To go ahead and get started, thank you everyone for joining us for the Acadia Pharmaceuticals Fireside Chat here at the 45th Annual TD Cowen Health Care Conference. I'm Ritu Baral, covering analyst, and with us from Acadia, we have, starting on that side, Catherine Owen Adams, CEO, Dr. Ponni Subbiah, Chief Medical Officer, and Mark Schneyer, CFO. Thank you everyone for joining us. So.
Thank you.
Let's start with Daybue. I think most of the focus, investor focus on the name is still Daybue. You're expanding your sales force by 30%.
Yes.
To help drive patient starts, specifically outside Rett Centers of Excellence. Can you review for us the current penetration rates in Centers of Excellence as you see it? High-volume institutions and community practices, respectively.
Sure. So right now, we believe there are about 5,500 to 5,800 Rett patients in the U.S. And from the data that we've gathered, we believe about 35% of those patients are treated in the 21 or 22 now COEs that exist in the U.S., which means about 65% of them obviously are treated outside those Centers of Excellence. And up until now, we've had a very strong focus, as you would imagine, in a rare launch, you do focus on the Centers of Excellence to get the KOL community engaged in the product, understanding it, and writing it, because those are the people that the community physicians look to for guidance. We're sort of now coming into our second full year of launch, and we believe there's a lot of opportunity outside of the Centers of Excellence to drive volume growth for Daybue.
Within the Centers of Excellence, we're about, it's varied, but we're about 50% penetrated in terms of patients that have tried Daybue. Outside, so the 65% of patients that are treated outside, we have a 25% penetration. So in terms of that opportunity to drive volume growth, it's definitely sitting outside the Centers of Excellence. Up until now, our reach and frequency, back to the old-fashioned reach and frequency model with sales forces, has been that we haven't been able to get to those physicians with the right frequency. And so on average, those physicians have seen an Acadia rep maybe once or twice. And that's not enough to get them confident to prescribe Daybue. They might see one, two, three patients a year, and it's just not top of mind when you've only seen that many representatives.
So really, the logical focus now is to ensure that we have enough representatives to reach that group at the right frequency.
So you mentioned something interesting. You said now 23 Centers of Excellence.
22, yeah.
It's 22. Okay. Is there a new one or?
I think Miami has just been.
Yes.
There were the three that were added last year, including Miami.
Okay. Is that something, is that something we should watch out for? Are there increasing Centers of Excellence for a broad swath of care? One thing we noticed when we were doing our tracking surveys is that there was this giant hole in the northwest, like over here, because we were trying to survey a good geographical distribution, and there seemed to be giant holes in parts of the country.
Typical for the IRSF centers.
Daybue Centers.
Yeah, so IRSF, I think, in collaboration with the directors of the current COEs, they're very much committed to ensuring there's Centers of Excellence across the country, but each of the centers have to meet a certain criteria and experience to get there, and that's why they do have to submit applications, it gets reviewed, and so it is encouraging that now they've added more centers in different parts of the country, which is helpful because not all patients are able to travel.
Exactly.
To those distances.
Exactly. Okay. Great. And then going back to what you said, Catherine, about the community setting, are you guys developing new materials, supportive care products such that are more tailored to a community setting in managing the GI side effects? Because the more community, the more community you go, the less time these.
The less time and the little, the less infrastructure, so the COEs generally have a lot more infrastructure in terms of additional physicians, nurse practitioners, etc., that can manage the other parts of the patient care. Outside of those centers, it's maybe one or two physicians in the practice, and so what we're doing, and Ponni's team are responsible for this, is putting in place peer-to-peer education programs. We're putting in place family-to-family education programs so that we can sort of start to talk about best practices. I don't know if you can talk about anything else we're putting in place to help those extra community physicians.
I think, as Catherine mentioned, you know, in the community, we need to be able to educate because they're seeing maybe one, maybe two patients in their practice. So what we've done is, in addition to publishing the GI management strategies, for example, most recently, the anti-epilepsy meeting, we did a survey of the COE directors, like how were they managing Daybue. We have presented that poster so that one of the things we hear from these community physicians is they want to learn from these experienced practitioners. So through publications, through our medical team, through our sales force team, we are going to be able to share this information so they can leapfrog from the learnings from the COE directors.
Got it. Got it. In the non-COE setting right now, is it really just the mind share question that is the gating factor, or are they, I guess, are they hesitant to use Daybue because of the manpower burden of managing the patient early on in titration?
I think that they very much mean clinicians in the community, when they do see them, they want to be able to provide best of care, right? At the same time, they are more constrained in the resources, like Catherine said, like they don't have a GI specialist that may be there. And so one of the things that's going to be important is we become a very important source of information for these physicians. And that's why expanding our field team members to be able to have more frequent contact with them is going to be very important.
Is assistance with insurance coverage and back office support also an element of this?
Yeah, so we're investing in more reimbursement specialists to support the offices.
Is this part of the 30%?
It is. Yeah. So we now have dedicated reimbursement specialists that are aligned to different parts of the country so that offices who are having, maybe they're doing a PA to label that they've been asked for additional documentation, our reimbursement team will sort of help them through that. We've learned over the last two years that it depends on the payer. It can be a little bit of a paperwork burden. So we are investing in more people to help support the back office.
Got it. And are these doctors managing towards a different goal than COEs? I know you mentioned they want to be able to offer, and they want to be able to help their patients. But what is—I guess, as we think about dose titration, what are they dosing towards versus what Centers of Excellence dose towards?
Yeah. So I think—so first, you know, I think the main thing that we're focusing on right now is the early experience for these patients. So one of the things we're sharing is, first of all, they need to better understand what Daybue is and how it is used. And also sharing, as I mentioned earlier, from what the experience of the COE directors. And the other important thing is we want them to be able to articulate what the benefits of the drug is. It's not just about GI management, right? And we need to have them have a successful conversation.
What's the point of titrating up in order to even risk?
That's right. So they need to give time to see the benefits. It's a chronic neurodevelopmental disorder. And so be able to, it's very important the clinician helps set those expectations with the parents.
Got it. And so going back to the COEs for a second, are there any additional resources or support that you think makes sense to deploy towards the COEs?
We're not taking our focus off the COEs. The expansion allows us to. It's an and strategy. It's the COEs now and outside. What we're doing right now is, Ponni said, you know, a lot of the COEs have had quite deep experience in terms of managing these patients. We're using their experience to publish additional sort of papers around GI management strategies. We're also using them to help teach through peer-to-peer programs, best practices. There are physicians within the COEs that still maybe are a little bit on the sidelines. Again, we're going out to the. Maybe each COE has three or four physicians that might prescribe, maybe one or two have. We're now focusing on maybe the others that maybe haven't tried it yet or need just a little bit more information.
Got it. And then given these efforts in the expansion, how much Daybue growth should we expect in the second half?
Mark, do you want to take that one?
Yeah, I think for maybe we'll split it between operational and financial, and maybe I'll talk qualitatively. I think for all the efforts that Catherine and Ponni have been talking about, we expect, and I would say you should expect kind of more operational pickup in the second half of the year than the first half of the year. When we talked about guidance on our last earnings call, it's the top of the funnel. It's referrals in the top of the funnel that are really going to make the difference within our range over the course of the year while we're looking to continue to improve, like as Catherine likes to say, and, right, continue to improve all the other metrics. All the other metrics have kind of settled into a more narrow band at the moment, roughly two years into launch.
But if you're thinking about for financial models, how our quarterly net sales sequence could be, keep in mind we do expect a sequential decline in the first quarter due to mostly seasonal and net price impact. Right. So once you factor that in, I would say if you look to Q2, Q3, Q4 from a net sales standpoint, it should be more consistent growth starting from where we come out of Q1.
Got it. Actually, that leads to a very interesting question on Q1 seasonality given the changes in Medicare, Medicaid, out-of-pocket caps, and the way that Wall Street has usually modeled Q1, down Q1, increased gross to net, lower percentage, lower market share due to patient switching, and also greater gross to net because of the donut hole. How should we think about that going forward with the redesign? Should it be an amplification of what we had previous years?
It's actually quite a different way of thinking about it, I think.
I think it's both Daybue and Nuplazid, but it's slightly different for both metrics.
We'll go back to Daybue in Europe in a second, but if you could address that for us.
So I think for us, right, so the Medicare part, let me kind of expand from there, but start with your specific question. So for Nuplazid, it'll be a tailwind, and for Daybue, it'll be a headwind. And the reason why I say that for the difference is on Daybue, we're starting there, we do have less than 10% of our patients are Medicare kind of primary payer responsibility. But what's happened between the Medicare Part D redesign for Daybue, since Daybue was launched after August 2020, even though we as a company qualify as a small manufacturer, Daybue doesn't.
Oh.
Right?
Oh, because it's your second product?
No, because the drug launched after a cutoff in the legislation.
Gotcha.
Because of that, our actual rebates on Daybue will increase year- over- year.
Okay.
So when we're thinking, when we talked about overall net price for Daybue year- over- year on our quarterly guidance call, midpoint of our range, we expect about 0.5 percentage point increase in net price. The vast majority of our increase in guidance is volume. Right? And so I think those dynamics flow through for Daybue. And I think what you'll see for both medicines, while the impact of inflation having kind of a general net realized price increasing over the year, there won't be these seasonal quarterly changes amongst either drug. There actually wasn't on Daybue historically, but it still won't be. On Nuplazid, it's the other way, right? So we do qualify as a small manufacturer under the legislation. Nuplazid qualifies.
If we've talked with the investment community, we expect just isolating the Medicare Part D redesign, we expect a 300 basis point improvement, so reduction in gross to net.
For 2025 and comparing lighting scale.
Right. And then our overall gross to net is not quite 300 basis points down just due to other changes in normal mix. But then for Nuplazid, as I said for Daybue, Nuplazid, we saw this big seasonal adjustment for first quarter being the highest, second and third quarter being lower, and fourth quarter gross net being slightly higher. We won't see that going forward. Daybue, Nuplazid will be more consistent gross to net throughout the year.
Got it.
And so any seasonality in the first quarter for both medicines will be volume-driven, insurance reauthorization, kind of typical Q1 seasonality for a volume basis, not necessarily the gross-to-net price impact that you've seen in past years.
Understood. Okay, let's move back to trofinetide or Daybue in the EU. You've guided to expected CHMP, I believe, in the first quarter of 2026. How's that application going? First of all, have you gotten the first round of questions back?
Not yet. So our day 120 questions come in Q2, and we're preparing for that. We put in our package of the Lilac and Lavender data. What was nice about the EU application was we were able to put a little bit more in terms of our real-world evidence with Lotus. So it's a little bit more of an expanded package of data that the EU will appreciate because obviously there's a strong focus in HTA markets on that sort of real-world evidence. So the team are expecting that to come in Q2. So everything is tracking according to plan.
Who are your rapporteurs?
Poland and the Netherlands, yes.
Okay. With the Netherlands having extensive experience with rare disease.
I think all of our rapporteurs appear to be very experienced, and we're very confident and happy with our rapporteur interaction so far. Yeah.
Great. As we think about Centers of Excellence and concentration of care in the E.U. versus U.S., how should we be thinking about that?
Unfortunately, it's a little bit of a country-by-country situation. But let me talk about the larger markets to help sort of guide the thinking. Unusually for Germany, we actually don't have a COE structure in Germany. It's much more of a diffuse care of patients in what they describe with a German acronym that I won't summarize, but they have about 120 centers that treat children with neurological disorders throughout the country. And that's where our Rett patients are treated. Contrast that to France, where we have four or five key centers of excellence around the large cities, as you would expect. So those two countries just out of the gate are very different. Italy and Spain seem to be much more along the lines of France in terms of more centers of excellence. Yes.
And then as you sort of move out to what we call the mid-size countries, it's a little bit much more of one or two centers of excellence. So Germany is probably the biggest outlier in terms of treatment in Europe. U.K. right now is more of a centers of excellence approach. And we're examining the U.K. in terms of our overall strategy, whether we will or will not launch in the U.K. because of the NICE situation.
Got it. Pre-launch activities, what do you have going on in Europe and what geographies will you be concentrating commercial investment in even before?
So we're building up our team in Zug in Switzerland. We'll have a sort of small European core there. We've just hired quite a few new people, but we've actually had our MSL team out in the field for about six months. And Ponni and I were out there in January to meet with them. So they're out there right now mapping all the centers of excellence, giving us this insight that I've just shared with you. And I would just say that the interest in Europe is very strong. And we have a lot of centers that are very keen to use Daybue. And so that's why we have decided, as we announced on our call, to go ahead with a managed access program in Europe and allow access to Daybue prior to approval.
What geographies is that allowed in? I think it's France and Italy.
Right now, Germany will go first, France, Italy, and Spain.
Germany has a managed access program.
They do. They do, and so we were able to tap into all of the different regulatory and legal systems, and some is charged, some is free of charge. It's different by country, but we are responding to clinician interest and ensuring that patients have access to Daybue before we launch, and we think that's important because the physicians in Europe were not part of our clinical trial program, and so we're really trying to ensure that the experiences that they have are guided by our learnings in the U.S. and that we have our MSLs out there able to support them prior to launch so that when we do launch, we feel very confident about the uptake and the ability for those physicians to prescribe with knowledge.
For the part of it that is charged, will you be keeping a reserve on the revenues?
Mark, do you want to talk about how we're going to treat that?
Most of it for what's charged will just be revenue. Right? Maybe in some particular jurisdictions, if there's future rebates regarding final price, there'll be some reserve or net sales adjustment because of that. But that's like the minority.
So there's no clawback in the majority of these medicines?
There is, but we understand the clawback system and how it works. So we will reserve according to that. I think, just to be clear, our guidance this year, the $380 million-$405 million, is U.S.-only sales. We're not guiding to include any outside of the U.S. sales because we just sort of don't know right now. And as we proceed through the year, we'll sort of give more clarity to that. But our guidance is excluding any sales outside of the U.S.
Got it, and then as you approach these health technology assessments, will the patients on these expanded access programs and your relationships with the KOLs assist in final pricing procedures? Can you talk to some of that?
Yeah. So we're actively right now interacting with thought leaders in Europe. So for example, as Catherine mentioned, when we were in Europe in January, we met with one of the top leaders in France. And she's very supportive, very excited about having Daybue as a treatment option for her patients. In addition, we're actively interacting with the patient advocacy groups, just as we have done in the U.S. They're also going to play a key part in ensuring that their voices are heard and they're very supportive of having Daybue as an option for their loved ones.
Got it. Great. So we're going to move on to 204. Unfortunately, we have less than 10 minutes left already. Yeah, we're going to move on to 204. So this is your next generation Nuplazid, essentially 5-HT2A agonist in development for ADP and now also Lewy body dementia. Can you walk us through the design of the seamless phase 2/3 ADP study and timelines for enrollment and data as you see them right now?
Yeah. So again, as you mentioned, ACP-204 is our next generation of a 5-HT2A inverse agonist/ antagonist. Now, we've really leveraged a lot of the learnings to develop 204. So right now, the phase 2/3 program is divided into two parts. So part one has the phase 2 study, which is a dose-confirming and efficacy-confirming study. Part two has two phase 3 studies, which are efficacy-confirming studies. Now, we intentionally designed these studies to be very similar to accelerate enrollment and for a seamless design. So all three studies are six weeks in duration. They are double-blind, placebo-controlled. They have three parallel arms, placebo, 30 mg, and 60 mg. We're targeting approximately 318 patients for enrollment in each of these studies. The primary endpoint is the SAPS-H+D, also called the Scale for the Assessment of Positive Symptoms, specifically hallucinations and delusions.
That'll be a total score change from baseline to week six.
Got it. What informed your decision to use tau-based serum biomarkers during patient enrollment?
Yeah. So as a neurologist, I'm very excited with how much the science has advanced in Alzheimer's disease. And one of that is actually in the area of diagnosis. So when I was practicing and even some of the clinical trials we've done, the enrollment of patients into the trials were based purely on clinical criteria that was set by the National Institute on Aging and the Alzheimer's Association. But now, with the advancement of the science and biomarkers, the field is definitely enlarging in research as well as in clinical practice. And even the FDA is very much asking companies that are going to work in Alzheimer's disease to include biomarkers to ensure the patients that are included in the trials are actually true Alzheimer's disease. And so that's one of the reasons we've included that as screening criteria.
Got it. Can you talk to the buy-in that you have from FDA on the SAPS-H+D? And can you talk a little bit about powering of the study?
Yes, so the SAPS-H+D, again, it specifically targets the symptoms of psychosis, which is hallucinations and delusions, and so we have been aligned with the FDA on the design of the study, including using the total score of the change from baseline. Also, the design of the study is six weeks for the double-blind phase, followed by a one-year long-term extension looking at the safety, tolerability, and the durability of the response, and this was felt to be sufficient to meet our goals in terms of getting approval.
Got it. And the effect size and powering?
Yeah. So we don't specifically share specific assumptions related to powering. But what I can say is we have a lot of learnings and data from the pimavanserin study. And we've done extensive work in the phase 1 study with 204 that has really helped us design the study both from the duration as well as the endpoints that we've selected, as well as the dosing.
Could the prior pimavanserin studies provide a fair assumption of what placebo is expected in these studies?
Yes. Both in this as well as in other Alzheimer's studies, just in terms of the disease progression.
Got it. Well, Harmony was a randomized withdrawal study. Why not pursue randomized withdrawal with 204?
I think learnings from that experience, I think we felt that having a single withdrawal study would probably not lead to approval. And I think what we've learned is you need to have parallel group design. And as I mentioned earlier, because we want to have accelerated enrollment, we intentionally decided to do a seamless design and with three studies that are very similar in endpoints and duration.
Got it. How do you think of the three studies as registrational studies? You're basically saying if one phase 3 fails, that you could file on the phase 2/3 together as the two pivotals. First of all, is that correct? Does the phase 2 generate all the data points needed? And also, within the trials, are you generating any sort of durability data that FDA might be looking for?
Yeah. So first, let me answer the second question first. The durability, as I mentioned earlier, we are going to have a long-term extension of one year. So that'll allow us to see the safety, tolerability, and exploratory efficacy.
Exploratory efficacy. So you're still taking the SAPS-H+D out that long?
Yes. But the primary part of the long-term extension is overall safety. Yeah.
Are there any requirements from FDA or questions from FDA on that 12-month SAPS-H+D data?
No. It's definitely having intermittent assessments. And with regards to your first part of that question, whether we're going to, what if one study fails? Well, the data will bear that out. But it is not unprecedented in the neuropsych space, even if there is failure.
That could be expectation.
That we are able to get approvals. So we'll be running these studies, as I mentioned, seamlessly. But we will definitely have learnings from phase two. So that will help us. So if need to, we can modify phase three studies if needed.
All right. I've left myself one minute on Daybue. I'm sorry, Nuplazid and one minute on ACP-101. Let's do 101 first, lightning round. This is your Prader-Willi syndrome compound. Can you quickly review where you are on phase three enrollment and the key efficacy endpoints and when that data will come?
I'll start on where we're at. We're actively enrolling. We're doing very well. Very pleased with the interest and the support of the community. And as we guided, we expect to complete enrollment by the end of this year. And if you want to just talk a little bit more about the study design.
Yep. So it is a 12-week study. And it's a parallel randomized double-blind study. It includes two arms. One is the active arm with 3.2 mg of intranasal carbetocin three times a day versus placebo. And the primary endpoint is called HQCT, is the Hyperphagia Questionnaire for Clinical Trials .
That is caregiver-based, correct?
That is a caregiver assessment, yes.
Got it. And then in our last minute, there's a new Nuplazid DTC campaign.
There is.
We see sort of renewed growth, which at least from the investment community sort of came out of nowhere. How do we see those two interplaying and what's going to drive continued growth?
Yeah, so we had a very strong Q4, as you heard on the earnings call, with 13% growth versus the prior year quarter and 11% year-on-year growth. So very strong. In terms of the DTC, we see that Nuplazid is highly promotionally sensitive, as I would say, from a commercial point of view. And what we're seeing is that patients are actively looking for information after seeing the direct-to-consumer campaign. They're coming onto our website. But more than that, we're not looking for clicks. We're looking for actual patients going to their doctors. We can track that. And what we're seeing is an increased number of patients actually going to their physicians and asking about Nuplazid. So with that confidence, we are continuing to invest in the direct-to-consumer campaign as we move into this year. It's very targeted, very specific. It's not blanket national.
It's very specific to where the patients are. And as a result, we're looking for continued growth. As you know, we've guided from $650-$690 this year, which is, I think, above most consensus expectations. And that's because we believe this growth will continue because it's highly sensitive.
I know consensus had not modeled significant growth going forward. Great. Thank you so much, Catherine and Mark, for joining us.
Thank you. Thanks so much, Ritu. Thank you.
Thank you.