Earnings Call Transcript - ACAD Q4 2021

Operator, Operator

Good day, ladies and gentlemen, and welcome to ACADIA Pharmaceuticals Fourth Quarter and Full Year 2021 Financial Results Conference Call. My name is Gigi, and I will be your coordinator for today. I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations at ACADIA. Please proceed.

Mark Johnson, Vice President of Investor Relations

Thank you. Good afternoon, and thank you for joining us on today's call to discuss ACADIA's Fourth Quarter and Full Year 2021 Financial Results. Joining me on the call today from ACADIA are Steve Davis, our Chief Executive Officer, who will provide an overview of our 2021 financial performance, a review of our business and our outlook for 2022. Following Steve, Mark Schneyer, our Chief Financial Officer, will then discuss our financial results and guidance. Also joining us today is Brendan Teehan, our Chief Operating Officer, Head of Commercial, who will provide updates on our commercial initiatives. Dr. Serge Stankovic, our President, will then discuss our two new drug applications and our pipeline progress before turning it back to Steve for final remarks and opening up the call for your questions. I would also like to point out that we're using supplementary slides, which are available on the Events and Presentations section of our website. Before we proceed, I would first like to remind you that during our call today, we'll be making a number of 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 a number of risks and uncertainties that may cause actual 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.

Stephen Davis, CEO

Thank you, Mark. Good afternoon, everyone, and thank you for joining us today. Please turn to Slide 5. To deliver on our mission, we are focused on three strategic pillars: First, drive growth of the NUPLAZID franchise where we continue to perform at a high level; second, advance our three late-stage opportunities by submitting applications for new approvals for pimavanserin in Alzheimer's disease psychosis or ADP and for trofinetide in Rett syndrome; and completing enrollment in our negative symptoms of schizophrenia program, also with pimavanserin; and third, develop the next wave of CNS breakthroughs with our early-stage pipeline while continuing to pursue strategic business development opportunities. Starting on Slide 6. For the full year 2021, we achieved net sales of $484.1 million, which represents 10% year-over-year revenue growth. During 2021, we grew both total prescriptions and market share as we continue to outperform the top neurology, Parkinson's, and long-term care drugs. We achieved this despite operating in a disproportionately affected Parkinson's disease market where in-person Parkinson's patient visits remain down approximately 20%, and occupancy rates in long-term care facilities remain down approximately 15% compared to pre-pandemic levels. Our strong performance during this time underscores our ability to grow the brand. As the pandemic conditions normalize and overall PD market dynamics improve, we are poised to accelerate this growth. As we look ahead in 2022, we expect to see improvement in the infection rates of COVID-19 but more importantly, as it relates to the Parkinson's market, we'll be looking for a normalization of staffing turnover and reduction of staffing shortages in both the office space and long-term care settings. We'll also be focused on the rate at which Parkinson's patients are seeing their physicians in person. As Mark will speak to in a minute. For the full year 2022, we expect net sales to be between $510 million and $560 million. What we achieve within this range will be a function of read through from the pandemic conditions, and our ability to continue to outperform the top neurology Parkinson's and long-term care drugs. Now let's turn to our three late-stage opportunities on Slide 7. We recently announced the resubmission of our sNDA for pimavanserin for the treatment of ADP. In addition, we look forward to submitting our NDA for trofinetide for the treatment of Rett syndrome around the middle of this year. Our Alzheimer's disease psychosis resubmission provides additional analyses from two previously conducted clinical studies HARMONY and study 019 to support a proposed indication for the treatment of ADP and is intended to address issues raised in the FDA's complete response letter. As we've previously described, this resubmission gives the FDA an opportunity to fully review our new, additional analyses and through this process gives us an opportunity to make our case that pimavanserin should be the first drug approved for the treatment of ADP. An important contextual point is that in our studies with pimavanserin, we did not observe impairment of cognition or motor function compared to placebo, a very important consideration in this elderly and highly medically compromised population and historical challenge in developing drugs to treat psychosis in Alzheimer's patients. We expect this to be a Class II resubmission, which would mean the FDA will be targeting a six-month review with an action date in the third quarter. Having recently submitted, we are not yet at the point where the FDA would assign an action date. We should reach that point soon, and we'll update you as soon as they do. Regarding our NDA for trofinetide, at the end of last year, we announced positive top-line results from our Phase III Lavender study of trofinetide for the treatment of Rett syndrome. Our NDA submission will be based on the pivotal Lavender study and its co-primary endpoints. In preparing for our NDA submission, we scheduled two meetings with the FDA. We've already met with the FDA to review the overall content and format of the clinical data to be included in our NDA submission. The second meeting scheduled for March will be dedicated to covering similar ground on CMC aspects of the submission. We are planning for an NDA submission around mid-year and expect a priority review with the PDUFA action date in the first quarter of 2023. Moving to our third late-stage opportunity. In our Phase III negative symptoms of schizophrenia program, we have something that's very rare in this space, and that is a positive pivotal study, our ADVANCE-1 study. The negative symptoms of schizophrenia patients suffer from have proved to be the most difficult to treat. The symptoms, which generally revolve around the social withdrawal aspects of the disease versus the hallucination and delusion symptoms have been the largest unmet need in schizophrenia for multiple decades. And today, we still have no FDA-approved treatment for negative symptoms. With one positive pivotal study complete, we're in the process of running a second pivotal study. This is our ADVANCE-2 study. ADVANCE-2 is designed to be virtually identical to our successful ADVANCE-1 study with an important difference. In ADVANCE-1, we observed that at the highest dose tested 34 milligrams the drug effect was markedly higher than the statistically significant and clinically meaningful results of the overall drug-treated group, which included lower doses as well. Therefore, in our ADVANCE-2 study, all patients are receiving the optimal 34-milligram dose. Please turn to our pipeline chart on Slide 8. Our third strategic pillar to grow our business is to develop the next wave of breakthroughs in our early-stage programs. Our early-stage pipeline is highlighted by our ongoing Phase II pain program, evaluating ACP-044 in two studies, one in acute and one in chronic models of pain, with data coming from both studies this year. And we have additional earlier-stage programs highlighted by collaborations with Vanderbilt University and Stoke Therapeutics as well as early-stage internal programs designed to leverage the learnings of pimavanserin to further our franchise and take advantage of indications we might never get to with pimavanserin. Finally, we look forward to continuing to evaluate and execute business development to grow our opportunity set in CNS, further leveraging our strong R&D and commercial capabilities. With that, I will now turn it back over to Mark to discuss our financial performance and guidance.

Mark Schneyer, CFO

Thank you, Steve. Today, I'll discuss our fourth quarter and full year 2021 results and our 2022 financial outlook. Please turn to Slide 10. In the quarter, we recorded $130.8 million in net sales, an increase of approximately 8% compared to $121 million of net sales in Q4 of 2020. This was driven by strong performance of NUPLAZID across channels with year-over-year volume growth. As part of net sales, we observed a gross-to-net adjustment of 20.7% which is up from 18.3% in the fourth quarter of last year. Moving down the P&L. GAAP R&D expenses increased to $67.1 million in the quarter compared to $62.1 million in the fourth quarter of 2020. GAAP SG&A expenses decreased to $105.8 million in the quarter from $120.8 million in the fourth quarter of 2020, which included sales and marketing expenses related to the potential DRP launch. Please turn to Slide 11. For the full year 2021, we recorded $484.1 million in net sales, an increase of 10% compared to $441.8 million of net sales in 2020. This was driven by 3% year-over-year volume growth. The gross-to-net adjustment for the full year was 19.1%. As a reminder, gross to net was higher in 2021 as we observed a higher percentage of 340B volume, though this remains a mid-single-digit percentage of our overall volume. Capital R&D expenses decreased to $239.4 million in 2021 from $319.1 million in 2020. This was primarily due to the typical ebbs and flows of clinical development and PD activity. For example, in 2020, we expensed in R&D a total of $62.8 million in upfront expenses related to the CerSci acquisition and Vanderbilt collaboration. GAAP SG&A expenses increased slightly to $396 million in 2021 from $388.7 million in 2020. We ended the year with $520.7 million in cash and investments on our balance sheet compared to $632 million at year-end 2020. Please turn to Slide 12 for our 2022 financial guidance. For the full year 2022, we are providing net sales guidance for NUPLAZID in Parkinson's disease psychosis of $510 million to $560 million. The midpoint of this range represents a similar level of demand for NUPLAZID as last year. The high end reflects an improvement in PD market dynamics with subsequent increased demand and the low end represents slower demand, similar to levels we experienced in the second half of 2021. Regarding gross to net, we are anticipating an increase to a range of 20% to 22% in 2022 as a result of higher 340B volume mix. At the midpoint of the range, this would be an additional $13 million reduction to net sales year-over-year. As a reminder, we expect gross net to be the highest in the first quarter due to the annual reset of the donut hole manufacturer obligation for Medicare Part D patients. Note if pimavanserin is approved for the treatment of ADP this year, both our revenue and expense guidance ranges will need to be updated. On the expense side for 2022, we expect GAAP R&D expenses to be between $355 million to $375 million, including approximately $25 million in stock-based compensation expense. While our R&D range does not guide for incremental spend for business development transactions, it does include the $60 million related to the upfront expenses associated with the Stoke collaboration that we executed in January. In addition, this year, we will have additional costs associated with trofinetide including manufacturing cost for commercial supply and a regulatory filing milestone payment. We expect GAAP SG&A expense to be between $360 million and $380 million for the full year, including approximately $45 million in stock-based compensation. The midpoint of this range represents an approximate 7% reduction in spend as compared to 2021. There are a few puts and takes encompassed within the range that I'd like to provide further color on. First, we are making investments in preparing for the potential launch of trofinetide in Rett syndrome. Second, we are focused on continuing our relative commercial outperformance in 2022 for NUPLAZID in PDP while efficiently managing our spend as a function of the PD market conditions related to the pandemic. And third, as it relates to the potential launch of NUPLAZID for ADP, most of the prelaunch work was already completed in connection with DRP, so we don't need to make a lot of additional investments prior to the ADP action date. We expect our 2022 year-end cash balance to be approximately $355 million to $405 million based upon our expected range of operational cash flows. As we look ahead, under our current business plan, we expect to turn cash flow positive during 2023. This holds true whether or not pimavanserin for ADP and/or trofinetide for Rett syndrome are approved but is subject to our standard caveats of future business development, one of our pipeline experiences less-than-standard rates of attrition. I'll now turn it over to Brendan, who will discuss our PDP commercial performance and outlook for 2022.

Brendan Teehan, COO, Head of Commercial

Thank you, Mark. Please turn to Slide 14. I'm extremely proud of our team's performance in 2021, where we delivered another year of double-digit percent revenue growth. Our results underscore our team's ability to adapt and find new ways to grow the brand, including our HCP and patient caregiver campaigns, which supported growth in the second half of the year and have positioned us well for continued growth in 2022. In 2021, we continued to outperform branded drugs in the space as NUPLAZID grew both total prescriptions and market share. In the office setting, NUPLAZID's current script levels are up 30% when compared to pre-pandemic levels. This continues to be nearly double the neurology segment branded average growth rate of 17%. During the same timeframe, the top 10 Parkinson's brands were down 7% and carbidopa/levodopa prescriptions were down 3% when under normal circumstances, we would expect them to be up 3% to 4%. This is particularly relevant because carbidopa and levodopa are essential PD motor medications. Let's turn to the long-term care setting. Here, carbidopa and levodopa remain even further down at 11%, a reflection of a significantly lower LTC occupancy rate. The top 15 LTC brands were even further suppressed, down an average of 24%. At the same time, NUPLAZID was actually up 4%. Most importantly, we continue to drive share growth in both the community and LTC settings for NUPLAZID. This tells us that while patient dynamics may be temporarily suppressed, our messaging is resonating with our customers, leading to NUPLAZID being selected as the therapy of choice more often in appropriate PDP patients. We outperformed despite significantly fewer in-person PD patient visits with their physicians and significantly lower occupancy rates in long-term care facilities. As the graphs at the bottom of the slide indicate, these market dynamics continue to persist. In addition, throughout the pandemic, NUPLAZID has maintained very high refill rates, which point to a strong user experience and the fact that refills are not impacted by the same market dynamics. To grow meaningfully, we will need to continue to drive new patient starts and those are most often diagnosed when patients have in-person physician visits or are admitted to a long-term care facility. Most importantly, based on our market research and forecast, we continue to see a significant opportunity to grow our brand for years to come. Beyond PDP, we have two near-term potential commercial opportunities. Let's start with NUPLAZID for the treatment of ADP on Slide 15. As you know, we were previously preparing our commercial teams for a potential NUPLAZID label expansion for the treatment of dementia-related psychosis, of which 70% are ADP patients and the market dynamics are very similar. While the ADP indication is much larger than PD psychosis, this indication will be a line extension of an established brand already on the market since 2016. For NUPLAZID, this means we will leverage and build upon our current commercial foundation and established infrastructure. For example, since its launch, NUPLAZID has generated significant brand awareness. We have a well-established patient support service to help patients and caregivers start and stay on NUPLAZID and will expand that capability for ADP. NUPLAZID enjoys broad formulary access in PDP with a well-recognized value proposition, and we anticipate similar access dynamics for this line extension. And finally, we have strong and experienced field teams in both the community and LTC market segments. Now let's discuss the opportunity with trofinetide for the treatment of Rett syndrome. With strong positive Phase III results in hand, we are now focused on preparing for a highly successful commercial launch. Today, we have developed partnerships with engaged and motivated patient advocacy groups within the Rett community and are working with the Rett Syndrome Centers of Excellence as we work to identify patients who can benefit from trofinetide at launch. We are evaluating opportunities to increase education and genetic testing to further support patient identification. And we will leverage our existing sales force and infrastructure while investing appropriately in further dedicated customer-facing roles for trofinetide where necessary. In summary, we are executing on prelaunch preparedness for both opportunities and look forward to helping patients and caregivers alike. I would now like to turn it over to Serge to provide an R&D update.

Srdjan Stankovic, President

Thank you, Brendan. And good afternoon, everyone. I would like to begin by taking a deeper dive on our two U.S. regulatory submissions this year. Please turn to Slide 17 to discuss the recent resubmission of our sNDA for the treatment of Alzheimer's disease psychosis. We estimate that there are approximately 900,000 ADP patients currently treated in the United States. The vast majority of which are with off-label, multi-receptor antipsychotics, which offer little to no proven efficacy and can accelerate cognitive decline and impact motor function. Today, there are no FDA-approved treatments for ADP. Our resubmission package focuses on additional efficacy analysis from two separate, previously conducted placebo-controlled studies of pimavanserin that included ADP patients. In the HARMONY study, where we observed highly statistically significant and clinically meaningful results in the overall DRP population, we also observed a meaningful benefit in ADP, a prespecified dementia support. As previously reported, the subgroups were not powered to show statistical significance. However, the additional analysis we've conducted show a consistency of effect that strongly support the meaningful benefit observed. Study 019 was designed and powered to evaluate pimavanserin in ADP patients and showed both statistically significant and clinically meaningful results demonstrating the benefit of pimavanserin in ADP. In our resubmission, we will include additional analysis, which support the benefit observed and specifically address the issues the FDA laid out in the Complete Response Letter. Given the high unmet need, the demonstration of benefit and the lack of negative impact on cognition and motor function observed with pimavanserin compared to placebo, we strongly believe that pimavanserin should be approved for the treatment of ADP. We would expect the FDA to notify us soon that this will be a Class 2 resubmission and as such, we expect an action day target in the third quarter. Let's turn to our trofinetide NDA, starting on Slide 18. Rett syndrome is a very serious and rare disorder for which we estimate there are between 6,000 and 9,000 patients in the United States and for which there is no FDA-approved treatment. The core symptoms of Rett that significantly impact the daily life of patients include loss of ability to communicate, both verbally and nonverbally, gait abnormalities and repetitive and relentless hand movements, motor and autonomic impact and serious GI issues, especially constipation. Ultimately, Rett syndrome patients lose their ability to maintain independent functioning on a daily basis and require round-the-clock support. Our positive results from the pivotal Lavender study demonstrated efficacy across multiple core symptoms of Rett syndrome. Trofinetide demonstrated statistically significant separation from placebo and meaningful benefit on the co-primary endpoints, the Rett syndrome behavioral questionnaire, a caregiver assessment tool as well as the clinical global impression of improvement, a physician assessment tool. Importantly, trofinetide showed improvement across all eight domains of the RSBQ. In addition, the study achieved statistical significance versus placebo on its key secondary efficacy outcome, another caregiver assessment focused on the patient's ability to communicate. This has the potential to address a significant challenge for parents and their children whose lack of ability to communicate fully interferes with many aspects of their daily living. Importantly, the efficacy results were consistent across all age groups and severity of disease. Trofinetide has been granted fast track status, orphan drug designation and rare pediatric disease designation, which means it's eligible for priority review and if approved, could be awarded a rare pediatric disease priority review voucher. We recently met with the FDA to review the overall content and format of the clinical data to be included in our NDA submission. We have a dedicated CMC review meeting in March and plan to submit our NDA around mid-year. Now let's discuss our negative symptoms of schizophrenia program on Slide 19. There are over 700,000 patients in the United States who are currently treated for schizophrenia but still have persistent and potentially debilitating negative symptoms such as social withdrawal, lack of emotion and blunted affect, among others, and for which there is no FDA-approved treatment. As part of our advanced program, we have one positive pivotal study already, ADVANCE-1 results for which were published last year in the Lancet Psychiatry. ADVANCE serves as a dose finding study where we clearly observed the most robust results on the primary endpoint in patients receiving 34 milligrams of pimavanserin. Please recall, this is the dose commercially available and recommended for PDP and showed the most robust results in ADP. We are now evaluating only the 34-milligram dose of pimavanserin in our second pivotal study ADVANCE-2. In addition, building on the learnings of our two previous studies in schizophrenia, ADVANCE-2 is being conducted in non-U.S. clinical trial sites. Enrollment is going well and expected to complete by the end of this year, with top-line results available in 2023. Slide 20 highlights our early-stage pipeline opportunities. For acute pain, we have an ongoing Phase II study evaluating ACP-044 for the treatment of postoperative pain following bunionectomy surgery and we expect results around the end of this quarter or early next quarter. And for chronic pain, we have an ongoing Phase II study evaluating ACP-044 for the treatment of pain associated with osteoarthritis that is expected to complete by the end of 2022. Our M1 PAM program that we licensed from Vanderbilt University has a lead compound, ACP-319 that is currently in Phase I multiple ascending dose trial. Another exciting opportunity is our recently executed collaboration with Stoke Therapeutics to pursue multiple RNA-based treatments for severe and rare genetic neurodevelopmental diseases including SYNGAP1 and Rett syndrome. And finally, we have multiple early-stage molecules which are focused on different targets such as analog compounds, which build upon the learnings of pimavanserin. With that, I'll turn it back to Steve for closing remarks.

Stephen Davis, CEO

Thank you, Serge. Please turn to Slide 22. Today, we are executing on our promise to deliver NUPLAZID in patients with PDP while preparing for a potential second indication in ADP. In addition, in the middle of the year, we expect to submit a new drug application for trofinetide for the treatment of Rett syndrome. And we continue to advance our third late-stage opportunity with expected enrollment completion of our pivotal Phase III study in the negative symptoms of schizophrenia with results expected in 2023. And from our early-stage pipeline, we have two ongoing Phase II studies for ACP-044 with results expected this year. In closing, I would like to thank our employees for their accomplishments and their continued commitment and passion as we continue our mission to elevate life. I'll now open up the call for questions.

Operator, Operator

Your first question comes from the line of Neena Bitritto-Garg from Citi.

Neena Bitritto-Garg, Analyst

I was just wondering if you could elaborate a little bit more on the SG&A guidance. And what specifically you're kind of cutting back on there? I know you did have some commentary around kind of reprioritizing spend. But if you could talk a little bit more about that and then how we should assume the SG&A spend kind of ramp if pimavanserin is approved in ADP. I know previously you were talking about maybe adding 250 reps if that number has changed at all. It would be good to know that, too.

Stephen Davis, CEO

Yes. Thanks so much for the question, Neena. Mark, do you want to take these?

Mark Schneyer, CFO

Sure. On the SG&A range, as we mentioned, we have a number of puts and takes, right? The investment in trofinetide. I know you asked a question about kind of PDP. I mean we have a mixture of activities that support it. We don't disclose exactly what we're spending on, but we are evaluating and focusing on the highest return investments. And yes, kind of within this range depending upon how the market dynamics progress over the year, there could be a reduction in overall PDP commercial spend. And as I mentioned in the prepared remarks, from an ADP standpoint, there is limited investment needed prior to our action date. I think we'll reserve kind of guidance for potential increases in expenses and revenue for ADP. If we get a positive approval, we will reflect kind of later in the year how to give guidance as appropriate at that time.

Operator, Operator

Our next question comes from the line of Tazeen Ahmad from Bank of America.

Tazeen Ahmad, Analyst

Can I just ask about the upper end of guidance that you provided for 2022 sales? What would you need to see in terms of the major driver to hit the upper end of guidance? Is it the ability to see more doctors in person, therefore, leading to additional scripts? Or is it that for doctors already prescribing, you need them to prescribe to more patients than they do?

Mark Schneyer, CFO

Steve, I think you're on mute.

Stephen Davis, CEO

Sorry about that. Thank you. Let me answer at a very high level, and then I'll turn it over to Mark. So as we mentioned in our prepared remarks, the range of revenues that you see are really driven by two undercurrents. One is the pandemic conditions and how they normalize as we move through the year. And then the second is our ability to continue to outperform other drugs in the sector. And so we're very confident in the latter and our ability to do that and the investments that we're making on SG&A. And the revenues that we have in our forecast reflect that. But the level of normalization and the rate of normalization in the pandemic, what I mean by that is our ability to engage particularly as it relates to the medical community and the Parkinson's community is something that we'll just have to continue to assess as we go forward. And the precise timing of those things is less clear. So Mark, I think Tazeen's specific questions were about things in particular that may drive the upper end of guidance that would reflect an improvement in pandemic conditions. I'll let you add additional detail and color.

Mark Schneyer, CFO

I think while we have, as always, a variety of assumptions that comprise our range, really the principal assumption underlying the range is what Steve reflected is really the underlying market dynamics. So I think Steve explained it well and just at the higher end of the range, as I mentioned earlier, would reflect an improvement in market conditions from what we've seen last year and recent months.

Tazeen Ahmad, Analyst

Okay. But by market conditions, are you seeing more interactions with physicians?

Mark Schneyer, CFO

I believe there has been an increase in staffing at both long-term care facilities and office settings. There are more in-person patient visits with their doctors, and this trend is continuing because we've seen improvements in our ability to have in-person visits with physicians.

Stephen Davis, CEO

Brendan, do you have anything else to add to that? I think you're on mute.

Brendan Teehan, COO, Head of Commercial

Sorry, thanks. Yes, Tazeen, thanks for the question. I just wanted to add to that. Yes. The biggest driver is patients returning for face-to-face visits increase in LTC census. Both of those are important market dynamics that as the pandemic abates, we'll have a better opportunity for new patient starts than we have today. With that said, as Steve pointed out, we have grown market share throughout 2021, which suggests that our message is absolutely resonating. We are gaining more and more share of first line setting patients. So it's really the opportunity for those patients to show up in the office or for new residents to enter long-term care facilities.

Operator, Operator

Our next question comes from the line of Cory Kasimov from JPMorgan.

Cory Kasimov, Analyst

I wonder if you have any insight from the agency yet as to whether or not you should expect an ADCOM for NUPLAZID in ADP. Is that something you've been communicated to already? Or would you expect to learn about that when you get the FDA response to your resubmission after, I think, 30 days? And just kind of taking a step back, would you look at the opportunity to go in front of an FDA advisory committee as a favorable development for you?

Stephen Davis, CEO

Yes. Thanks so much for the question, Cory. Serge, do you want to take that?

Srdjan Stankovic, President

Yes, Cory. Thanks for the question. In respect to the advisory committee, this is a decision for the FDA and at this time, it's really difficult for us to speculate on whether or not they would request it. It is very unlikely. It's unlikely, I would say that we will learn about that in the 30-day communication when the FDA responds following our submission. But we would anticipate considering a six-month review cycle that fairly soon, we should learn about that. All I can say is in regard to advisory committee, we will be ready to make our case to the FDA advisers as well. We look for every opportunity to make the case of the efficacy and safety of pimavanserin in treatment of Alzheimer's disease psychosis. But we'll just wait for the ultimate decision of the FDA in regard to whether or not they will move toward the advisory committee.

Operator, Operator

Our next question comes from the line of Ritu Baral from Cowen.

Ritu Baral, Analyst

It's on trofinetide for Rett. Have you guys discussed functional unblinding analysis as part of the FDA meeting that you had on the data? Or was it submitted as part of the statistical analysis plan? And then further, can you just go through what the gating items are aside from the CMC link for that submission?

Stephen Davis, CEO

Thanks for the questions, Ritu, Serge?

Srdjan Stankovic, President

Yes, thank you, Ritu. In our briefing documents for the meetings, we provided detailed information on the results from our pivotal trial, including complete efficacy and safety information to the FDA to prepare for the meeting. Regarding your question about the discussion of potential functional unblinding, the answer is no. That question was not raised during the meetings or our communications with the FDA, so we did not discuss it.

Stephen Davis, CEO

Just to recap the analysis that we've done on this point. Sorry, Ritu.

Ritu Baral, Analyst

Go ahead.

Srdjan Stankovic, President

We conducted a thorough analysis, examining the efficacy data for patients both with and without diarrhea for each of the co-primary outcome measures. We also reviewed scatter plots and responder analysis. Our detailed assessment consistently indicates that there is no sign of bias in the evaluation of efficacy related to diarrhea as an adverse event. However, I want to emphasize that this question was not raised, and there was no discussion regarding it during the meetings.

Ritu Baral, Analyst

Got it. Were those analyses prespecified and submitted as part of the statistical analysis plan?

Srdjan Stankovic, President

Those analyses will be included in our NDA submission. However, the statistical analysis plan is always submitted before unblinding the data. Therefore, these analyses were not included in the statistical analysis plan because there wasn't any information available that would have allowed for anticipating those analyses.

Operator, Operator

Our next question comes from the line of Jeff Hung from Morgan Stanley.

Jeff Hung, Analyst

For your collaboration with Stoke on Rett, can you just remind us of how that may be differentiated from trofinetide and how different might the patient population be than those that you could treat with trofinetide?

Stephen Davis, CEO

Sure. Serge, do you want to take that question?

Srdjan Stankovic, President

The Stoke technology addresses around one-third of the patients who show signs of genetic hypermorphism. This means it does not cover the entire patient population, but rather about 35% to potentially 40% of patients overall. The technology differs in that the intervention leads to an increase in the protein related to a gene that is underperforming. This represents a completely different approach compared to trofinetide.

Stephen Davis, CEO

I would like to add a couple of points. We have rights to trofinetide in North America, and with our collaboration with Stoke, we hold worldwide rights for that program. The collaborative approach with Stoke offers greater potential for disease modification, which could lead to a more significant impact. We believe that this program is a valuable addition to the portfolio we are building around trofinetide.

Operator, Operator

Our next question comes from the line of Marc Goodman from SVB Leerink.

Marc Goodman, Analyst

Yes, Serge, I was wondering if you could talk about 044 and the upcoming data in acute pain. What are we going to see kind of what's the bar for you to move forward and get excited about the product? And then just talk about whether the mechanism works both in acute and chronic in the same way such that the first study would give us a good sense of how the second study is going to report out later this year.

Srdjan Stankovic, President

Thanks, Mark. The bunionectomy study is the first Phase II study assessing ACP-044 for managing postoperative pain after bunionectomy. It’s an acute model where we randomized, double-blinded, and placebo-controlled around 240 patients, ensuring it's appropriately powered. The aim is to evaluate the safety and efficacy of ACP-044 in the specific patient group and to examine its effectiveness against placebo for pain control. We would consider the study successful if we observe a statistically significant difference from placebo in pain control, coupled with an acceptable safety and tolerability profile for the drug. In relation to your question, we are also conducting a chronic osteoarthritis study, which will take longer to finish, so we expect results next year. Based on preclinical animal models, the drug was effective in both acute and chronic pain models. Therefore, we anticipate that success in one model may indicate possible success in the other. However, I want to caution that pain studies are highly sensitive to placebo effects and are challenging to conduct. Thus, we should be cautious when interpreting and applying results from one model to another.

Operator, Operator

Our next question comes from the line of Jay Olson from Oppenheimer.

Matthew Nirenberg, Analyst

This is Matt on for Jay. The first question we had was just on your M1 PAM program, just in terms of data timelines. And as a corollary, if you would ever plan or imagine doing a combination trial of your M1 PAM with pimavanserin. If you could imagine any combination of synergies, there that would be interesting to hear about and also in terms of what indications could make sense. And then separately, we were just curious about any physician feedback you might have gotten so far after the Phase III Lavender results for trofinetide and how you're currently thinking about the market opportunity in terms of driving diagnosis rates. That would be really helpful.

Stephen Davis, CEO

Okay. I have a few questions to address. I'll start by responding regarding the combination and then turn it over to Serge for more details on the M1 PAM payment program, followed by Brendan about trofinetide. When it comes to a combination, I want to emphasize that for competitive reasons, we don't discuss the opportunities we are exploring, especially those in the early stages of our pipeline or those we may consider pursuing. That said, we find the potential applications for 319 to be very interesting. We've gained valuable insights from the development and commercialization of pimavanserin that we believe we can leverage with new molecules, including future combinations. Serge, would you like to elaborate on 319? Brendan, could you provide insights on trofinetide?

Srdjan Stankovic, President

Yes. Just as a reminder, Matt, our ACP-319 M1 PAM program is for the potential treatment of cognition, cognitive impairment in Alzheimer's disease and negative symptoms and cognitive impairment in schizophrenia. As we announced, we initiated a multiple ascending dose Phase I study last year. It's currently ongoing. It's a multiphase study. And we look forward to providing additional updates later this year on the study. Even in this early development Phase I studies, we will be evaluating target engagement to try to better understand whether there are benefits and what may be the potential for our further development. But as I said, we look forward to updating you later this year on progressing with 319. And just not to forget to address your question on the feedback that we are receiving on the results from the Lavender study. I can say that we are quite pleased with the level of enthusiasm and excitement that we are seeing with treating physicians and experts out there in regard to the data. I mean it's, to some extent, understandable, considering that so far, there haven't been successful late-stage programs in Rett syndrome, for treatment of symptoms of Rett syndrome. So from that perspective, there is quite a big excitement not only in the medical community, in the scientific community but also in the parents and caregivers and community. So bottom line, we are very enthusiastic to see the level of excitement and enthusiasm across and look forward to the NDA and approval.

Brendan Teehan, COO, Head of Commercial

And I just want to echo, Serge's comments. The Rett treatment community has given us very encouraging feedback on what they've seen of the Lavender results. But to address your question specifically, Matt, around Rett diagnosis. As with a number of rare pediatric diseases, the pursuit of a diagnosis has increased pretty dramatically over time. There is already a high diagnosis rate for Rett. So we have access to databases that will show us physicians and numbers of patients that they have that are already diagnosed with Rett. There's also been a significant increase in genetic testing in recent years. And we, as an organization, will work diligently and are pursuing a number of avenues to educate on MECP2 testing and then looking at potential partnerships to have confirmatory MECP2 testing for suspect Rett patients post-launch.

Operator, Operator

Our next question comes from the line of Ami Fadia from Needham.

Ami Fadia, Analyst

I had two questions. Firstly, just with regards to the PDP indication for NUPLAZID. Has something changed structurally with regards to the market because of which we may not see a recovery in patient inflow or patients being admitted to long-term care for quite some time? Can you sort of comment on that? And then just separately on the ADP indication, should you get approval, can you talk to the market opportunity there? And your expectation for being able to tap into that market relative to PDP?

Stephen Davis, CEO

Brendan, do you want to start?

Brendan Teehan, COO, Head of Commercial

I appreciate your questions, Ami. Regarding PDP, I don't believe there have been significant structural changes in the market. With the decline in Omicron trends, we anticipate an increase in in-person PDP patient visits. Some of our leading physicians have already noted that patients who were not visiting in December are beginning to return in the first quarter. Therefore, as pandemic-related challenges diminish, we expect improvements. In long-term care, as you mentioned, the census rate has been low. Steve addressed staffing challenges in long-term care facilities. We are witnessing gradual improvements in staffing, which allows for new residents to become available to us. These changes are temporary adjustments we need to navigate, but we remain optimistic that as the pandemic conditions improve, these areas will also begin to recover. Concerning ADP, this presents a significant opportunity for us, as it has approximately seven times the number of available patients compared to PDP. Currently, we have reported around 900,000 patients being treated. This is an extension of an existing and well-established brand, NUPLAZID, which was launched in 2016. The reasons for treatment are quite similar to those for PDP, and there is overlap among the providers treating both conditions. We will certainly broaden our outreach to target additional psychiatrists and PCPs for ADP. This opportunity allows us to be the first to market with a product designed specifically to treat ADP.

Stephen Davis, CEO

I want to add a quick thought to Brendan's point about PDP. The question was whether we are observing a structural change in the market. As Brendan indicated, the main leading indicator impacting new patient starts is staffing levels. In all other areas of our franchise, we are still experiencing very strong results. Our refill rates remain very high and have not fluctuated. In fact, our conversion rates when prescriptions are written have increased during this period. However, the pandemic has had a significant effect on staffing rates and on Parkinson's patients' ability to see their doctors in person, which has had a greater impact on initiating new patients. Therefore, as conditions normalize and these factors shift, we anticipate an increased opportunity for starting new patients. Additionally, we have continued to gain market share during this time. So, as these conditions improve, we expect substantial growth rates.

Ami Fadia, Analyst

If I could follow up, it seems that you've assumed comparable volume to last year in your midpoint guidance. Should I consider that approach conservative? As trends develop, will you reassess that assumption? Is that the way I should interpret it, or is there something else that has influenced your decision to present guidance indicating flat volume compared to last year?

Stephen Davis, CEO

Mark, do you want to respond to that?

Mark Schneyer, CFO

Yes. Just to clarify, the midpoint of the range indicates similar volume growth compared to last year, rather than flat volume. There is underlying growth, although it is not as high as we have experienced in the past, and this is largely due to the ongoing pandemic. The higher end of the range suggests a recovery from the pandemic, moving towards higher growth, which we hope will continue over the long term. We're currently in the third year of the pandemic, and I believe we are improving our forecasting abilities. I would not label our approach as conservative, but rather, I would express confidence in the range provided. The pandemic is still a factor influencing this projection, but we anticipate exiting this situation in the near future, allowing us to focus on further investment and growth in the brand.

Stephen Davis, CEO

And Mark spoke to the midpoint of the range and the upper end. Just for the sake of completeness, of course, when we provide a guidance range, we model a number of scenarios. At the low end of the range, we were reflecting the recognition that it's possible that we're going to have another variant besides Omicron or what, it will be Omicron 2. But there are other things that we just can't predict today that could impact us. And at the lower end of the range, you do see flat volume there. That's not our expectation. Our expectation is as infection rates subside, most importantly, as staffing stabilizes, as Parkinson's patients get more comfortable coming to their physicians in person that will get lift from that. The timing of those changes and the magnitude of them, directly correlate to the scenarios that we've modeled.

Operator, Operator

Our next question comes from Paul Matteis from Stifel.

Alexander Thompson, Analyst

This is Alex on for Paul. Just one question on the ADVANCE-2 study. I was wondering if you could comment on impacts from sites in Ukraine and Russia as it relates to data integrity as well as potential timing of the study.

Stephen Davis, CEO

Sure. Serge, do you want to take that?

Srdjan Stankovic, President

Yes. ADVANCE-2 is a multinational study taking place in 12 countries across various regions including Western Europe, Eastern Europe, and South America. While there may be some localized effects due to the current geopolitical situation in Russia and Ukraine, we anticipate that no single country or region will significantly affect the overall recruitment or execution of the study. Throughout the pandemic, we made several adaptations for remote data collection and interruptions, and we have mechanisms in place to manage these types of situations. I also want to express my deep concern for the Ukrainian people during this unprovoked attack. However, regarding our trial, we do not foresee any dramatic impacts.

Operator, Operator

Our next question comes from the line of Gregory Renza from RBC Capital Markets.

Gregory Renza, Analyst

Thanks for the update. Maybe just a quick one, Stephen, in the event that I missed, and I'm just curious if you could comment just a bit about what you're seeing in this current quarter with nearly two months down. Just as far as that recovery is concerned. And while I certainly appreciate the general comments on the full year, I'm just interested in some of your thoughts on that recovery and some of those market dynamics for NUPLAZID in PDP as we've come out of the gate not just with 2021 but exiting January and also exiting February to that extent.

Stephen Davis, CEO

Yes. Thanks much, Greg. So I'll just need to start by saying we don't guide quarter-to-quarter. And so the guidance we gave for the year today reflects very up-to-date information in terms of what we're seeing in the marketplace. And the thing that I would like to stress is the factors that we believe are responsible for us outperforming a basket of top neurology, top Parkinson's, top LTC drugs, continue to be very much at play. So we're continuing to see strong performance on those elements. We continue to see very strong performance in terms of our refill rates, our conversion rates, et cetera. And so as we move forward in the year, we're at a point right now where we're just now kind of coming out as a society, kind of coming out the fears of the Omicron wave. We don't know what the impact will be from a reduction of mask requirements and just the way we behave as a society. But I would just simply say that as it relates to our business and specifically around PDP, we've tried to cover the range of outcomes for the year. And everything we've seen right up to today is consistent with the scenarios reflected in the scenarios that we've run. And again, the two underlying undercurrents that will determine where we fall in this range are both our ability to continue to outperform drugs in the sector. We're highly confident of that. And then just precisely, the precise timing, magnitude of normalization of pandemic. And for that, I think that we're as well informed as anyone can be, particularly as it relates to the impacts on the Parkinson's community. But we do take a little bit of time to see this play out through the year.

Operator, Operator

Our next question comes from Jason Butler from JMP Securities.

Jason Butler, Analyst

Just wondering if you can speak to the commercial prep work, you'll be doing in Rett this year. Obviously, I assume that the infrastructure outbuild will mainly be towards the end of the year and into next. But from a medical education perspective, just can you walk us through the work you're going to be doing to get the market ready for the drug?

Stephen Davis, CEO

Sure. Brendan, do you want to start?

Brendan Teehan, COO, Head of Commercial

My humble apologies, Jason, thanks again for the question. Yes, obviously, we're very excited about the trofinetide opportunity. And we have been preparing even as the Lavender study was ongoing in Phase III for a favorable result. The initial work, obviously, we want to work with the payer community to make sure that they're aware of the burden of illness, understand the unmet medical need and the size of the patient population, roughly 6,000 to 9,000 patients. We also have developed over time strong relationships with the foundations that support patients, caregivers, and the health care community, which has helped us to understand where we're going to find our Rett patients and the volumes of patients that we're going to want to support. And then broadly, another area that we'll focus on are our white glove support services to be prepared by the time of launch, to support families, not only getting started on trofinetide, but to have a successful clinical experience, all of the support that they need from a clinical perspective as well as prior authorization assistance with co-pay and so on. So those are probably the principal areas where we'll focus as they relate to the product. For the disease state, obviously, this is a tightly knit community. There's a high level of awareness of Rett syndrome. We will work with the community to make sure that where necessary confirmatory MECP2 tests will also be available for suspected patients with Rett at any of their HCPs.

Stephen Davis, CEO

Mr. Davis, please proceed to closing remarks. Thank you, operator, and thanks to each of you for joining today. We appreciate your time and attention and support, and we look forward to updating you as we go forward.

Operator, Operator

Thank you for your participation in today's conference call. This concludes the presentation. You may now disconnect.