Excited to be joined for our next fireside discussion with Acadia by Acadia Pharmaceuticals. With us, we have Kimberly Manhard, SVP of Global Strategic Planning and Execution, and Mark Schneyer, the CFO. So Mark, Kimberly, really appreciate you guys being here. I'll just turn it over to you to give a quick intro, and then we'll jump into the Q&A.
Yeah, sure. Thanks for that, Jason. We're very happy to be here. You know, at Acadia, we have, you know, we're a commercial stage biotech company. We have two, first- in-class assets on the market that are first and only a true approved, approved treatments for their therapies, so NUPLAZID for Parkinson's disease psychosis, and DAYBUE for Rett syndrome. And then behind that, we have a pipeline both of disclosed and undisclosed programs, to support long-term and future growth. You know, our two latest stage assets are ACP-101 for Prader-Willi syndrome and ACP-204 for Alzheimer's disease psychosis, and we can get into all of this as we progress with the Q&A.
So, you guys have had long-standing success with NUPLAZID. Obviously, you really managed through some headwinds through COVID, and things are moving back in the right direction. I'll leave that one till second.
Sure.
I think what's been really exciting over the last 12+ months has been the DAYBUE launch. It's fair to say that it's gone really well.
Yep.
Can you maybe just give us a high level of what you think resonated most with healthcare practitioners and caregivers during the first year of the launch? And I say that in the context of running up into the launch, I think a lot of investors were trying to ascertain with, you know, there being nothing available for Rett patients, what would be clinically meaningful, what would really drive adoption? So what do you think has resonated?
Yeah, so let me just kind of jump off from where you left the question. I mean, I think as I mentioned, just kind of in a 1-minute, you know, overview, you know, DAYBUE is the first and only approved treatment for Rett syndrome. Unfortunately, you know, this is a really debilitating disease where you have, you know, children born and, you know, after kind of 18 months or 2 years of normal progression and development, start to regress, right? And they lose motor function, lose ability to speak and communicate, and really just, unfortunately, just kind of become trapped in their own bodies. And so the children are there, and then adults, but the caregivers really, you know, struggle to engage, communicate, and take care of their children that are suffering really this debilitating disease.
So the question is, you know, efficacy, any meaningful improvement from kind of the current state is something that caregivers and their healthcare professionals are looking for, and these are children and adults that go into care facilities that really need care 24/7. This is not, you know. It, it's not a disease where it's, you know, it's okay for hours, and then you kind of have to step in. So really, to be able to move the needle on efficacy, and that's what's kind of resonated. That's where caregivers were interested that knew about it. They became interested where we were able to make them aware of it, and then to see the results kind of in the real world.
I guess what, you know, maybe the layman's explanation is, you know, if a patient is suffering from Rett syndrome, the neurons in their brain are not communicating and not properly, and DAYBUE helps restore that communication. So if you're able, you know, you can lose all ability to communicate, verbal and nonverbal. DAYBUE help, you know, for patients that are successful in getting to efficacy, can see improvements in that. They can see improvements in their motor function and being able to control kind of their arms and hands in a way that's uncontrollable for a Rett patient. And they're able, you know, they experience better, you know, mood, behavioral problems can improve in using DAYBUE. So what does that mean, I guess, to the real world? I mean, a common example that we hear is that, "You know, my daughter's more alert. She's present. We've re-met her.
Right.
Right? She's able to engage in computer communication, tell me her- what she wants or doesn't want, when she wasn't able to do that before. She can participate in a conversation, laugh at an appropriate moment, and be there and be present with, you know, their community, whatever that is." And so those are all real-world, tangible benefits that that HCP values, and what we hear feedback, and why those are the stories that we want to continue to tell to get more patients who have yet to try DAYBUE to initiate therapy.
Great. That's really helpful. So obviously, you know, now you have several quarters of the launch experience. You're continuing to generate data that informs, you know, how, you know, again, that it's going well, but also why you think it'll keep going well. You hit on some of those drivers on your earnings call last week, so just wanted to touch on a couple of them. You know, we talked about, you know, the clinical data, the trial data, and how relevant that was to caregivers. Can you. You're also now saying that you're taking the real-world experience and the benefit the patients are seeing, and you're using that as part of your education messaging to providers and caregivers.
Yeah, so operationally, I think, so we talked about, just in the last question, kind of the real-world benefits. I think the other thing that we may need to make sure we're educating about is that there's a known tolerability.
Yep
Is sue with the drug. So in the clinical trials, about 80% of patients experienced diarrhea. That's happening in the real world, but there are management strategies to deal with that, that were not implemented or implemented early in the clinical trial. So, you know, being able to communicate that and also to be able to communicate time. And they kind of all relate to each other.
And sorry to interrupt. I think it's a really important point, because you identified this tolerability point during the trial experience, and had a strategy at launch to manage it. And I think it's really notable that not often do you see that actually succeed in clinical practice a nd it really has done. You have patients now that you are successfully managing that tolerability.
We are, but I would say it's still variable.
Okay.
Right? I think there are physicians that have really dialed in on it, and there are multiple strategies to deal with it. But there are, you know, there are best practices. I think for, from our kind of commercial and medical education efforts, are to make sure those best practices are more widely known. Because there are some physicians who will say, "Listen, I'm able to". You know, without wanting to be graphic, but to say, "All right, from a child's stool, to get it to peanut butter level consistency," you know, we have practitioners that say, "I'm able to do that with essentially all of my patients.
Mm-hmm.
And so to be able to communicate those best practices more broadly, if people can effectively manage the number one tolerability issue, that could lead to them seeing. You know, getting through time to see, and I can come back to that, to see efficacy or at least just get to efficacy, which can then just add to our enduring patient population. So ultimately, you know, we wanna make sure that patients, for those that. You know, this is a drug that, you know, is, it was approved based upon subjective endpoints, like NUPLAZID, right? For these types of medicines, they work for many patients, they don't work for others, and that's, that's fine, and that's to be expected.
B ut we wanna make sure that, physicians, caregivers, are using best practices on GI management strategies, so they can work through the tolerability to see that there's efficacy there, and if there's efficacy for the patient to remain on therapy.
Got it. Obviously, we learned early in the launch that you were able to get patients on drug. And that's not. That's both from a, an awareness perspective, a reimbursement perspective. One of the questions that we had to wait for the answer was persistency.
Right.
We now have, you know, some really interesting data there. Can you, can you maybe just give us, you know, what your thoughts on where persistency is tracking today versus your expectations, and what are the drivers? Obviously, you know, tolerability is gonna be one of them. But, you know, what are the drivers that are really we should focus on for persistency?
Right. So I think the, I mean, like the drivers is kind of what we just talked about.
Right.
We want. If you're having a good experience on the drug and it's effective, you're going to maintain, you know, stay on therapy. And if you're not, for whatever reason, there'd be a reason or a good reason to stop therapy. I think. So we're tracking on persistency, I would say, meeting our expectations, right? I think we talked about a little earlier, right, the rate of diarrhea was not known going into the phase 3 trial, so it wasn't actively managed. Coming out of it, we knew, right?
So, our expectations kind of at launch would be, we should be able to do better than what we saw in terms of, you know, persistency or people remaining in the clinical trials in the commercial setting. And what we've done for the investment community is, as time progresses, and we are expecting we should be able to do better than a clinical trial experience. And the measurement we're using is, you know, while there's no 100% best comparator, we think the best comparator, say, is for those patients that were on placebo in LAVENDER, but then in our LILAC open- label extension, at the first time went on to trofinetide . Well, they didn't know that they were or were not on, or were not on active in the phase 3. They at least knew when they started the open-label extension, they were getting active at that time.
Yep.
Certainly in the commercial setting, you know you're getting a script for DAYBUE, which is the FDA-approved drug, and it's, and it's active. So if we can compare over time, you know, how patients are doing in the commercial setting versus what they did in for this group of patients, the placebo rollovers in LILAC, we think we could do better. And what we've consistently done through kind of the first 12 months of launch has been able to maintain a 10 percentage point differential between the commercial setting in favor of the open-label LILAC. And so we have released data, kind of as we progressed, and have had enough patients that it's meaningful. And so on our last, you know, earnings call, we released the nine-month data.
Right.
So for the cohorts of patients that were on or could be on for at least nine months, 58% of those patients remain on therapy versus 47%, the comparator for this group, for the LILAC open-label extension. In addition to that, where we've talked about, well, what does that really mean? So obviously, we're, we're happy with that performance. We, we always want to do better. But what does it mean for the enduring patient population? Because that's ultimately what's gonna serve patients, and then for those, you know, in the investment community that say, "Well, what, what's the revenue base for this?" You know, that enduring patient population is gonna be kind of the, you know, the ballast for revenues going forward. And if we just look at any patient that started in our clinical trials, about 40% of those patients remain on therapy today.
Got it.
So, so if we're able to maintain this kind of 10 percentage point differential, you know, is our kind of belief expectation that we'll be able to say, "All right, if you've " If, for patients that start therapy on DAYBUE, about half of them will be enduring patients over the long term.
Got it. The other thing you gave some good data around on the earnings call was market share, market penetration, and also thoughts about market growth. Can you just kind of hit the high points there of where you're at today? And obviously, you talked about the different segments of the market, so Centers of Excellence versus non-centers of excellence. Can you?
Right
Just run us through those numbers?
Today, there, and we know from claims data, there are, in the U.S., right, there are about 5,000 patients that are diagnosed and treated for Rett syndrome. About 1,300 of those have initiated treatment, you know, so tried DAYBUE at some point, and, you know, little over, you know, and we, and we had 862 patients on today as of our earnings call last week. So that 1,300 is, you know, roughly 25, a little over 25% of the known diagnosed patient population. So that gives us, you know, excitement of there are a lot more patients to serve, right? So that's where we see, you know, significant future growth from where we are today.
Right.
And then as far as prevalence is concerned, I mean, there's always a difference between, you know, known and what is expected.
Sure.
You know, the data suggests that there's you know, 6,000-9,000 patients in the US that have Rett. So that's you know. So where will that number ultimately fall out? Time will tell. That'll be part of our disease awareness efforts to try to close that gap. When we started, before launch, the 5,000 you know we shared with the market was our estimate at the time before launch was 4,500.
Right.
It's increased a little bit. We would say some of that is probably just due to better data.
Yep.
But, you know, it's just kind of part of the theme. The more information that's out there, the more there's known of treatments, you know, the bigger those numbers get because you get towards kind of maximum possible diagnosed. But is the number some 5,000, something north of that, something where between 6,000-9,000? You know, time will tell.
That's not specific to Rett, right? We've seen that in other rare disease.
Correct
Examples where the diagnosis rate does increase with an effective therapy.
Correct.
Okay, last couple questions here on, on DAYBUE. You reiterated guidance, you also gave a little bit of color around some seasonal dynamics. Can you just walk us through what we should think about the cadence for growth for the, for the rest of the year, both in terms of demand and revenue?
From revenue standpoint, we reiterate guidance, as you mentioned. You know, we'll expect growth from here. There were specific dynamics we're happy to get into on kind of why we had a sequential decline in revenues in the fourth quarter, but we expect sequential growth quarter over quarter here through the remainder of the year.
Great. And then just lastly, what are your plans for beyond the U.S., and is that something that you plan on taking on yourself, or will you consider a partnership or partnerships to help?
Yeah, I can address that, Jason.
All right, Kimberly, jump in here.
Yeah. First of all, for Europe, we received some positive feedback from the Pediatric Committee on our Pediatric Investigation Plan, in which they required no new studies other than the clinical studies we already completed, so that was very positive news. So we are aiming to file the Marketing Authorization Application by the first quarter of next year.
Okay.
There, we're planning on maybe our own footprint, so we're still building that out, the strategy for that, and so we'll have more in the future to talk about. Then, for Japan, we have a PMDA meeting towards the end of this quarter, actually, very soon, so we're very looking forward to that, and that's to discuss our clinical program that will support registration in Japan. There, we are more likely to partner out, but we're still determining the best strategy for Japan.
Yeah.
And then, in Canada, we announced last month that the New Drug Submission was accepted for filing by Health Canada, and also they gave us Priority Review, which means that we expect to hear from them, hopefully approval, by the end of this year.
Great.
Mm-hmm.
So, switching over to NUPLAZID, this is a product that obviously is several years into commercialization. You've spoken about your focus on the profitability of the franchise. It's a franchise that's producing substantial cash flow. Can you maybe just talk about that balance between investing to drive more growth versus maximizing profitability?
Yeah, sure. So, as we said, our goal, you know, at this point, is to maximize from a financial standpoint, right?
Right.
To maximize, you know, cash flow. And this is a franchise, when we look at our cost base on a fully allocated basis, is generating over $300 million of cash on an annual basis. And I think it's just the natural evolution of any pharmaceutical product, right? When you launch, as we're doing with DAYBUE, you're investing for long-term profit. You're not. We're not investing. No company's investing for negative profitability, but it's long-term profitability. You're trying to build awareness, build a market, you know, get market share to the extent there are competitors in the market, and all of that is kind of an investment for not just today, but really as much for the future. You know, NUPLAZID is in its midlife cycle.
Right.
Right? So we wanna make sure we kind of naturally transition to our from. It's not long-term future growth, it's growth today and in the near term, or profitability today and in the near term. So we've kind of made that transition over the last few years. You know, we've taken, you know, over $100 million on an annual basis of expenses out of the system. So, you know, I'm sure we could have more revenue today if we were still spending that money. But the question is, since we're looking at profitability today and in the near term, is it worth spending that money and versus reducing that money and having a slightly lower revenue base? We've obviously chosen the latter. But we've never said that. And part of this was in COVID, right?
Right.
So some of the investments that we were making were just not meeting our ROI thresholds during kind of the two years of COVID for, you know, this elderly and frail patient population, where unfortunately, there was, you know, a significant level of mortality.
Right.
So you need to make those adjustments, and we'll make those adjustments going forward. So today, really, we're just evaluating what are the right investments to make, and we can dial up or dial down, but the focus is on near-term profitability and it doesn't need to necessarily be, you know, spend a dollar today, make a dollar plus tomorrow, right? But your horizon is just more nearer term than thinking, "All right, we're making investments today that we're expecting to pay off, you know, several years down the road.
Great. I mentioned before that the Parkinson's market was definitely impacted by COVID, and that was an impact that persisted for really a couple years post-COVID.
Yep.
Where do you think we are today in terms of that, those market dynamics, and how does that inform how you think about the potential for NUPLAZID to continue to grow in coming years?
Yeah, I think at this point, we're out of the COVID period, right? So, you know, unfortunately, you know, I think if you look at just, you know, base Parkinson's disease medicines, you know, the carbidopa-levodopa, these are medicines that patients don't stop taking. They're still lower than they were, right? And so that just suggests that there's overall lower patient population. But unfortunately, that patient population will kind of regenerate, 'cause as just natural disease progression in the population, people will get Parkinson's disease, and those that have it or will get it, you know, about half of them later in their disease will get suffer from hallucinations and delusions, and that's what NUPLAZID treats. So the patient population will, you know, regenerate, that's then, and that's fine.
But I think for us, we'll monitor that, but when we look at investments, really, our investments are on new patient starts, right? And how effective are we there, and can we dial up or dial down expenses to maximize kind of our cash generation from new patient starts? Because, you know, patients that are on therapy today, yes, there's some level of information that will help them maintain, but that's not really the focus of our efforts. Our focus are on new patients, and we have, you know, 8 years of historical data that tells us, well, if a patient starts, you know, 100 patients start, you know, what's the distribution of how long they stay on? We know what that is.
That data's pretty consistent over time, and we can say, "All right, well, how are our efforts and commercial efforts, what's happening for new patient starts, and can we invest more to drive more new patient starts in a way that that financial equation is better? Or can, on the other side, can we reduce expenses?" And that would. You know, it is a promotionally sensitive product, but if that reduction in expenses reduces new patient start, but overall that's a positive financial equation, we'll look to do that.
Great. I'll spend a couple minutes on the pipeline here. So maybe starting with ACP-204, this is a molecule that's similar to NUPLAZID. Also talk in this context, NUPLAZID, you generated data in a large phase 3 trial showing efficacy in treating psychosis symptoms in Alzheimer's patients. You're now in a phase 2/3 program for 204 in that same patient population. Can you maybe just give us an overview there of the trial design and what, you know, the progress you've made in that trial?
Sure, I can, I can take it. So basically, we already initiated the phase 2 portion of the seamless phase 2/3 study, and that, seamless design was already agreed to with the FDA. So that's enrolling. We anticipate, basically the phase 2 portion to read out in about two years. But, once we stop that enrollment at phase 2 and read out, then we will continue on to phase 3 without waiting. So there, there's two phase 3s. So there are three very similar design trials, all adequate and well-controlled, similarly sized, over 300 patients in each, all placebo-controlled, double-blind, and randomized, and all include two doses of ACP-204, 30 and 60 milligram doses. And we're very excited that we can go up to the 60 milligrams.
That was one of the target product profile features we were going for when we designed ACP-204, to be able to dose higher, as well as lack of a QT signal, and also faster onset of action, which we think will be the case, based on the very short half-life, the faster the time to steady state, et cetera. So we're very excited about ACP-204 and its opportunity in Alzheimer's disease psychosis, which, by the way, has also no approved treatments.
Right. Right. Are there other patient populations or indications that you're thinking about for ACP-204? You know, there were, there were several that you considered for NUPLAZID along the way, and.
Mm
Obviously, the focus on 204 now takes into account patent life, so.
Mm-hmm
W here should we think about the potential, the, to take that asset?
Yeah, we're still evaluating that in-house. But you're right. There's a lot of opportunity there for different forms of psychoses.
Mm
E specially related to dementia. But also, like negative symptoms of schizophrenia. We're still evaluating the data, but FDA has a meeting coming up in mid-August on clinical trials for negative symptoms of schizophrenia, so that will kind of inform our future direction with ACP-204, with that one, but we're also looking at others.
Great. And then another, what we think is exciting pipeline asset is, ACP- 101 in Prader-Willi syndrome, another rare disease.
Mm-hmm.
Can you maybe just give us the overview of that program and the phase 3 trial there, please?
Yeah, absolutely. The phase 3 trial is designed based on the experience that was had with the prior phase 3, in which the 3.2 mg dose of ACP-101 was able to show benefit over placebo. So now we have a 12-week study, double-blind, placebo-controlled, and we'll be evaluating that using the same endpoint, HQ-CT, so Hyperphagia Questionnaire for Clinical Trials, as was used in the prior studies, it's widely used. And so, we were very excited about that, the possibility for that program, especially because, you know, hyperphagia is unrelenting hunger, and Prader-Willi syndrome is just a absolutely devastating disease because that hunger can lead to obesity.
Yeah
A nd the consequences, and it's a very short lifespan, only 30 years.
Great. We're out of time, but I'm gonna add just one more question, just to wrap this up. When you think about investment into both the commercial and the pipeline, to what extent does continuing to bring new assets into the pipeline factor? What's the priority there? And, you know, obviously, you're an established commercial infrastructure, so just should we expect. Is there capacity to bring new assets in?
Yeah, there certainly, it's kind of, yes, all of the above.
Yeah, right.
So.
There you go.
I t's probably the simple question, as we're out of time.
Fantastic.
Okay.
All right, Mark, Kimberly, really appreciate you being here.
Thank you.
Thank you so much.
Thank you.
Great seeing you.
Thank you.