For joining us at Baird's Global Healthcare Conference. I'm Joel Beatty, one of Baird's biotech analysts, and I'm pleased to have Acadia Pharmaceuticals with us, and with us, we have Mark Schneyer, CFO. Thanks for joining us, Mark.
Yeah, good morning, and thanks for having us.
Great. So, to begin, could you provide an overview of Acadia?
Sure. At Acadia, we're a commercial-stage biotech company. We focus on neuroscience and rare disease. We have two products on the market today. The first is a product called NUPLAZID. It treats a Parkinson's disease psychosis , and our guidance for this year should get us in the range of plus or minus $600 million in net sales for this year. Our second product was approved last year and launched, called DAYBUE, treats a rare neurodevelopmental disease called Rett syndrome. We're very pleased about our progress to date, and we expect sales to be in the range of $340 million-$370 million this year.
Behind those two products, we have both of those products are the first and only approved therapies to treat their indications, which is kind of a theme across our portfolio. We have, you know, a pipeline of both late and early-stage assets behind NUPLAZID and DAYBUE. Our two late-stage assets, the first is ACP101, which treats a rare disease, we're studying in a rare disease called Prader-Willi syndrome. And then our next generation 5-HT2A program, ACP204, we're running a phase II/III program in Alzheimer's disease psychosis. Both the ACP101 and 204 programs initiated in the fourth quarter of last year. They take about two years to enroll patients, so as we progress further, you know, we'll update the street on our timelines for data.
Behind those programs, we've got a rich early-stage pipeline, some disclosed, some undisclosed programs. Business development continues to be an important strategic pillar of the company as we look to expand the portfolio with the overall goal of, you know, continuing to build a growing and sustainable company. And, you know, lastly, from a financial perspective, we're a cash flow positive company, and as of the second quarter, we had just over $500 million of cash on our balance sheet, no debt, and ability to invest, you know, in our current business, as well as to expand, you know, through our business development initiatives.
Terrific. So let's begin by jumping into Parkinson's disease psychosis . what's the opportunity to grow revenue there longer term?
Yeah, we're very excited about the opportunity to continue to grow NUPLAZID. I think NUPLAZID is in its midlife cycle, so at least from a financial perspective, our goal is to maximize the cash flow and near-term profitability of this franchise. And you do that two ways: both by growing the top line, and by being judicious in managing expenses. And we've been doing that, you know, over the last few years. I think what is important to quickly remind folks is that, you know, the patient population for Parkinson's disease psychosis is an elderly and frail patient population. So as we went through the pandemic, unfortunately, there was a fair amount of mortality in this patient population.
And so as we continued to serve this community, but also be mindful of, you know, the investments we're making as a company, you know, we pulled back on expenses, 'cause some of the investments that we were making for more growth-oriented were not hitting the ROI, you know, thresholds that we expected and had achieved in the past. But now that we've come out of the pandemic, there's two things, right? One, the market conditions for the patient population have improved overall, and then over the last year, I would say, you know, we've had, you know, two initiatives that we've been sharing with the market that has driven growth, and now we have a new initiative that I'll touch on to have growth and top line beyond that.
So what we've been doing over the last year is sharing a couple of, or three real-world evidence studies, two of which that, you know, compare mortality and the use of, you know, NUPLAZID in this patient population versus off-label antipsychotics, and it shows a mortality benefit to this patient population when using NUPLAZID. And then the third is looking at healthcare utilization, and that it's lower for patients that are on NUPLAZID, and that third study particularly resonates with our long-term care community customers. And so that overall has resonated with kind of the HCP and long-term care communities and has led to an, you know, uptick in new patient starts and overall growth of the franchise.
In addition, last year, we did have a label update for NUPLAZID, and I would say this is kind of a minority of the physicians. There was some confusion in the market of whether or not NUPLAZID was indicated to treat patients that Parkinson's disease psychosis but also dementia. It's always been part of our label, and that clarification helped, I would say, with the minority of the HCP community. All these things together has led to nice growth as we've kind of had new patient starts over the past handful of quarters that has exceeded the previous handful of quarters, and that's led to nice level of volume growth for this franchise, you know, eight years into its life cycle.
I think the other thing that we, and the new thing that we are, have just launched now is a disease awareness campaign, as well as, you know, some branded direct-to-consumer advertising. As we pulled back on this during the pandemic, we've just noticed that, as expected, you know, the awareness in the caregiver community has just reduced significantly for NUPLAZID. This is a patient population that, you know, about half of patients that are diagnosed with Parkinson's disease will ultimately experiencing hallucinations and delusions, but they do it late in their disease progression, and these patients, on average, you know, live about four to five years once they're diagnosed with Parkinson's disease psychosis .
So we haven't really reached out on a DTC basis to this community, you know, in a number of years, and so that should, you know, be not surprising to all of you that, you know, as this patient population turns over, and their caregivers that come along with them turn over, the awareness just has dropped, and we see an opportunity to do some disease awareness, to have people talk to their physicians. 'Cause the one thing that has not changed is HCP's willingness to prescribe NUPLAZID if it's requested by a patient or caregiver. So we wanna activate that and, you know, and believe that we'll there's an opportunity to drive, you know, growth beyond where we are today.
Most of the investment will happen this year, but the benefit of that bet, it usually delays a quarter or two, so we expect the benefit of that investment through top-line growth to come in, you know, over next year and the year after, so as those patients refill. So those are the opportunities for growth, but again, wrapping it all together with a financial focus on maximizing cash flow for the franchise.
Terrific. Great overview, and quite a few opportunities there. Thinking more about this opportunity, what % of Parkinson's disease patients could potentially benefit from NUPLAZID?
Yeah, so I think, as I mentioned, about half of patients with Parkinson's disease ultimately experience hallucinations and delusions, and when we, you know, just do our own work on the market size, in the U.S., approximately one hundred and thirty thousand patients are Parkinson's disease psychosis , you know, at any point in time.
Okay. What's the status of IP for NUPLAZID, and how long does the exclusivity runway look like?
Thanks for the question. So, you know, I think for those of you familiar with our story, we have composition of matter and formulation and method of use patents on pimavanserin. The composition of matter, we're doing work on to get qualified for the pediatric extension, so it'll be. You know, if we get that, it'll, you know, it will be October twenty thirty, and our formulation and method of use patents go out to twenty thirty-seven. Maybe embedded in your question, there's been ongoing litigation on both our composition of matter and formulation and method of use patents over the past, you know, several years. In December of last year, we had a ruling on our composition of matter case. We won that case decisively.
We put forward two arguments to support our position. We won both of those. We only had to win one. As expected, the generic company that is challenging us is appealing that ruling, and we're going through kind of the appeal process now. Again, they need to overturn both arguments. You know, I guess a recent event that we would point to is there's another case that's ahead of us that Allergan is litigating with the same generic company. Allergan won their appeal, and one of the arguments in their case is similar to one of our two arguments, so we think that's a good read-through to our case, and just gives us even more confidence that we'll prevail.
But, you know, again, we still have both arguments, and the generic company needs to prevail on both of those. On the formulation and method of use, you know, the trial court hearing is in December of this year. We want a Markman hearing, you know, at the same time December of last year as our composition of matter patent case read out. So, you know, just continues to strengthen our position there, and, but that litigation is in front of us and ongoing.
Great, so jumping to DAYBUE for Rett syndrome, could you help frame what % of patients who start on DAYBUE stay on it longer term?
Yeah. So from a persistency standpoint, you know, this is, you know, important point for the investment community and us. I think we have kind of two datasets that we consistently share with investors. One is, how are we performing in the commercial setting compared to our clinical trials, and how are the patients' you know, persistency levels of patients that have been on DAYBUE long term? So our patients that were in the clinical trial, you know, where are they today, and how do we look at both of those together? So in the first one, what we've...
While no dataset is perfect, what we, what we've been doing for our, our own internal management perspective is to say, "All right, for patients that start in the commercial setting, the best comparative we have is what the persistency rates of patients that were placebo patients in our LAVENDER phase III trial but then became, you know, active patients in our open-label extension." Because at least those patients, while they didn't know what they had in the phase III, they knew at the time they were in LILAC or open-label extension, that they were on active trofinetide, and then we know that that was the first time that they were on trofinetide. So when we look at...
So the most data we have now that goes out to nine months, 'cause that was the timeframe of our LILAC open-label extension trial, patients that were through nine months on LILAC, 47% of those patients were still on therapy at that point in time. And in the commercial setting, 58% of patients were on therapy at nine months. And when we looked for earlier data points, what we've seen is we've had this consistent ten percentage points differential that patients in the commercial setting are staying on longer, have more robust persistency than those patients in the open-label extension. The longer-term data point that we have is any patient that was on trofinetide in our clinical trials, whether or not in the phase III or the open-label extension, 40% of those patients are on therapy today.
That group has been remarkably persistent in the commercial setting. You know, the latest data we have, I think we only lost about three of those patients have discontinued over the past year plus in the commercial setting. So we have kind of nine months of data and kind of three years of data, and so what we expect to do and think we can even do better is if we can have this 10 percentage point differential over the long term, so that 40% long-term persistency data, that leads us to believe that, you know, approximately 50% of patients can stay on therapy long term after they initiate.
Great, so persistency in the real world seems to be outperforming clinical trials. And then, you know, some patients still dropping off. Any kind of examples of the opportunity to get those patients who do drop off back on therapy at a later point in time?
Yeah, that's definitely an opportunity. I think what we've had a little bit of that. So I think we've said to the investment community, "I wouldn't yet put that in your models, but there is an opportunity for us, and that's something we can share as we go forward." One aspect of our commercial organization is our Family Access Manager. So this is a group of people that are in touch and communicate with the families directly, both to help them initiate treatment, get through the reimbursement process, and be a liaison to them while they're on therapy. And so our FAMs, you know, do maintain contact with families that have discontinued, many of which express a desire to resume therapy at some point later in time.
We just, you know, we haven't seen a, I would say, a significant number of restarts. We've seen some, so, you know, but we do see that opportunity, too. So stay tuned as we progress further, you know, in our commercialization efforts.
Great. And then for the patients in the U.S. who have not tried DAYBUE, could you characterize their level of awareness with DAYBUE and how you plan to reach those patients?
Yeah. So when our market research suggests the unaided awareness of DAYBUE across the caregiver community is very high. It's in kind of the 75%-80% range. I think launch to date, you know, through the data released on our last earnings call, approximately 30% of patients in the U.S., at least defining it as the 5,000 identified and diagnosed or treated and diagnosed patients, have initiated therapy on DAYBUE. That's really high, and we're very pleased with that number, whatever it is, 14 or 15 months into launch.
Despite all of us thinking that everyone's gonna show up in their doctor's office day one of launch, and we certainly had a surge of demand at the start of launch, it does take some time to educate and reach deep into the patient population. So we will continue to educate HCPs, caregivers. You know, the best thing, you know, being able to share efficacy and stories of success of patients that are on DAYBUE is some of the most compelling information that we have, and we'll do the good work to try to continue to reach out deep into the community and get patients to initiate therapy on DAYBUE.
Great, so moving to ACP101 for hyperphagia for Prader-Willi, any hypothesis on why the lower dose in the previous study looked stronger than the higher dose in the phase three?
Yeah, I mean, there are a number of theories. I think the most, you know, the one that we would think is possibly the best explanation is that there was just, you know, at the higher dose, there were some off-target activities that led to, you know, other conditions or ailments like agitation that could have influenced the, you know, the measurement of the scale. You know, we can't say for certain what the issue is. I think for us, when we look at, you know, the totality of data that the previous, you know, owner of ACP101 generated, we just see activity across primary and secondary endpoint at the 3.2 milligram dose.
We're gonna replicate the study for the most part that they did, and that, you know, we aligned with the FDA on doing that. Obviously, the proof will be in the data that we generate, as the FDA will always wanna see, you know, see the data that you generate. And we think it's a very good investment and supports it. So we'll. You know, and the other thing that we're doing, you know, Levo had done an admirable thing of trying to do the dose ranging, which is, you know, which is typically difficult to do in rare disease. It also happened during the pandemic, and, you know, so, you know, to best position this for success, you know, we have a robust study.
We're gonna have more patients in the one dose than they had across both doses, and so we think that, again, positions it best for success, and we're eager to see the data, you know, when it comes out some period of time later from now.
Terrific. And yeah, could you tell us more about the phase III trial design and how it compares to the phase II trial design?
Yeah, it's very similar. So it's the same questionnaire, the same endpoint, and as I just mentioned, just we're gonna have a higher n in patients, not do it across two doses, and we think that altogether will best position the program for success.
Terrific. So jumping to ACP204 for Alzheimer's disease psychosis, I guess to begin, how does that agent compare with NUPLAZID?
Yeah, so it. You know, from comparing to pimavanserin as I mentioned kind of just in the brief intro remarks , this is. It's our next generation 5-HT2A molecule. So it's you know similar, I would say, chemically and biochemically to pimavanserin, but it's a different molecule, different IP. But what's helpful with that is you know since we discovered both molecules and we have a robust data pool for pimavanserin for all the studies we've done early and late, we're able to just compare 204 to all that data. And we designed 204 to have specific advantages relative to pimavanserin, and that again gives us you know confidence that we're making a good investment, and we're best positioning 204 also for success going forward. Obviously, it's science and neuroscience.
We have to do the studies, read out the data, but we're very excited about this program.
Good. What's the status of the program?
The program, we're running a phase II, phase III program. We started the program in the fourth quarter of last year. As I mentioned earlier, it will take about two years to enroll patients. As we progress further, we'll update, you know, all of you on our timeline and what we're saying here with the phase II. Just because of all the knowledge that we have, we're doing a phase II, phase III program, which will overall save us a year in development timelines, you know, if we're successful, but what it doesn't do is commit us to any timeline so we will have the phase II portion. What will happen operationally is sites that finish phase II will just continue enrolling patients in phase III, but we'll see, just like any phase II trial, the full data set.
We'll read it out, we'll share it with the investor community as well, and if everything goes according to plan, we'll just continue with the phase III portion, and we'll save about a year in total development timeline. If we're surprised for whatever reason, and we want to adjust, do something different, we can do that. We can stop the phase III program. Those patients that are currently in phase III would just go into our safety database, so it won't be for naught, and then we can adjust as needed going forward, you know, if we're unlucky and it just doesn't seem that the molecule has activity, we can, of course, then shut it down.
We're positioning ourselves for success, just adding a little financial investment, which we think is a very sound thing to do in light of the knowledge that we have of this space, but it doesn't preclude any optionality going forward.
Got it. And so the history of the earlier generation molecule, pimavanserin, is there was a CRL for dementia-related psychosis. Can you help put that in context, and, you know, what gives you confidence that ACP204 could be successful in Alzheimer's disease psychosis now?
Yeah, maybe I'll try to give a brief review of what we did and but more focused on what we're doing going forward. So we did study pimavanserin, which is the active in NUPLAZID. There were an earlier Alzheimer's disease psychosis, but our last trial, phase III trial, was to run a basket trial for the disease you mentioned, dementia-related psychosis. One of the subgroups in that is Alzheimer's disease psychosis. The data from our HARMONY study was very robust, highly statistically significant, but when we reviewed the data with the FDA, the FDA at that time was focused on subgroups, and you know, from their perspective, they didn't approve the basket indication of dementia-related psychosis.
We had further discussions with them on just the Alzheimer's disease psychosis subgroup, but our program wasn't designed to study Alzheimer's disease psychosis. It was. While there was a robust signal there, it wasn't statistically significant, and the trial wasn't designed to achieve statistical significance in Alzheimer's disease psychosis. So ultimately, the FDA declined giving us the Alzheimer's disease psychosis indication for pimavanserin. But with the totality of data that we have and the fact that the ACP204 trial is now being designed specifically to study Alzheimer's disease psychosis, we think that positions us you know, well positions us for success.
Great. That makes sense. Maybe I'd be interested to jump to thinking about the ex-US opportunity for Acadia, specifically, DAYBUE in Rett syndrome. What's the status of bringing DAYBUE to ex-US markets?
... Yeah, so maybe I'll touch on three geographies. So we've filed in Canada, which was part of our original territory, so we had been moving forward there fast, you know, just prior to other territories, and we expect to hear from the regulators before the end of this year. We expect to file in Europe in the first quarter of next year. And then we are continuing our discussions with the regulators in Japan. As expected, we'll need to do some clinical work in Japan, and we're having the right and good discussions with the regulators there to advance that program.
Got it. How could the size of the ex-U.S. opportunity compare to the U.S. opportunity?
Yeah, so you know, the incidence rates for eczema, it's the same around the world, so there's no kind of ethnic or national differences across populations. So and then, when you look at populations, and do some adjustments for age, you know, for three territories we just mentioned, you know, Canada, there's, you know, should be around 600-900 patients. Europe's bigger than the U.S., so we estimate there be 9,000-14,000 patients. I mentioned earlier, 5,000 in the U.S., you know, treated and diagnosed, but that's from claims database.
When we look at prevalence in the U.S., you know, we get to numbers of six to nine thousand, so Europe's slightly bigger than that, and Japan should be in kind of the order of magnitude of, you know, one to two thousand patients.
Great. In the prepared remarks or at the beginning of our conversation, you mentioned business development. Could you elaborate more on the opportunities you see there?
Yeah. I mean, there still continues to be, you know. We're very active in the business development environment. You know, trofinetide or DAYBUE is an example of our success there. We also brought in ACP101 through business development. You know, we have, you know, franchises in neuroscience and rare disease. We'll look to invest, and mostly through business development, to support both of those. I think what you'll see is the mix probably will skew more towards rare disease, just because as we look over what kind of the VC community has invested over the last decade plus, there's just been more in rare disease than neuroscience. But neuroscience investments, early-stage investments have been robust, and so we continue to look at both sides of our business.
You know, it's a little hard to predict, you know, it's a lumpy business on when you get things done, so. But we remain active, and when obviously we add things to the portfolio, we'll share it with all of you.
Great. What's the cash runway for Acadia?
As I mentioned earlier, you know, we are a cash flow positive company, so we don't look at runway. We're just accumulating. We don't need to finance. You know, I've been CFO about three years, and so when I started, we were still a cash utilizer, but we saw the pathway to getting to cash flow positive. So I said it at the time, that we don't need to raise money, and that's that was true and continues to be true. You know, with the one caveat of what the topic we just talked about is business development. So the more cash we generate, just the bigger bite size we have with our own resources.
But if there are things to do that we think are value-enhancing to the company, where we would need to raise money for, you know, we wouldn't be shy about that. But, you know, it's all, you know, positive and on the upside, as opposed to, you know, any need to raise money for the existing business.
Great. Thank you very much for joining us today.
All right. Thank you. It's great to be here.