol that includes a phase two followed by two phase three trials. It's probably worth pausing briefly on the advantages of that. It gives us the opportunity for seamless enrollment.

So once a trial site is done enrolling in phase two, they can move directly to enrolling in phase three, which gives us some potential time advantages. However, it's also important to note that we did set this up so the studies are statistically separate. And that means we have the opportunity to analyze the phase two portion and make modifications as needed to the phase three. So it does give us the opportunity to learn, which we think is an advantage of this program. Generally speaking, the phase two is three arms.

The lower dose is the same exposure as the currently marketed dose of NUPLAZID, and the higher dose is roughly twice that exposure. So like I said, we think one of the advantages here is the ability to go to higher exposures and potentially get greater efficacy, And this is really going to let us try that out. Overall, it's about three hundred patients in this study. We're going to have a six week primary endpoint. And as I think Katherine mentioned at the beginning, we anticipate completing enrollment in this trial by the first quarter of next year and therefore having in the phase two portion, I should be clear, and therefore having data in roughly midyear next year to share.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. Alright. Now can we just go back to the data that was generated for pimavanserin previously, in the Alzheimer's disease patient population? Of course, there, you had a broader study, and then you'd looked at the Alzheimer's disease patient population as well. As we just think about the phase two study that's being run, what are the similarities or differences with versus the pimavanserin study that had been run previously?

Liz Thompson, Head of R and D, Acadia: So there were actually couple of prior pimavanserin studies, one that was specific to Alzheimer's, and one, as you say, that is in broader dementia related psychosis. What I'll say generally is that there are, particularly compared with the DRP or the dementia related psychosis trial, there are a number of differences. Population wise, we are focusing in here on Alzheimer's, and actually going the extra mile and not just requiring a clinical diagnosis, but also confirming that with biomarker confirmation. So a much more refined and directed patient population. It is a parallel group design versus the withdrawal study that was used in DRP.

And there are some specifics around the use of endpoint. We did use SAPS H and D in both cases, but they're being used a little bit differently. That said, we have been able to take information from a large number of studies with pimavanserin, the HARMONY DRP study, as well as our prior use in Alzheimer's and some of the learnings from PDP as well that help us inform what we're doing with ACP two zero four in this program.

Ami Fadia, Senior Biotech Analyst, Needham: Mhmm. Now so you you mentioned SAPS, HND. You know, that specifically targets hallucinations and delusions, whereas the NPI and H provide sort of a broader assessment of various sort of neuropsychiatric symptoms, including psychosis, depression, anxiety, etcetera. So can you tell us about kind of how pimavanserin may have done in the SAP HND endpoint?

Liz Thompson, Head of R and D, Acadia: Yeah. So I think the background of this question is that in that phase two ADP trial, the endpoint we looked at NPI NH. But I do think it's important to note that even in that study, there was a focus on the psychosis component as the primary endpoint, not some of those other facets like depression, anxiety, and agitation. So even looking at the NPINH, we were focusing in on the psychosis component in Alzheimer's, and it should be noted that that phase two did meet its primary endpoint in the Alzheimer's disease population, focusing in on psychosis and hallucinations and delusions. So that's generally consistent with what I think we know that PIM is good at.

Our labeled indication is based on psychosis and hallucinations and delusions. But in particular about the endpoint, SAPS H and D, and our prior use of it, we have actually used this in a couple of different settings. The first of these is it was in our pivotal PDP study, and it was also used in harmony in that dementia related psychosis study that I just referred to. So we do have a variety of experience to draw upon. And in both settings, I think it's worth noting that there was separation from placebo using this instrument.

So we do have good experience with this instrument itself, as well as, of course, some learnings about pimavanserin's general focus on psychosis, hallucinations, and delusions.

Ami Fadia, Senior Biotech Analyst, Needham: Could you remind us so it sounds like it was the second one of the secondary endpoints that was measured in the the DRP harmony study. Is that right?

Liz Thompson, Head of R and D, Acadia: And was included in DRP.

Ami Fadia, Senior Biotech Analyst, Needham: Yeah. So was there a p value for that?

Liz Thompson, Head of R and D, Acadia: So there was there was a p value. I will say, obviously, a withdrawal study is set up rather differently from a parallel group perspective study. So it's it's difficult to draw specific comparisons there. But definitely with SAPS H and D, we have seen separation from placebo in in a couple of different settings, which is reassuring.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. Maybe just dwelling a little bit more deeply. You you mentioned that, you know, with all the experience that you've had with pimavanserin in in studying this in ADP population as well. You've kind of taken some of the learnings and, you know, the obvious sort of differences around, you know, QT prolong prolongation and kind of the PK curve, through sort of, you know, faster titration, etcetera. All all of those are, you know, fundamental differences of e c p two zero four with Pima.

But in terms of maybe clinical trial design or any other learnings that we may not have spoken about? Anything else that's worth highlighting here?

Liz Thompson, Head of R and D, Acadia: Yeah. I mean, I think we have touched on many of them. There are inherent differences of two zero four versus pimavanserin in terms of what we think it can do from an exposure perspective. And again, we think that exposure response potentially gives us the opportunity for better efficacy. So that is a very important component of what we're doing differently in this study.

And then I did touch on the fact that I think we have learned a lot about conducting ADP trials. And in particular, one of those things that we've learned is the importance of dedicated trials that's focusing specifically on that population. And so I do think that focusing in on not just a clinical diagnosis, but biomarker confirmation to be very clear that what we're looking at is an adequately powered, specific to Alzheimer's disease population, is going to be helpful. There are other things that we've done in terms of slight modifications to have a more severe patient population, because we did see some evidence that there was a higher signal, and that's not an unusual outcome. But generally, I think it really is about a molecule that we think helps us achieve some important things from a TPP perspective, as well as focusing in specifically on that Alzheimer's disease population.

Ami Fadia, Senior Biotech Analyst, Needham: Mhmm. Okay. Just from a regulatory standpoint, of course, you know, you're gonna launch two phase threes off of the phase two. You does the phase two potentially serve as a phase three should, down the line, one of the phase threes not work?

Liz Thompson, Head of R and D, Acadia: You know, that's always gonna be very subject to the data we actually see out of the program. But what I will say is certainly there are precedents generally, but specifically in the neuropsychiatric space, of drugs getting approved with one or sometimes even more than one failed study. So I think that, you know, subject to compelling data at in some portion of the program, there at least would be an opportunity to engage with regulators even in the context of having at least one of those trials not work out the way we might want it to.

Ami Fadia, Senior Biotech Analyst, Needham: Sure. Of course. Okay. Maybe just, switching gears to the Lewy body dementia, trial that you guys, announced. You know, how would that phase two study design, be relative you know, would it look exactly like the the one that you're running in ADP?

And, why not wait to at least learn about the doses from the ADP study before you start that one?

Liz Thompson, Head of R and D, Acadia: So I'll briefly say that we are very enthused about the Lewy Body program. While the amount of data we have direct from PIM is limited, certainly what we did see is in patients with Lewy Body, there was a pretty compelling separation in the Harmony trial, in that withdrawal trial, with of those patients who stayed on drug, only about five percent of them relapsed, whereas those who were withdrawn from drug, more than fifty percent of them relapsed. So there was a pretty striking distinction in between those two patient populations. Mind you, limited number of patients is about 20 patients per arm. But we thought that this was really quite interesting, and we are excited to be able to take two zero four here.

In terms of your point about differentiation, so this is maybe we'll call it a slightly more traditional development approach. We're going to start with a phase two trial, and then we will have a completely separate phase three program. So it won't be that seamless enrollment that we're doing with ADP. We're taking a little bit more of a staged approach here. We do think, though, that starting this program now gives us some opportunity to jump start learnings that are specific to this disease and this population that's going to help us better design a phase three program.

While there are some things we could learn about dosing, we do feel confident in the two doses of two zero four and that they're going to be acceptable from a tolerability perspective. Obviously, we're going have to run the studies and see. But we think that running this study now gives us the opportunity to learn some things that are specific to Lewy Body that we would want to know before we go into a later stage program. And overall, we're committed to maximizing two zero four's potential, and we think Lewy Body is an important part of that. So we wanted to keep those programs going as consistent in time as possible.

Ami Fadia, Senior Biotech Analyst, Needham: So you're studying the same two doses and the same endpoints in Lewy Body?

Liz Thompson, Head of R and D, Acadia: Well, I guess what I'll say is I'm really looking forward to discussing the design in more detail at R

Ami Fadia, Senior Biotech Analyst, Needham: and D Day in June. Alright then. I will keep my ears open.

Liz Thompson, Head of R and D, Acadia: We are gonna be looking at multiple doses. I will at least say that.

Ami Fadia, Senior Biotech Analyst, Needham: Amazing. That make now now it kinda makes sense. Okay. Alright. That's helpful.

Alright. Why don't we, talk about the ACP one zero one asset, in hyperplasia and PWS? Can you maybe talk about that trial and where you are with regards to enrollment? And maybe just I think PWS seems like a difficult, disease to treat with multiple different, you know, symptoms. So maybe just talk about kind of your confidence level that, you know, hyperplasia can be addressed with ACP101.

Liz Thompson, Head of R and D, Acadia: So where we are now is we have a phase three study that is running currently. We're pleased with how enrollment is going along. We have said that we expect to have this enrolled by the end of the year and expect, therefore, to have data out of it in the first half of next year. PWS has been a challenging space historically, but I will note there is now the first approved agent there, which I think gives us some confidence that with a robust positive result in this phase three study as designed, we think we would have a very compelling data package to discuss with regulators. We do have data from ACP101 in a prior phase three trial that is supportive of efficacy.

But I should be very clear that in that study, the primary endpoint, which was based on the higher dose, did not meet statistical significance. But we did see some good consistency of information at the lower dose, and the lower dose is what we're focusing in on in our phase three trial.

Ami Fadia, Senior Biotech Analyst, Needham: Mhmm. Maybe just as a follow-up to that, should we not have seen a dose dependent improvement in response, or, you know, is there a rationale for why we're not seeing that in this case?

Liz Thompson, Head of R and D, Acadia: Yeah. So, you know, when I'm looking at trials that didn't, you know, didn't hit their primary endpoint, I look for a few things. The first thing I look for is mechanistic rationale, and there is a number of different points that suggest the relevance of oxytocin and Prader Willi. But then I look for some consistency of data within the place where you saw positivity. So with the three point two milligram dose, we do see positive impact on more than one endpoint and more than one time point.

And that is generally reassuring. And then to your point, the last thing I look for is, is there a plausible alternative explanation? And the data we have aren't enough to be able to specifically prove that this is the case, but there is reason to believe that there is the potential for off target impact through the vasopressin receptor, and that that off target impact could interfere with our ability to see a positive outcome on the primary endpoint. So that's our hypothesis. I think it's a reasonable one.

We're gonna run the study and see.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. Great. I think we have maybe just maybe time for one quick question on Nucleosid, if I may. Sure. Maybe if you could sort of just touch upon some of the recent, you know, volume growth trends that we've seen with Newplazit and how you're thinking about continuing to drive growth with that.

Catherine Owen, Unidentified Role, Acadia: Yeah. No. Absolutely. So let's just sort of consolidate what what we saw in 2024, which was really a couple of things. The first was clarification of the label that NUPLAZID can be used in patients with or without dementia.

And that clarity has provided a lot more physicians confidence to start and continue to prescribe NUPLAZID. On top of that, we had a lot of new real world evidence data in very large Medicare patient populations to show that NUPLAZID had a significant effect versus off label antipsychotics in both mortality and morbidity endpoints, which again gives physicians a lot of confidence in prescribing. And then we realized that we needed educating a new generation of caregivers because we hadn't done a lot of DTC education since really COVID. And so we started an education campaign making people aware of the symptoms that can be associated with Parkinson's disease. And what we've seen is a lot more inquiries on our websites, etc, wanting to learn more.

And as a result of that, we've actually now seen an increase in patients going into their physicians and asking to learn about NUPLAZID. So all of those three areas, label clarification, real world evidence to support the use of NUPLAZID, and a campaign that's educating doctors and their caregiver families around the symptoms. Those three things gave us a change of momentum in Q4, which we believe will continue as we move into 2025. We look forward to sharing the impact of all of that as we move through this year, but we do feel very confident that we can continue to grow Neuplazid.

Ami Fadia, Senior Biotech Analyst, Needham: Okay. Alright. Well, that was really helpful. Thank you so much for the time. We are out of time, unfortunately, but thank you so much to all of us as well.

Catherine Owen, Unidentified Role, Acadia: Thanks a lot, guys. Thank you.

Mark Schneider, CFO, Acadia: Thanks so much.

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