ACADIA Pharmaceuticals - Q3 2023

Transcript

Operator (participant)

Good day, ladies and gentlemen, and welcome to Acadia Pharmaceuticals' third quarter 2023 financial results conference call. My name is Kathy, and I will be your coordinator for today. At this time, all participants are in a listen-only mode. We'll be facilitating a question and answer session toward the end of today's call. I would now like to turn the presentation over to Al Kildani, Senior Vice President of Investor Relations and Corporate Communications at Acadia. Please proceed.

Al Kildani (SVP of Investor Relations and Corporate Communications)

Thank you, Kathie. Good afternoon, and thank you for joining us on today's call to discuss Acadia's third quarter 2023 earnings. Joining me on the call today from Acadia are Steve Davis, our President and Chief Executive Officer, who will provide some opening remarks, followed by Brendan Teehan, our Chief Operating Officer and Head of Commercial, who will discuss the debut launch and NUPLAZID execution. Doug Williamson, our Head of Research and Development, will provide an update on our pipeline programs, and Mark Schneyer, our Chief Financial Officer, will review the financial results. Steve will then provide some closing thoughts before we open up the call for your questions. In addition, both Kathie Bishop, our Head of Rare Disease and External Innovation, and Parag Meswani, Senior Vice President, Trofinetide Rare Disease Franchise, will be available for the Q&A session.

We are using supplemental slides, which are available on our website's Events and Presentations section. Before proceeding, I would like to remind you that during our call today, we will be making several forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, timing of events, or future results, are based on current information, assumptions, and expectations that are inherently subject to change and involve several risks and uncertainties that may cause results to differ materially. These factors and other risks associated with our business can be found in our filings made with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date. I'll now turn the call over to Steve.

Steve Davis (President and CEO)

Thank you, Al. Good afternoon, everyone, and thank you for joining us. Please turn to slide five. Acadia is entering a transformational period of growth, delivering record revenue in the third quarter. Our rapidly growing franchise in DAYBUE complements our highly profitable NUPLAZID business, and our robust R&D pipeline provides rich opportunities to fuel growth to even higher levels in the years ahead. We plan to capitalize on this opportunity set by executing on our strategic priorities. Let me touch briefly on... First, we are extraordinarily pleased with the success of DAYBUE. We generated $66.9 million of net sales in the third quarter, our first full quarter since launch, demonstrating a high level of excitement in the Rett community as soon as DAYBUE became available. As we'll discuss today, we're seeing strong indicators across all launch metrics underlying these results, including demand, persistency, and access.

Second, our NUPLAZID franchise continues to be highly profitable and strongly cash flow positive. NUPLAZID revenues for the quarter were $144.8 million. These results reflect our ability to continue to gain market share and grow the revenue base. Third, in addition to these successful marketed products, we have a deep and growing pipeline, including our Phase III ADVANCE-2 study of pimavanserin in negative symptoms of schizophrenia, where we expect to have top line results in the first quarter of 2024. Our Phase III study evaluating ACP-101 in Prader-Willi syndrome, where we expect to commence enrollment later this month. In leveraging our learnings from NUPLAZID, we have developed ACP-204, our next generation 5-HT2A blocker. Here, too, later this month, we will commence enrollment of patients in our seamless Phase II, Phase III program, studying ACP-204 in Alzheimer's disease psychosis.

Fourth, the success of DAYBUE's U.S. launch underscores the opportunity we have to expand in the global markets following our expanded license agreement for DAYBUE, announced in July, which granted us worldwide rights to the asset. Our early U.S. experience serves as an important reminder of the significant unmet medical need worldwide, with no approved treatments for Rett Syndrome outside the United States. We're meeting with Health Canada this month to discuss a planned new drug submission for trofinetide in Canada. In addition, we're engaging with European regulators in advancing plans in other geographies. Fifth, we have a deep early-stage portfolio that includes disclosed and undisclosed programs focused on neuropsychiatric and rare disease disorders that represent significant opportunities to continue to build on our current growth.

In addition, we continue to remain very active in business development to further expand our portfolio and build on our success with DAYBUE and NUPLAZID in CNS and rare disease. Let's discuss our DAYBUE launch and some of the launch dynamics on slide six. Five and a half months into the launch, we've provided hope to a community that has never had an approved treatment for Rett syndrome. We've seen Rett patients respond in amazing and inspiring ways to DAYBUE therapy. We've established critical relationships in the medical and caregiver communities, and we've provided a strong base for future continued success. During this time, from mid-April through September, we've booked approximately $90 million in revenue.

In preparing for the approval and launch, we made significant investments in both the medical and caregiver communities, in medical education, in launch preparations, and the result, everything about the launch thus far has gone either according to plan or exceeded our plans, and in some measures, greatly exceeded our pre-launch expectations. Prior to launch, we expected demand to be high. It has been. In fact, one area where we significantly exceeded our pre-launch plans is just how fast the demand came immediately upon launch, particularly from centers of excellence. Another area where we have exceeded pre-launch expectations is the speed at which we've established access with payers.

As Brendan will speak to shortly, this access has come faster, both in terms of the pace at which payers have adopted formal coverage plans and the pace at which they have approved treatment under letters of medical necessity prior to the adoption of written plans. These two dynamics, pent-up demand from centers of excellence and more rapid access than anticipated, coupled with high levels of patient persistence on therapy, have resulted in just over 800 patients on DAYBUE as of September 30. Importantly, these dynamics have produced a substantial foundation that will continue to benefit our launch as we move forward. We've established significant breadth and depth of physician experience with DAYBUE in a short amount of time. A high number of patients and families are sharing their positive experiences at this early stage, enabling us to gain momentum sooner.

Establishing access well ahead of plan enables us to further build on that momentum. Turning to persistence, we previously reported that we are very encouraged by what we're seeing, and that continues to be the case. As Brendan will discuss shortly, our real-world evidence to date indicates 81% of patients starting DAYBUE remain on therapy four months after treatment initiation, and only an additional 6% are beyond 60 days since their last scheduled refill. In comparison, in our LILAC-I open-label extension study, 65% of patients who started DAYBUE treatment after rolling over from placebo remained on therapy four months after initiation. To sum up, we continue to operate at or ahead of plan. Prior to launch, we projected a linear growth curve producing attractive revenue growth year after year. This is what we typically see in rare disease launches.

Of course, what we didn't anticipate with the debut launch is the surge in demand that accelerated our penetration and the associated contributions to revenues in these early quarters. As we move forward, we'll continue to leverage this strong foundation as we increase breadth and depth in all sectors of the Rett community. Let's turn to a snapshot of our current products and pipeline on slide seven. What we see is an overview of our two successful commercial products and our pipeline of late and early stage programs that represent substantial long-term growth opportunities for Acadia. As we've noted, NUPLAZID continues to be a highly successful franchise, generating significant cash flow. In Parkinson's Disease Psychosis, we continue to gain market share in both our office-based and long-term care channels, and we booked another record quarter in the long-term care channel.

Our commercial team is continuing to successfully leverage the real-world evidence studies rolled out earlier this year, and the impact is becoming increasingly evident each month and quarter. Building on this, DAYBUE provides dramatic growth potential to our business, and we have a robust pipeline behind that, where we'll be commencing late-stage studies in two programs later this year. In our negative symptom schizophrenia program, we have something rarely seen in this indication. That is a positive pivotal study. There are no FDA-approved treatments to treat the negative symptoms of schizophrenia. The unmet need is high, and we look forward to having results from our second pivotal study in the first quarter of next year. Later this month, we will commence our Phase III study with ACP-101 in Prader-Willi syndrome. Prader-Willi is a rare and debilitating genetic disease, where patients have an unrelenting drive to eat.

Here, too, there are no FDA-approved treatments. November will be a busy month for us as we also commence our seamless Phase II, Phase III program with ACP-204 in Alzheimer's disease psychosis patients. And behind that, as I've mentioned, we have a rich pipeline of early-stage, disclosed and undisclosed programs that position us for long-term growth. I'll now turn it over to Brendan to provide additional insights on our debut launch execution and NUPLAZID's commercial performance on slide eight.

Brendan Teehan (COO and Head of Commercial)

Thank you, Steve. Let me provide additional commentary on our two commercial franchises, DAYBUE and NUPLAZID, and the terrific performance both delivered in the quarter. Let's begin with DAYBUE on slide nine. We have three commercial execution priorities I'd like to discuss today: demand, persistency, and conversion to paid treatment. DAYBUE's launch has outperformed across each parameter since approval. As Steve noted, we have seen a surge in demand for DAYBUE since the launch in mid-April, resulting in just over 800 patients on DAYBUE as of September 30th. This initial wave of demand for us was a bit unique, likely due to several factors, including a very strong patient advocacy community. 800 patients on therapy is a great start, but we still have a lot of Rett patients who can benefit from DAYBUE, many of whom have fewer interactions with centers of excellence and with patient advocacy organizations.

This segment represents the majority of patients who have not yet been prescribed DAYBUE. As we previously described, approximately 25% of Rett patients are treated in centers of excellence, another 60% are treated in high-volume institutions, and the remainder in community practices. As we look to engage this next significantly larger segment of the Rett market, we expect a more linear adoption curve, as we've seen with other orphan rare disease launches.... New patient requests are coming in at the rate we expected at this point in the launch and will support the continued attractive growth of DAYBUE. Our experience so far with new starts, coverage, efficacy, and persistency reinforce our conviction that DAYBUE will achieve a high degree of penetration in the Rett market.

To penetrate this larger segment of the market, we are now employing a number of initiatives, including delivering HCP and caregiver webinars, which bring together experienced HCP treaters and caregivers with loved ones already on therapy to speak about their successful experience starting and staying on DAYBUE. We're participating in local Rett events, especially during Rett Awareness Month in October, that provide an opportunity to bring together patients and families already on DAYBUE treatment with those that are still looking to learn more. In addition, we're delivering HCP peer-to-peer programs to have experienced treaters help newer-to-brand HCPs with best practices on getting started and remaining on DAYBUE to realize long-term benefit. Let's next turn to a discussion of persistency on DAYBUE on slide 10. Real-world persistency thus far is meaningfully better than we saw in our clinical trials.

When we measure persistency based on confirmed discontinuations, 81% of patients who started DAYBUE remain on therapy at four months since treatment initiation. When we measure persistency based on confirmed discontinuations, plus any other patients who are more than 60 days past their last scheduled refill, the real-world persistence is 75%. In comparison, in our LILAC-I open-label extension study, 65% of patients who rolled over to drug from placebo remained on therapy at the end of four months. This is important because we believe high levels of persistence early on translate into a higher number of patients staying on therapy long term. Further supporting this outlook is the extremely high level of persistency we've seen from patients that transitioned from the open-label extension to commercial therapy. This stronger early persistency does not surprise us.

We expect the real-world experience to be different from what we observed in our clinical trials, where caregivers and patients did not have all the information we now have about proven clinical benefits, as well as proper GI management, including specific language in our label that instructs HCPs and caregivers to discontinue anti-constipation medications prior to initiating DAYBUE, further supporting a better initial clinical experience. I'd now like to turn to a discussion of conversion and dose compliance on slide 11. In addition to outperforming on demand, we executed well ahead of plan on access. This is what enabled us to take that surge of demand and quickly convert it to paid therapy. A significant proportion of this surge converted to paid in the second quarter, but most converted in the third quarter.

This leaves a smaller number of yet-to-convert patients carrying over into the fourth quarter as we continue shortening the time between a script being written and converting to paid treatment. To quantify our progress with payers, our early foundational work has resulted in payers adopting formal plans covering almost 80% of lives to date. Now let me turn to titration and compliance to dose, two factors that have been helpful in starting and keeping patients on therapy. Compliance to dose through three months is in the range of 75%-80% of the labeled dose. As we expected, the majority of patients begin DAYBUE treatment by titrating up from a lower dose to determine their optimal long-term dose. Most patients typically start at approximately 50% of their prescribed dose and titrate up over a period of four to six weeks.

We believe this compliance range provides insight into using titration to find the most appropriate dose, so caregivers and patients can benefit long term. Finally, I'd like to turn to what matters most, the real-world benefits caregivers are sharing with us about the improvements they're seeing in their loved ones being treated with DAYBUE. Please turn to slide 12. We are excited and gratified to see the real-world daily stories of the impact DAYBUE is having on the lives of Rett Syndrome patients through the caregiver testimonials you see on this slide.

A few representative examples of the day-to-day important benefits families are describing include: improvement in speech or even speaking for the first time in years, broadening vocabulary and improved engagement in conversations, improved gait and feet placement, purposeful eye contact and improved communication through the patient's eyes, decreased hand wringing and stereotypies, coupled with more purposeful use of hands. We also regularly hear feedback about the loved one's increased alertness, with patients now being able to better follow conversations or complete activities they were previously unable to complete. These testimonials all speak to the promise of treatment with DAYBUE, and we'll continue to monitor experiences as patients continue treatment. I'd now like to move to slide 13 for a discussion of the great progress we're seeing in our NUPLAZID franchise.

As Steve noted, the NUPLAZID franchise is increasingly cash flow positive and continues to provide a strong foundation for our overall business. Leveraging the emerging real-world evidence data, we continue to increase our PDP market share versus off-label atypical antipsychotics in a contracted overall Parkinson's, Parkinson's disease market. Product sales of NUPLAZID in the third quarter were $144.8 million. The broad educational campaign we started at the beginning of the year, leveraging the real-world evidence studies, continues to deliver increasing value. The more often we are able to speak with customers about these important observations regarding NUPLAZID and off-label antipsychotics, the greater their confidence in choosing NUPLAZID over other alternatives. These results reinforce the impact these data sets have on our efforts to drive new patient starts.

Looking at the broader market dynamics, we see that Carbidopa/Levodopa prescriptions remain essentially flat over the first three quarters of 2023 versus the first three quarters of 2022, while NUPLAZID continues to grow, outpacing the market by a wide margin. As you can see on this slide, in the office-based channel during this time frame, we've grown new patient starts 9%, while all other PDP products have increased only 1%. Turning to the LTC channel, where we delivered a record bottle quarter for NUPLAZID, we also continue seeing improvement in new resident admissions, indicating some degree of market recovery. In this channel, NUPLAZID has substantially outpaced the class, growing 16% during this time period, while all other products used to treat PDP in the long-term care setting have grown just 7%.

Understanding that the large majority of revenues we record during any given quarter are the result of refills by continuing patients, these significant increases in NUPLAZID new patient starts in both market segments are encouraging. I'll now turn it over to Doug Williamson, our Head of Research and Development, to provide an update on our pipeline programs, starting on slide 14.

Doug Williamson (Head of Research and Development)

Thank you, Brendan. In addition to our two commercial products, we have a strong pipeline of clinical programs providing us with several opportunities to further expand our growth. Let's start with pimavanserin as a potential treatment for the negative symptoms of schizophrenia on slide 15. Predominant negative symptoms remain one of the largest unmet needs in schizophrenia, and as of today, there are still no approved treatments for these symptoms. Our adjunctive pimavanserin program is designed to treat patients whose positive psychotic symptoms are adequately controlled, but who still suffer from persistent and uncontrolled negative symptoms, inhibiting their ability to lead a normal, productive life. As we stated last quarter, we have completed enrollment in ADVANCE-2, our second study of pimavanserin in negative symptoms of schizophrenia. We look forward to sharing top-line results in the first quarter of 2024. Please turn to slide 16.

We also have two pipeline programs with entirely new compounds in development, ACP-101 and ACP-204. I'll begin with ACP-101. We have completed all the necessary steps to initiate the Phase III study, evaluating ACP-101 for the treatment of hyperphagia in Prader-Willi syndrome. This is a program we're very excited about. Prader-Willi syndrome is a rare genetic neurobehavioral syndrome that affects approximately 8,000-10,000 patients in the United States and represents a significant unmet need. There are currently no therapies approved to treat the characteristic hyperphagia in patients with PWS. On this slide, we've laid out the design of the Phase III global, multicenter, randomized, double-blind, 12-week, placebo-controlled study, evaluating the efficacy and safety of ACP-101 in approximately 170 Prader-Willi patients. The primary efficacy endpoint is improvement of hyperphagia, as measured by the Hyperphagia Questionnaire for Clinical Trials, or HQCT scale.

Those patients who complete the study will be eligible to enroll in an open-label, long-term extension study. If data from this Phase III study is positive, we plan to submit a new drug application for the treatment of hyperphagia in PWS to the FDA. We look forward to working with the Prader-Willi community and clinical experts as we continue to advance development of this program. Please turn to slide 17. We continue to advance ACP-204, our next generation 5-HT2A compound, which we're developing as a potential treatment for Alzheimer's disease psychosis. As we previously described, ACP-204 works primarily as an inverse agonist of the 5-HT2A receptor. Our experience with pimavanserin suggests that this mechanism is very well suited for elderly populations with multiple comorbidities and concomitant medications, providing antipsychotic efficacy with a very attractive tolerability profile and low drug-drug interaction liability.

With ACP-204, we're seeking to build on those learnings and believe it has an exciting future. Our work completed to date includes a comprehensive Phase I program and supports our target product profile for ACP-204. As you can see on the slide, ACP-204's profile could represent a significant improvement over an already strong product profile for pimavanserin. Please turn to slide 18. Armed with this strong data from phase one, we're preparing to start our seamless phase II, Phase III program for ACP-204 in the coming weeks. Our plan includes an initial Phase III study with over 300 patients, which is designed to roll seamlessly into two phase three studies. This phase II study has been designed and sized in such a way that if successful, it could be considered a pivotal registration study.

As a reminder, with this accelerated development plan, we can eliminate dose finding and move from Phase II directly into two Phase III studies with the same sites continuously enrolling patients. As each site completes their Phase II site allocation, they will move directly into recruiting patients for one of the Phase III studies. Once the full study allocation of patients for Phase II is complete, we will analyze and report Phase II results, by which time the two Phase III studies will already be underway. This plan, which we've aligned on with the FDA, will ultimately provide three potential pivotal studies for a submission. Overall, we're very excited with the progress of this program. It represents an important component of our strategy to continue to provide attractive opportunities to grow our business. Now I'll turn it over to Mark for a financial update on slide 19.

Mark Schneyer (CFO)

Thank you, Doug. Let's review our quarterly performance on slide 20. In the third quarter, we recorded $211.7 million of total revenues. NUPLAZID net product sales were $144.8 million in the quarter, compared to $130.7 million in the prior year. The $14.1 million increase year-over-year is comprised of a $7 million in-channel inventory reduction in the prior year that did not recur this year. $4 million is attributable to lower 340B volumes and $3 million as a result of 2% demand growth. Our gross-to-net adjustment for NUPLAZID was 19.9% for the quarter, as compared to 18.6% in the third quarter of last year.

The increase to gross-to-net was primarily attributable to increased rebates associated with the Inflation Reduction Act, partially offset by the reduction in 340B volumes I just mentioned. Turning to DAYBUE, net product sales were $66.9 million in the first full quarter of commercialization, reflecting the significant early demand and strong commercial performance described earlier by Steve and Brendan. R&D expenses increased to $157 million in Q3 2023, from $81.3 million in Q3 2022. The increase was mainly due to the $100 million upfront payment to Neuren Pharmaceuticals for the worldwide rights to trofinetide, partially offset by a reduction in other R&D expenses. SG&A expenses increased to $97.9 million in Q3 2023, from $78.1 million in Q3 2022.

The increase was driven by commercial costs associated with our stronger than expected DAYBUE launch, partially offset by reductions in our spend on NUPLAZID. We ended the quarter with a cash balance of $345.9 million. On a year-to-date basis, excluding the upfront payment for worldwide rights to trofinetide, we were cash flow neutral as a company. With our successful launch of DAYBUE, we were cash flow positive in the third quarter, also when excluding the recent trofinetide upfront payment. Going forward, we expect to be cash flow positive over the long term, subject to the size and scope of future business development. Turning to slide 21, we are raising the bottom end of our full year NUPLAZID net sales guidance, and our new range is $537.5 million-$545 million.

We are also raising the bottom end of our full-year NUPLAZID gross-to-net guidance, and our new range is 24.5%-25%. Additionally, we are providing fourth quarter DAYBUE net sales guidance of $80 million-$87.5 million. On the expense side, we are narrowing our guidance ranges as we near the close of the year. Our full-year R&D guidance of $340 million-$350 million narrows to the middle of our prior range. Our full-year SG&A guidance of $390 million-$400 million narrows to the upper half of our prior range. Now I'd like to turn the call over to Steve for closing remarks on slide 22.

Steve Davis (President and CEO)

Thanks, Mark. Acadia is entering a transformational period of growth as we continue to execute across all our strategic priorities, and I would like to thank our employees for their accomplishments and their ongoing commitment and passion as we continue our mission to elevate life. Operator, I'll turn it over to you to start the Q&A.

Operator (participant)

Yes, thank you. Ladies and gentlemen, if you wish to ask a question, please press star one one on your telephone. If you wish to withdraw your question, press star one one again. Please limit yourself to one question. I repeat, please limit yourself to one question. Please stand by while we compile our Q&A roster. Our first question comes from the line of Ritu Baral of TD Cowen. You may proceed.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Thank you for—

Steve Davis (President and CEO)

Ritu, you're coming through very muffled.

Operator (participant)

Could you turn up your volume, please?

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

I do have my volume.

Steve Davis (President and CEO)

Yeah, I'm sorry, Ritu. We can hear you talking, we can't understand what you're saying.

Operator (participant)

You could get in the queue again and try again, but we'll bring our next questioner up. Just a moment, please... Your next question comes from the line of Tess Romero with J.P. Morgan. You may proceed.

Tessa Romero (Biotechnology Equity Analyst)

Good afternoon, everyone. Congratulations on all the progress. Our question is around cadence of patients starting DAYBUE, specifically in 3Q and how that looked exiting the quarter. And then second question, if I could, any trends with respect to the type of patient that might drop off earlier than the average? Thanks so much.

Steve Davis (President and CEO)

Yeah, thanks much for the question. Brendan, do you want to take this?

Brendan Teehan (COO and Head of Commercial)

Yeah, sure. Tess, thank you so much for the question. I think the right way to think about our demand early on is a pull forward of the demand we would have expected to see in the first place. We had a highly engaged group of families that got started early. It's important to note that prescriptions that came in the second quarter, many would be filled in the third quarter simply due to conversion. Then in the third quarter, continued to see in the early part of that quarter that surge, many of which were then filled in the third quarter. Some, I think, will also carry over into the fourth quarter.

So what we're seeing is, I think we've brought the launch to sort of a stepped-up basis in terms of number of families and patients already on therapy. And what we would expect to see leaving the third quarter is more linear growth, but on the same slope, very familiar to seeing in other rare disease launches, though some of those didn't have the early step up that we've seen.

Tessa Romero (Biotechnology Equity Analyst)

Brendan, I think the second part of the question was regarding any differences we see in terms of patients that discontinue.

Brendan Teehan (COO and Head of Commercial)

Sorry, great question. No, I would say that it's been what we would have expected in terms of discontinuations. As with any rare disease, a product launch with subjective endpoints, you know, some patients aren't going to see benefit early enough to stay on therapy. Some will discontinue due to tolerability, but we've seen that across age ranges and weights.

Operator (participant)

Okay, thank you. Our next question comes from the line of Yatin Suneja with Guggenheim. You may proceed.

Yatin Suneja (Managing Director and Biotechnology Analyst)

Hey, guys. Thank you for taking my question. Very impressive results today, just particularly on DAYBUE. So I have a question on the guidance. Could you comment on, you know, some of the push and pulls into that guidance of $80-$87.5? Like, what constitutes the lower versus the high end? What are some of the drivers that can, you know, help you maybe be closer to the higher end versus the lower end? Thank you.

Steve Davis (President and CEO)

Yeah, thanks much for the question, Yatin. Mark, you want to take that?

Mark Schneyer (CFO)

Yeah. So, you know, as we've been discussing, I think we've looked at kind of all the key parameters that kind of build up to a financial forecast, you know, persistency, demand, access, and conversion, and all of those together kind of come together to the range. Obviously, higher, it gets you towards the higher end, lower towards the lower end. One other thing, kind of on potentially on the lower end, you know, we've yet to go through, you know, the Christmas holiday period with DAYBUE. So, we don't know if the last couple of weeks of the fourth quarter could impact bottles and sales on the lower end of the range.

Operator (participant)

Okay, thank you. Our next question comes from the line of Ritu Baral with TD Cowen. You may proceed.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Hi, guys. Can you hear me now?

Operator (participant)

Yes.

Steve Davis (President and CEO)

Yes. Thank you.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Okay. I'm so sorry about that, train station noise.

Steve Davis (President and CEO)

No worries.

Ritu Baral (Managing Director and Senior Biotechnology Analyst)

Apologies. So obviously, congratulations on a series of consensus-leading quarters. I wanted to ask about insurance coverage. As I'm sure you know, we've been conducting tracking surveys of the debut launch, and one of the things we hear over and over again from doctors is complaints about coverage denials. You know, despite the good numbers, it seems like there's still patients left on the table because of denials around efficacy, denials around this, denials around that. I wanted to see what you guys were hearing around denials, maybe how long it takes for these exception letters to come through. And now that we're six months out, what are you seeing on reauthorization? Thanks.

Steve Davis (President and CEO)

Thanks, Ritu. Brendan?

Brendan Teehan (COO and Head of Commercial)

Sure. Thanks, Ritu, and thanks for the question. So what we've seen is that published coverage policies have been very helpful. Now, obviously, in the early days, there's going to be a bit of a backlog in patients because we'll get the prescription in, we have to work through the prior authorization process. And this is probably a bit compounded by the size of the rare disease-treating audience. As you know, this tends to be even in centers of excellence, maybe a single physician and an assistant doing some of this work. That's why we've provided them with so much support in the prior authorization process and the work that our hub can do on their behalf. What I can say is that approvals have continued to accelerate as we've moved further into the launch.

coupled with these, coverage policies that we've seen now covering approximately 80% of lives. For your specific question around reauthorizations, those have very much been consistent with our expectations and are reflective of what we've seen for other rare disease specialty products. They generally require a physician attestation that the patient is receiving clinical benefit, from DAYBUE, and most of those reauthorizations are at a six or 12-month period. Some of them are at three months, and then annually thereafter. But thus far, we have not had a final denial for, a reauthorization for any DAYBUE patients.

Steve Davis (President and CEO)

Just to maybe annotate on that last point, there are denials, and there are denials. So it's not uncommon, particularly if a plan doesn't have a formal coverage policy in place, when a prescription comes in to issue an initial denial. And so that is kind of noise in the system much of the time, and but, you know, still, doctors and their office have to deal with that as we do in terms of supporting them. But as Brendan mentioned, the other kind of denial is a denial where a plan just does not move off of that. That is very rare. And so, so it does create a little bit of noise and administrative effort in the system, which does then subside as more and more plans get formal policies in place.

Operator (participant)

Thank you. Our next question comes from Gregory Renza with RBC Capital Markets. Your line is open now.

Gregory Renza (Director and Senior Biotechnology Research Analyst)

Hi, this is Anish on for Greg. Congrats on the quarter, and thanks for taking my questions. Firstly, from your interactions with physicians treating Rett, what should one expect on seasonality of diagnoses, perhaps even stratified by age? Also, if I could, how should we be thinking about potential value unlock for DAYBUE availability ex-US, specifically by region? Thanks again.

Steve Davis (President and CEO)

Yeah. Thanks much. I'm going to ask Parag Meswani to take the first question and the second question. Parag?

Parag Meswani (SVP of Trofinetide Rare Disease Franchise)

Sure. Sure, thanks for the question. So what I'll say at the outset is that overall physician feedback regarding DAYBUE is encouraging and points to a high level of caregiver interest, regardless of age, gender, weight range, so on and so forth. So we feel very confident about their view of the product profile. In terms of diagnosis rates, you know, we don't really see any variance or differences as to when patients are diagnosed. What we do see are differences in when patients are coming in for their follow-up assessment. One of the things that Brendan mentioned in his prepared remarks is that there is a different cadence of when patients are going in to see their clinician, and over time, we expect that to accelerate as more and more patients become familiar with DAYBUE and DAYBUE's product profile.

Steve Davis (President and CEO)

Yeah. Thanks, Parag.

Parag Meswani (SVP of Trofinetide Rare Disease Franchise)

Thanks.

Steve Davis (President and CEO)

Brendan?

Brendan Teehan (COO and Head of Commercial)

Yeah.

Steve Davis (President and CEO)

Ex-US.

Brendan Teehan (COO and Head of Commercial)

So for outside the United States, we are obviously excited about the opportunity to be able to bring trofinetide to a broader audience. Our first progress will be in Canada. As we've described, we're already in conversations to bring DAYBUE to Canada in the next 18 months. We've also began our conversations with regulators in taking scientific advice in Europe, and are also prepping for Japan. We will look opportunistically at the rest of the world as well for opportunities for us to continue our global expansion from there.

Operator (participant)

Thank you. Your next question comes from Jeff Hung with Morgan Stanley. Please proceed.

Jeff Hung (Biotechnology Equity Research Analyst)

Thanks for taking my question. You said that centers are treating existing prevalent patients during planned clinic days. So I guess with expectations of more linear trajectory going forward, have the number of clinic days remained stable, or are they starting to decrease as centers work through existing prevalent patients? Thanks.

Steve Davis (President and CEO)

Thanks for the question, Jeff. Parag, you want to take that?

Parag Meswani (SVP of Trofinetide Rare Disease Franchise)

Yeah, happy to take that question. So, I would say that it's variable. We know that a number of centers of excellence have actually increased their clinic days as a consequence of the approval of DAYBUE. Some have gone from a clinic day a month to a clinic day a week. Others don't have the infrastructure yet. As Brendan mentioned before on the payer question, there may be just one or two clinicians who are responsible for everything, from clinic visits to payer access issues and managing clinical trials as well. So over time, we are seeing more and more clinic days being added. We're encouraging that and facilitating those sorts of connections through centers of excellence and through the community as well. But this is a new muscle that they're learning to flex in many ways.

As more patients are being treated and seen, clinic days are being added to meet the demand that's coming in through the clinic doors.

Operator (participant)

Thank you. Your next question comes from the line of Charles Duncan of Cantor. Please proceed.

Charles Duncan (Managing Director and Senior Biotechnology Analyst)

Hey, good afternoon, Steve and team. Congrats on a great quarter, out of the box for DAYBUE. I think I'll ask a couple of questions on the pipeline, since other good questions have been asked on the commercial. On the pipeline, first of all, question regarding ACP-101, helpful context in terms of the number of patients. Can you give us a sense of how quickly you would anticipate that study to enroll? And for ACP-204, you know, I guess I'm assuming that they're going to be primarily Alzheimer's disease patients that are later on in their journey. And how will you confirm that they're Alzheimer's patients versus other etiologies, or is that not an issue for you for the conduct of this study? Thanks.

Steve Davis (President and CEO)

Yeah. Thanks, Charles. You know, as tempting as to answer the first question, we just typically don't comment on projected enrollment until we actually get some enrollment experience. So we'll have to get back to you on that. And then I'll ask Doug to answer the second question regarding Alzheimer's patients.

Doug Williamson (Head of Research and Development)

Yeah, and it's a great question, Charles, because that's actually a conversation we had with the FDA, and their outcomes assessment group are increasingly interested in validating the diagnosis of Alzheimer's. So we've agreed with them that we'll conduct a biomarker, a blood-based biomarker, into the diagnostic procedure to just add extra, an extra level of certainty that we're getting the diagnosis correct.

Operator (participant)

Thank you. Your next question comes from the line of Ash Verma with UBS. Please proceed.

Ash Verma (Executive Director of SMID Biotech and Biopharma)

Hi, thanks for taking our question. So, just in terms of persistency on DAYBUE, I wanted to get your thoughts on how you think this could trend over time. I mean, it's very encouraging to see this four-month data and get this type of granularity, but how do you think this might look at, like, six, nine or 12 months? And any updates on the LILAC-II study, and would that be a more representative data point for what we are seeing in the real world? Thanks.

Steve Davis (President and CEO)

Yeah, thanks much. I'll take the first question, I'll ask Kathy to take the second. So, with respect to the first question, it's early still. You know, we do have, as we've mentioned, 800 patients on therapy, so now we have a meaningful amount of data on multiple parameters, including persistency. So we have, you know, a strong number of patients that have completed four months of therapy, and as we go forward, we'll continue to monitor this and update. We have obviously not as many patients at 5 months as we have at four, and at six months and five, et cetera.

But I would say that as we look at the data that we have with this separation between what we're seeing in the real world and what we're seeing from the LILAC-I open label rollovers, which again, as we said, we think is the best clinical trial comparison, because those are patients starting therapy, knowing they're starting on DAYBUE. We continue to see this separation. And so, we'll look forward to updating you as we go forward, but we're highly encouraged by what we're seeing. We expected to be able to improve on our clinical experience. We put significant investments in it, and so far we are. Kathy, you want to take the second question?

Kathie Bishop (Head of Rare Disease and External Innovation)

Yeah. With regards to the LILAC-II study, we just completed that study as we had those patients continue on therapy until the drug was approved and they had the opportunity to go on commercial therapy. Over 90% of those patients did roll over directly onto commercial therapy. We now have those results in hand, and we actually plan on presenting them in early December, so in about a month, at the American Epilepsy Society meeting. But I will say in LILAC-II, we had very, very few dropouts. So as long as they enrolled in LILAC-II, they stayed in LILAC-II, and I think that's consistent with what Brendan mentioned, is we think if we can sort of get them through that first period, then they continue to stay on trofinetide or DAYBUE.

Operator (participant)

Thank you. Your next question comes from the line of Tazeen Ahmad with BofA Securities. Please proceed.

Tazeen Ahmad (Managing Director in US Equity Research)

Hi, guys. Good afternoon. Thanks for taking my question. Maybe I'll switch topics for a bit. On the upcoming ADVANCE-2 study, can you just remind us what type of data to expect at that top-line readout in 2024? And what would you consider to be good data? Thanks.

Steve Davis (President and CEO)

Thanks for the question. Doug, you want to take that?

Doug Williamson (Head of Research and Development)

Sure. So the top line data we expect to see, we're using the NSA-16, and the primary outcome is the overall change in the NSA-16, which is a very well validated and accepted scale for assessing negative symptoms. In terms of what does good data look like, the effect size that we saw at the 34 mg dose in ADVANCE-1 was around about 0.3, I think it was 0.34, coincidentally. This 0.34 was the effect size. So I think, you know, that's consistent with what generally constitutes a clinically significant change in psychiatric studies. So if we saw that replicated, I think we'd regard that as good data.

Steve Davis (President and CEO)

Operator, next question. Operator, can you hear me?

Operator (participant)

Yes, thank you. Our next question comes from the line of Uy Ear with Mizuho. You may proceed.

Uy Ear (VP and Senior Equity Analyst)

Hey, guys, congrats on the good quarter. I guess I'll switch drug. On NUPLAZID, you mentioned that you benefited from the 340B program this quarter. Just wondering if this is a one-time thing, or do you expect this benefit to persist going forward? Thanks.

Steve Davis (President and CEO)

Thanks much for the question. Mark, you want to take that?

Mark Schneyer (CFO)

Yeah. So generally speaking, kind of the 340B volumes as part of our mix has been, you know, slowly growing. I think what you saw in the results this quarter was the artifact of kind of a one-time increase last year. That didn't happen this year. So with that, provided kind of a net change benefit in revenue when you're comparing the quarters. I think as we go forward, we'll continue to expect, you know, you know, slow to modest growth in the 340B volumes as we've seen over the last couple of years.

Operator (participant)

Thank you. Our next question comes on the line of Marc Goodman with Leerink Partners. You may proceed.

Madhu Yennawar (Equity Research Associate)

Hi, thanks. This is Madhu on the line for Mark. A couple other follow-up questions on DAYBUE from us. First, are you seeing any increases in overall diagnosis rates or numbers of Rett patients who have been identified in the community? Or when might you start to expect to see that? And then for the side effects, are you hearing anything on whether the side effects are better tolerated in specific patient subgroups, like older versus younger patients? Thanks.

Steve Davis (President and CEO)

Brendan, why don't you take the first question? Parag, you want to take the second?

Brendan Teehan (COO and Head of Commercial)

Yeah. So, thanks for the question. Can you forgive me, can you repeat the first question? I apologize.

Speaker 22

The point was, did we see or have we seen any increase in diagnosis?

Brendan Teehan (COO and Head of Commercial)

Oh, yeah. Forgive me, forgive me. So diagnosis rates. Yes, we are. So we're about two quarters into the launch of the drug, and as we look at data at this point, we're not seeing meaningful changes in diagnosis rates. I think it's safe to say that it's early on. Our first goal is obviously to try and close that gap between the prevalent population, which we know is 6,000-9,000, and the 4,500 or so diagnosed and treated patients in the U.S. We will continue to track that very closely. We know as a first-to-market drug is approved, you tend to see increases, you can see increases in the diagnosed population, and I think we'll continue to share those insights over time.

Steve Davis (President and CEO)

Thanks, Brendan. Parag?

Parag Meswani (SVP of Trofinetide Rare Disease Franchise)

Sure. And then the second question, you know, what I'll say at the outset is that we're very encouraged with the real-world experience, both from an efficacy perspective and from a tolerability perspective. Remember, we learned a lot from our phase III program, and that informed the basis of a very comprehensive approach to educating both providers and caregivers at the outset, post-approval. And I would say that that's been received really favorably. We've designed a footprint inclusive of a patient support services team that is paired with every single new caregiver, every single new family that goes on DAYBUE, and we supplement that with extensive education to providers as well. So that is, you know, started at launch. It remains a core part of our communication point, day in and day out with providers and with caregivers.

Because of that, the experience that we're seeing and hearing, both from a prescriber perspective and from a caregiver perspective, is that a much better tolerability experience with tools to mitigate any tolerability issues as they arise, whether that's diarrhea or other issues as well.

Operator (participant)

Thank you. Your next question comes from the line of Salveen Richter with Goldman Sachs. You may proceed with your question.

Matt Dellatorre (VP and Equity Analyst)

Hey, thanks. This is Matt on for Salveen. You all highlighted NUPLAZID's increasingly cash flow positive. Could you share what kind of margins you have right now and where you see that headed longer term? And then on the litigation, the patent litigation for NUPLAZID, I think we were expecting an update by the end of the month. Do you have any update there for us? Thank you.

Steve Davis (President and CEO)

Yeah, I'll take the second question first, and I'll ask Mark to answer the first one. So, the district court has not issued a decision yet. We think highly likely that the court will by the end of the year, for sure. And, just in terms of update or commentary, you know, it's litigation, there's nothing really that we have to say at this point, other than I'll just say what we've said before, and that is, we believe the law is on our side, and we're highly confident in our position, so we're eager to get to a decision as well. Mark, you want to take the second one?

Mark Schneyer (CFO)

Yeah. On the cash profitability of NUPLAZID, you know, we generate, you know, approximately $300 million of cash flow on a fully allocated cost basis of the franchise. And, you know, we expect that to continue to grow over time. Obviously, on a year-to-year basis, you know, as we go through our budget plans and investment cycles on a for year-over-year, we'll decide to, you know, the level of support and investment for the franchise, you know, with the focus being both on top line growth and near-term profitability.

Operator (participant)

Thank you. Your next question comes from the line of Sumant Kulkarni with Canaccord Genuity. You may proceed.

Sumant Kulkarni (Senior Biotechnology Analyst)

Good afternoon, thanks for taking my question. Assuming that pimavanserin is successful in negative symptoms of schizophrenia, how are you thinking about potential pricing, given the product is already on the market? And do you think you're appropriately resourced from a sales force perspective?

Steve Davis (President and CEO)

Two-part question. Brendan, why don't you take the second part? Actually, why don't you take both of them, if you don't mind?

Brendan Teehan (COO and Head of Commercial)

Yeah, sure. So for us, in terms of pricing, we're not going to discuss where we are at this point, other than to say we certainly will be looking at pimavanserin's value across our portfolio of indications. When we stop to think about resourcing, we are a CNS-focused company, and there's a fair amount of crossover between the treaters of negative symptoms of schizophrenia, which will allow us to kind of capitalize on core resources we have within the organization. But we will obviously logically expand our footprint to cover both the locations treating these patients and the broadened psychiatry population that tends to focus on these negative symptoms patients.

Operator (participant)

Thank you. Your next question comes from the line of Ami Fadia with Needham and Company. You may proceed.

Ami Fadia (Senior Biotech Equity Research Analyst)

Good evening. Thanks for taking my question, and congratulations on the strong performance of DAYBUE. Maybe just one follow-up on DAYBUE for me. Can you talk about sort of the time to approval for patients, you know, whether they are under medical exception or whether they're under an insurance plan where DAYBUE has been put on the formulary? And I'm trying to sort of get a better sense of where you are in the launch as you've indicated that the growth from here will be more linear. Is this more to do with you know sort of the initial bolus of patients already getting on DAYBUE, and now it's more about really you know blocking and tackling and getting, waiting for new patients to be diagnosed? So if you can give any color on that. Thank you.

Steve Davis (President and CEO)

Thanks much for the question. Two-part question. Brendan, you want to take the first and Parag, the second?

Brendan Teehan (COO and Head of Commercial)

Sure. That would be great. So, thanks so much. What we've seen, and unsurprisingly and very similar to other rare disease launches, the initial approvals have come through letters of medical necessity, letters of medical exception. That was in the second quarter and somewhat in the third quarter. As I've pointed to, we now have almost 80% of covered lives that have planned, written plan coverage for DAYBUE. And as we've seen, almost on a month-by-month basis, we've seen more in the same month approvals, second-month approvals, third-month approvals, over time as these written plans have gone into place. So as I think we said on our last call, by the end of the year, we'd expect most of those policies that are going to be published to happen before the end of the year.

We would expect to see a few more between now and the end of December. But we are pleased with the coverage we already have and the increasing pace at which those enrollment forms are becoming prescriptions. Do you wanna take the second piece, Parag?

Parag Meswani (SVP of Trofinetide Rare Disease Franchise)

Yeah, Amy, repeat the second question, please, if you don't mind. Or Steve, do you wanna repeat that?

Brendan Teehan (COO and Head of Commercial)

I think it was the linearity of the adoption of DAYBUE as a function of sort of what's happening for treatment dynamics in the fourth quarter-

Parag Meswani (SVP of Trofinetide Rare Disease Franchise)

Sure.

Brendan Teehan (COO and Head of Commercial)

- as opposed to a surge.

Parag Meswani (SVP of Trofinetide Rare Disease Franchise)

Yeah, sure. So, you know, at this stage, as Brendan mentioned, you know, in his prepared remarks and in the Q&A as well, through a really effective pre-launch education and connecting closely with the Rett community, with providers, we have led to a step-up in uptake during the first couple of quarters. At this stage, you know, our plan for growth is to really identify physicians and patients that have a smaller number of Rett patients, and patients that aren't having the same degree of frequency, as visits, in the clinics as they had in the first couple of quarters of the year.

So our goal moving forward is to establish a strong foundation that we've had so far in terms of demand, which is a significant breadth and depth of physician experience so far, a high number of patients and families sharing positive experience in the marketplace, and access that has happened much faster than our initial pre-launch expectations. So looking ahead, given this early demand, we're expanding our efforts beyond COE to reach physicians who have fewer RET patients, as well as families that aren't as connected to clinicians or regularly visiting their RET providers on a day-to-day basis.

Operator (participant)

Thank you. We have time for one more question, which comes from the line of Jay Olson with Oppenheimer. You may proceed.

Jay Olson (Managing Director and Senior Analyst of Biotechnology)

Oh, hey, congrats on the quarter, and thank you for taking our question. Based on the impressive DAYBUE launch dynamics so far, could you please share your latest thoughts on the longer-term commercial potential in terms of what peak sales are achievable, and how does the commercial value of the ex-US opportunity compare to the U.S. opportunity? Thank you.

Steve Davis (President and CEO)

Thanks so much for the question, Jay. Mark, you want to take that?

Mark Schneyer (CFO)

Yeah, clearly, Jay, thanks for that. You know, we're very excited about what we have experienced in the launch so far of DAYBUE. As we've said many times, you know, we expect this to be a very, very meaningful product in terms of size in the U.S. It could be similar to pimavanserin, just as a matter of, and higher, but as a matter of kind of just our company policy in this, we don't put out peak sales estimates. The size of the opportunity, you know, outside the U.S., you know, there are, you know, more you know, more Rett patients just by population in Europe than there are in the U.S., little less in Japan than there are in the U.S.

The pricing dynamics in those markets, you know, could be a little different, but we're still working through that, as we advance towards our regulatory efforts. So more to come to discuss in the coming years.

Jay Olson (Managing Director and Senior Analyst of Biotechnology)

Thank you very much.

Operator (participant)

Okay, thank you. This completes our question and answer session. Mr. Davis, please proceed to closing remarks.

Steve Davis (President and CEO)

Great. Thanks much, operator. Thanks again, everyone, for joining us today. We look forward to updating you on our progress next quarter.

Operator (participant)

Thank you again for your participation in today's conference call. This concludes the presentation, and you may now disconnect. Good day!