Everyone, thank you so much for joining us. Salveen Richter, biotechnology analyst at Goldman Sachs. We're really pleased to have the ACADIA team here with us. Next to me is Catherine Owen Adams, CEO, Elizabeth Thompson, Head of R&D, and Mark Schneyer, CFO. With that, Catherine, you've been at the company now for a little bit, and we've seen various management changes at the firm. Could you just walk us through what your business and strategic priorities are at this point and the changes that you've made since you entered the company?
Yeah, so I'm entering month eight now, so it seems to have flown by. In that time, we have made a switch in the commercial structure so that Tom Garner is our new CCO, and we've just put in Alison McMillan as the head of our Daybue franchise. Both of those people I brought in for their commercial expertise, both in the US and globally, but also their rare disease expertise as well. We're excited to see what Tom and Alison continue to do, but up until now, Tom's had a real focus on Daybue and the commercial strategy there, which I can elaborate on. Liz was two or three months ahead of me in joining ACADIA. She came from Horizon, and she has really had a focus on upskilling her team in certain areas, but really accelerating the focus on the clinical trial programs.
The output of that, we've already seen an acceleration in our Prader-Willi trial now coming in a couple of quarters earlier than we had expected. We've seen some great progress there. Also focusing on getting a new trial up for Lewy body dementia psychosis and a new clinical trial for Daybue in Japan. Lots of real focus from Liz and the team. Mark and our BD team as well have been focused on ensuring that we're looking at inorganic growth as well as the organic growth. We signed our own deal in December. Yeah, there's been a lot of activity, but it's been a great ride for the last eight months. I'm enjoying it.
To start here with on the IP front with Nuplazid, recently you won a method of use patent litigation versus generic manufacturers. Just looking at the totality of verdicts and settlements, when are we likely to see generic competition from Nuplazid? Walk us through the process here with appeals and so forth, where we can get that kind of final confirmatory aspect.
Yeah, so Mark's our IP specialist, and he has some late breaking news from this morning, actually.
Yeah, it'd be great to stop talking about IP, right? I think the late breaker this morning is that we did win the appeal that was outstanding on our composition of matter patent. That takes us through October 2030 for composition of matter. As you mentioned a few weeks ago, we were the winner in the trial on our formulation patent. In totality, the exclusivity for Nuplazid lasts through February 2038. That is the first time that an AB-weighted switchable generic could come to market. If other companies want to bring a formulation of pimavanserin that's outside our formulation patents and launch and market that with all the challenges that come with that kind of in post the composition of matter, they're free to do that.
We're happy to compete with them in the commercial environment to the extent those formulations ever come to market.
If you looked at Aurobindo and MSN here, I guess, are those really the two players that are left that would appeal in this context for any of the.
They were the litigants in the formulation patent, so it would be up to them if they want to continue that or not.
Got it. At the same time, you did reiterate guidance for this asset for this year, and it represented about a 10% year-over-year increase at the midpoint versus 2024. We saw an uptick recently versus what's played out in the past. Help us understand what the key drivers are for the underlying trajectory that you're seeing and maybe what sales efforts you're putting into place as you look to the forward.
Yeah, so when I came into the role, the team had just put in place a new strategy to drive awareness of the symptoms of Parkinson's disease, hallucinations, and delusions specifically with Ryan Reynolds. That unbranded campaign has been very successful. As a result, we've seen more patients coming into the office to ask their doctors about options for their loved ones with Parkinson's disease, hallucinations, and delusions. At the same time, we've also launched a direct-to-consumer campaign for Nuplazid, which is kind of tied. Both of those kind of marketing strategies have really helped us drive new patients into our funnel. We were happy to report in Q1 we had the highest number of MBRXs that we've had since 2020.
We continue to see that strategy playing through, as well as since Tom's arrival, pushing new, more predictive data analytics into the field so we can better understand where the patients are and which doctors they're seeing to get our field force in the right place, right time. We're excited to continue the consumer strategy, but at the same time, also reinforcing with a lot of real-world evidence to show that Nuplazid has a mortality difference versus the off-label antipsychotics that are currently used for many of these patients. We believe Nuplazid has a bright future. Now that we have the composition of matter and formulation matter patents sort of put to bed, we're really excited to continue to invest in Nuplazid. We only have a 20% market share.
We're the only branded product in town, and we believe there's headroom to really grow this brand beyond current expectations.
What do you think was left on the table to date?
You know, I think we've always been a little cautious about the patent. There was the COVID pandemic, which unfortunately wiped out a lot of patients, and there were decisions taken around that in terms of investment. As I say now, coming into this, I see a lot of potential to grow Nuplazid. Many doctors are using it, but there are plenty more that aren't. We have a real opportunity to get to those physicians. Also, if you think about the caregivers, they cycle once every two to three years in terms of those patients who have a loved one with Parkinson's disease psychosis. Again, there's a real opportunity to continue to stimulate the caregivers to be aware that this is a symptom of Parkinson's.
Great. What is the current discontinuation rate or the turnover rate, just especially when you look at long-term care facilities among other places?
Mark, do you want to talk to us sort of the annualization of Nuplazid?
Yeah, I think for us, what we see, there's a long tail. We have patients that have been on therapy since the drug was launched in 2016, but that's a very small percentage because unfortunately, most of those patients are no longer living. It is really when people get on in the first quarter, like any drug, it's a psychiatric drug. People evaluate that they believe it works or not. We see some discontinuation in the early time period. As people get through that and see the benefit of Nuplazid, they usually stay on through the rest of their lives. That can be a couple of years or many years. Just between the channel, people tend to live longer in the community than they unfortunately do into long-term care.
Our patients, we tend to have a longer persistency for patients in the community than we do in long-term care.
Can you also touch on the pipeline associated with Nuplazid here and what we're looking for on the forward from a data standpoint?
Yeah, so Liz, do you want to talk about ACP204 and the new?
Absolutely. ACP204 represents an opportunity for us to learn from and build upon Nuplazid. It is our new 5-HT2A inverse agonist. We designed it very intentionally to address some things about Nuplazid that we thought could be better in a second-generation molecule. One of the things there is that Nuplazid is associated with QT prolongation. That is impactful. It is relatively small, but it is impactful in a frail, elderly patient population. It is also important in that it impacted our ability to dose range with Nuplazid. We were really limited to the currently marketed dose, which is the 34 milligram dose. Why that matters is there is some suggestion in Nuplazid data suggesting that there is an exposure-relationship for efficacy, suggesting that if we were able to go to higher exposures, we would have the potential for higher efficacy.
The other thing we were looking for was a potential faster onset of effect because that would give us the opportunity to address patient needs faster, potentially. The data we have to date with 204 across something like 200 patients in phase one, as well as a non-clinical program, suggests that 204 is able to address all of those. We are looking at 204 currently in Alzheimer's disease psychosis, and I'm happy to expand on that later, as well as a study that we're looking to get up and running in the third quarter in Lewy body dementia psychosis. A lot of opportunity that we see for 204.
Okay, perfect. You also spoke to a new strategy with regard to Daybue. If we could just touch on that. We saw resurgence in patient growth after three relatively flat quarters. What were the drivers of this? How much does education play a role in this aspect?
Yeah, the Daybue strategy has continued to evolve as we've learned through the launch and now entering our sort of third year of launch. What we've learned are quite a few things associated with the start of patients on therapy. In Q3, Q4, the sales force really had started messaging more about the efficacy associated with Daybue as opposed to the side effects, which really dominated for a while in terms of ensuring that patients were transitioned onto Daybue and managed through the GI symptoms. However, we kind of took our foot off the efficacy message a little bit. We've really dialed back up the efficacy messaging with some new data that we're sharing actually today at the IRSF, showing that you probably need to have about six months on therapy with Daybue to see the effect that you're going to see with your loved ones.
Encouraging doctors to think about ensuring that their patients stay on for at least six months. We've also really tried to learn from how doctors are managing their patients and ensure that they are thinking through some key things that sound obvious. Making sure they're stopping the anti-constipation meds, making sure their patients are taking fiber and liquid to help manage those first few months on the GI side. That has sort of continued to evolve. In terms of the commercial strategy, one of the things that Tom has put in place is expanding our field force. We were very focused on the centers of excellence, and so we could really only properly get to about 35% of the patients who are currently treated in centers of excellence.
Now that we've expanded our field force, we can now get to those 65% who are outside and be much more sort of able to see those doctors at the right frequency that we now need to get them to think about prescribing Daybue for their patients. We've upsized the field force. We've really emphasized the efficacy messaging, and we've also reinforced the management of those first few months of symptoms. Those three things together, we now believe, can drive our growth for Daybue that we've factored into this year's guidance. As we've said at our previous calls, we expect to start to see that kicking in in the second half of the year.
Could you provide some color on the persistency and compliance rates for Daybue and how these metrics have stabilized or have they stabilized?
Yeah, so I'll start, and maybe Mark can add a few points. What we talk about is over time, about 50% of our patients remain on Daybue at a year. Of those that start, at a year, over 50% are still on therapy. What we've seen is that continue through the sort of second and third year now of launch. That's really stayed very, very steady. We see that being a fairly steady part of the Daybue persistency curve. At this point in time, we now have over 65% of our patients have been on Daybue for more than a year. Again, a much more stable base of patients. We're seeing those discontinuations drop off. We reported in Q1 the 35% discontinuation rate as opposed to the Q4. It's definitely become more predictable and more consistent in terms of our patient base.
I don't know if you want to add anything out of that.
I think that, yeah, it's more of a story of consistency and more recently improvement, like some recent cohorts due to all the initiatives that we have in place. We're seeing some improvement in those rates in recent cohorts.
Was that related more to tolerability issues or just they were not waiting for the efficacy to play out or a combination thereof?
We think it was mainly due to the management of the patients more closely. Also, a number of physicians have started to titrate the doses a little bit more closely. What we are seeing is more patients starting on a lower dose than they would expect to be on versus their weight. Over time, they are being titrated back up. We think that titration helps them to manage those GI side effects a little bit better. That titration schedule, everybody is doing it a little bit differently, but most people are doing it now.
Okay.
Yeah.
Walk us through the XUS expansion plans here.
Yeah. So Liz, why don't you start on the regulatory side of it?
Absolutely. First is we have submitted for Daybue in the EU. We made that submission in the first quarter of this year. We are continuing through the regulatory process, tracking on schedule. Our projection at this point would be that it would be a potential approval in the first quarter of next year from a regulatory perspective. The other geographic expansion we're thinking about, again, from a regulatory perspective, is Japan. We've had good conversations with PMDA, gotten a lot of feedback about what would be an approvable data package, and are looking to start a phase 3 study in Japan in the third quarter of this year. That one's a little bit further out. Those are the two main focuses for us from a regulatory perspective. I don't know if you want to expand.
Yeah, so commercially, we're starting to build out our team in Europe. We've hired a very experienced general manager who has extensive rare experience. They're now based in Zug, and we're building out our team there. We're going to market this ourselves. We're not just doing it through a partner or distributor. We are building up our field forces out there. Right now, we have MSLs in several countries getting out, trying to understand how patients are being treated. We are getting ready to support the regulatory approval in Q1 and then start the reimbursement discussions, which obviously then start after that initial approval.
Yeah.
Yeah.
The pipeline seems like that's going to start to be a key focus for the company in the second half onwards.
Yeah.
We'll see phase three data, top-line data for ACP101 in PWS in the fourth quarter. Can you frame the expectations for this readout and the differentiation versus Soleno's recently approved VYCAD or how you think that might play out?
Happy to start out by just noting that the early fourth quarter readout of that trial is an acceleration compared with what we were originally expecting. I'm really pleased to see that. It is a combination of good hard work by the internal team, but also I think a reflection of enthusiasm in the community. That's great to see across the board. In terms of how I think about expectations out of the trial, what would be a positive from my perspective is to see something that largely replicates what we saw with the 3.2 milligram dose in the prior phase three that was run in terms of the magnitude of effect on hyperphagia, as well as the safety and tolerability profile that was shown there.
As I think about that in context of potential differentiation, I mean, obviously, at the end, this is going to be informed by the individual data packages that each agent has. We are currently running our phase three. I will note a couple of things. We spend a lot of time talking with advocacy organizations, caregivers, KOLs. What we do hear routinely and robustly from them is that the magnitude that we saw in our prior trial would be a meaningful effect for them. Also, even though there is now an agent for this community, which we are all thrilled about, they have been waiting for a very long time, there is continued unmet need in this patient population. These are complex patients with a wide variety of needs.
Physicians and caregivers want to be able to make that match between a given agent and the person who's sitting in front of them. I will say one thing that I think would be a strength out of our data set, depending on what we see in our trial, is that if we do have a positive result in the currently running trial that we have, it's a prospective parallel group design. That is going to help physicians be able to look at the patient in front of them and describe what they can expect when they start therapy.
I think that's going to be helpful for a patient and physician to be able to think about what this is going to look like in the first few months compared with what you might expect when you discontinue therapy, which is an important thing to understand as well, but it's a little different in terms of patient expectations.
Can you walk us through the dose response work that's been done to date and whether there is some dose response dynamic playing out or there's an absence of that?
Absolutely. There was a prior phase three that was run with ACP101, which is inhaled carbetocin. In that study, there was a 3.2 milligram dose and a 9.6 milligram dose. The 9.6 milligram dose did not show statistically significant results. The 3.2 milligram dose did show evidence, clinically meaningful levels of benefit at a nominally statistically significant perspective. Anytime I look at a phase three trial that did not meet its primary endpoint, there are a few things that I think through. The first of these is, is there mechanistic plausibility to this agent to think that it would work? There is a variety of data that suggests the relevance of oxytocin, which is what carbetocin is a derivative of, in Prader-Willi. That is nicely checked. I look for consistency within the data set.
The 3.2 milligram dose arm did show meaningful changes both at a number of time points and on a number of different endpoints. That is reassuring in terms of consistency of benefit. Finally, I look for a plausible explanation of what might have happened. It is unusual to have an inverse dose response or a dose response that is not linear in a positive direction, but it is not impossible. With these kinds of agents, it is potentially something that you could expect based on the potential for off-target effects. That is our current hypothesis as to what happened: we have some off-target effects at higher doses that sort of counteracted the ability to show efficacy.
You also have phase three data for 204 and Alzheimer's disease psychosis mid next year. What, in your view, is the bar for success for this trial?
Yeah. I'll start with a very minor clarification, which is it's phase 2 data.
Sorry, phase two.
No, no, not at all.
Jumping in.
That we expect to get in the middle of next year. I'll take a step back and say that Alzheimer's disease psychosis, there's roughly 7 million patients with Alzheimer's disease in the US, and about 30% of these are experiencing psychosis, hallucinations, and delusions. There aren't specifically approved medications. This is a pretty significant area of unmet need. I think about a bar for an agent in this space in the following ways. Certainly, of course, we need to have efficacy. I think it's going to be important also to look at the ability to spare cognitive impact, have minimal daytime sleepiness, have minimal off-target motor impacts, and have something that's going to be easy for this patient population to take because this is a complex patient population.
Many of those aspects we already know to be true for 204, either from the preclinical or the phase one data. Some of that we have some real belief in based on Nuplazid and its data. Some of it will be informed by the phase two trial we're currently running.
What were the learnings from Nuplazid that can be applied here?
In the Alzheimer's disease psychosis space in particular, there are a few. We had previously tried to get approval for Nuplazid in ADP and were not able to do so. There are a number of reasons that go into that. I'll focus on a couple of things where we thought we had easily applicable lessons. First is that in the Nuplazid data package, we only had one study that was specifically looking at the Alzheimer's disease population. We think that is a critical piece, obviously, of regulatory thinking. The program that we have ongoing right now has a phase two component as well as two phase threes. We think that will be a robust data package. It is specifically in an Alzheimer's disease psychosis population. I'll say that we're also biomarker confirming that population.
We'll be able to very robustly demonstrate that that is the disease under study. I think that's going to be an important piece. I alluded earlier when I was talking about 204 to the fact that Nuplazid was limited in its dose ranging. We do see some evidence of that exposure response. I think the fact that we'll be able to look at, we've got two doses in the phase two that we're running. The lower dose is the equivalent of the currently marketed dose of Nuplazid, and the higher dose is roughly twice that exposure. I think this really gives us the opportunity to get the most efficacy we can out of this mechanism. Those are two of the main things that I think that we've been able to apply here in terms of learnings for 204 and ADP.
The rationale for going forward in Lewy body dementia.
Yeah. Yeah. Lewy body is actually, it maybe doesn't get the press that Alzheimer's does, but it is the second most common dementia out there. It's roughly a million patients in the US. I would say it's especially pernicious in terms of psychosis. It's 50-75% of that population will have psychosis, will experience hallucinations and delusions. Again, there are no specifically approved therapies here. I'll say that these patients are probably even more fragile in terms of how they can be treated compared with the Alzheimer's disease population. The unmet need here is striking. As I think about it in terms of the rationale for 204 in particular, certainly the Nuplazid data we have there are limited in terms of the number of patients. I think they're quite interesting.
We have roughly 20 patients per arm, placebo and Nuplazid treated, in the context of a withdrawal study. What we saw there is that patients who continued on Nuplazid, only about 5% of them relapsed, whereas those who were withdrawn, about 55% of them relapsed. A pretty striking differential there, giving us reason to believe that 5-HT2A inverse agonism is going to be relevant in this patient population. Certainly, it is a patient population in desperate need of therapeutic options. We're looking to get that study started in the third quarter of this year.
Great. You're hosting an R&D day coming up this month.
Yes indeed.
What are you looking to showcase there? I believe we're going to see some early data from your GABA PAM. What is the overall, I guess, framework for what we'll see?
You will see presentations across the entire pipeline. What I'll say I'm particularly interested in, and what I think is going to be the most novel for the audience around here, is additional data that gives you some insight into our reasons for enthusiasm on some of the pipeline molecules we've talked about less, the more recently disclosed pipeline molecules. In particular, I'll highlight ACP211, 271, and 711, where we're going to be able to share some more information that hopefully will help you see some of the things that we see with these molecules.
That's great. Just a final question here. Maybe speak to your strategy now with the company overall. You've been neurology or neuroscience focused to date, and you've talked about going broader into rare disease. How does your business development strategy play a role on this frontier? What is the balance sheet capacity or capabilities in order to kind of enact the vision?
I'll start, and then Mark can talk. Just as a company, our strategy moving forward is to continue to consolidate our commercial brands and to bring to market the very exciting pipeline that Liz and team are going to share more about on June 25th. However, we still have a strong focus on inorganic growth through BD. As you rightly pointed out, we have a fairly strong balance sheet with which we can use to ensure that we can achieve that. We have declared earlier this year that we are expanding our focus from neuropsychoneuro rare to other rare diseases outside of neurology, including cardiovascular, endocrine, metabolic, nephrology, etc. With Liz's experience in rare disease and mine, we believe that our capabilities are such that in both R&D and commercial, we make a very sensible home for a rare product that might be out there.
That's exactly where we're looking right now. Not moving away from neuro, but just expanding our rare disease aperture to bring some of those other products potentially into Acadia. Maybe Mark, you can talk to our balance sheet.
Yeah, so I think our financial capacity is strong, where we have over $680 million of cash at the end of the last quarter, even after paying about $100 million in milestone or value share payments to our partner Neurim on Daybue in the first quarter. Our bite size gets bigger every day because the business itself is cash flow positive. It is adding to that. The last several years, as I've been CFO, we've been able to fund everything from business development, bringing in and funding the pipeline as we have it today. That should continue to be the case. If there are things that there's an opportunity to expand beyond that and have to raise capital for an exciting investment, we'd be very happy to do that. That would be the exception, not the rule.
Great. With that, thank you so much.
Thank you so much, Shelby. Appreciate it.