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spk09: 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. At this time, all participants are in listen-only mode. We will be facilitating a question and answer session toward the end of today's call. If at any time during the call you require assistance, please press star followed by zero, and the coordinator will be happy to assist you. I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations at Acadia. Please proceed.
spk17: 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 Schneier, our Chief Financial Officer, will then discuss our financial results and guidance. Also joining us today is Brendan Thien, our Chief Operating Officer, Head of Commercial, who will provide updates on our commercial initiatives. Dr. Serge Stankovich, 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 supplement 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. Your caution 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.
spk03: Thank you, Mark. Good afternoon, everyone, and thank you for joining us today. Please turn to slide five. To deliver on our mission, we are focused on three strategic pillars. First, drive growth of new clients and franchise where we continue to perform at a high level. Second, advance our three late-stage opportunities by submitting applications for new approvals for Pimivanserin in Alzheimer's disease psychosis, or ADP, and for terpenetide in Rett syndrome, and completing enrollment in our Negative Symptoms of Schizophrenia program, also with Pimivanserin. 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 six, For the full year of 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 continued 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 remained 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 will 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 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 seven. We recently announced the resubmission of our SNDA for Pimivanser for the treatment of ADP. In addition, we look forward to submitting our NDA for terpenetide 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 Pimivanserin should be the first drug approved for the treatment of ADP. An important contextual point is that in our studies with Pimivanserin, 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 a 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 terfenetide, at the end of last year, we announced positive top-line results from our Phase III lavender study of terfenetide 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're planning for an NDA submission around mid-year and expect a priority review with a BDUFA 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 One study. The negative symptoms that 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 hallucinations 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 Advanced 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 Pima-Vancerin to further our franchise and take advantage of indications we might never get to with Pima-Vancerin. 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 the mic over to Mark to discuss our financial performance and guidance.
spk02: 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 New Plaza across channels with year-over-year volume growth. As part of net sales, we observed a gross 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. GAAP 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 BD activity. For example, in 2020, we expensed in R&D a total of $62.8 million in upfront expenses related to the SIRSI 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 New Plaza and Parkinson's disease psychosis of $510 to $560 million. The midpoint of this range represents a similar level of demand for New Plaza as last year. The high end reflects an improvement in PD market dynamics with subsequent increased demand. And the low end represents lower demand, similar to levels we experienced in the second half of 2021. Regarding gross 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 PIM of answering 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 and $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 tropinotide, including manufacturing costs for commercial supplies, and a regulatory filing milestone payment to NERD. We expect GAAP SGA expense to be between $360 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 Trifentide and Rett Syndrome. Second, we are focused on continuing our relative commercial outperformance in 2022 for New Closet and 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 New Closet for ADP, most of the pre-launch 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 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 PIM of answering for ADP and or tropinotide for Rett syndrome are approved, but is subject to our standard caveats of future business development or if 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.
spk16: Thank you, Mark. Please turn to slide 14. I am 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 space setting, Nuplazid 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 scripts 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, New Placid was actually up 4%. Most importantly, we continue to drive share growth in both the community and LTC settings for New Placid. This tells us that while patient dynamics may be temporarily suppressed, our messaging is resonating with our customers, leading to New Plaza 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, New Plaza 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 forecasts, 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 Nuplasid for the treatment of ADP on slide 15. As you know, we were previously preparing our commercial teams for a potential Nuplasid 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 New Placid, this means we will leverage and build upon our current commercial foundation and established infrastructure. For example, since its launch, New Placid has generated significant brand awareness. We have a well-established patient support service to help patients and caregivers start and stay on New Placid and will expand that capability for ADP. New Plaza enjoys broad formulary access and 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 Trophinatide for the treatment of Rett syndrome. With strong positive phase three 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 Trifinitide where necessary. In summary, we are executing on pre-launch 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.
spk04: Thank you, Brandon. And good afternoon, everyone. I would like to begin by taking a deeper dive on our two US 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 pre-specified dementia subgroup. 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 analyses 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 II resubmission, and as such, we expect an action-day target in the third quarter. Let's turn to our trophinotide 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 RAT 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, RAD syndrome patients lose their ability to maintain independent functioning on a daily basis and require around-the-clock support. Our positive results from the Pivotal Lavender Study demonstrated efficacy across multiple core symptoms of RAD syndrome. Trophinatide 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, tropinotide 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. Trophinatide 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 MDA 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 ADVANCE program, we have one positive pivotal study already, ADVANCE-1, results for which were published last year in the Lancet Psychiatry. ADVANCE served as a dose finding study where we clearly observed the most robust results on the primary endpoint in patients receiving 34 milligram 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-US 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 two study evaluating HCPO44 for the treatment of postoperative pain following banyonectomy surgery, and we expect results around the end of this quarter or early next quarter. And for chronic pain, we have an ongoing phase two study evaluating HCPO44 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 ACP319 that is currently in phase one 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 Pimavancer. With that, I'll turn it back to Steve for closing remarks.
spk03: Thank you, Serge. Please turn to slide 22. Today, we are executing on our promise to deliver new plans into 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 three study in the negative symptoms of schizophrenia with results expected in 2023. And from our early stage pipeline, we have two ongoing phase two studies for ACP044 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?
spk09: Ladies and gentlemen, if you wish to ask a question, please press star followed by 1 on your touchtone telephone. If your question has been answered or you wish to withdraw your question, press the pound key. Please limit yourself to one question. I repeat, please limit yourself to one question. Press star 1 to begin. Please stand by for your first question. Your first question comes from the line of Nina Vitrido-Garg from Citi. Your line is now open.
spk06: Hey, guys. Thanks for taking the question. 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 could ramp if PEMA 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 great to know that too. Thanks.
spk03: Yeah, thanks much for the question, Nina.
spk02: Mark, do you want to take these? Sure. On the SD&A range, as we mentioned, we have a number of puts and takes. We're into investment in tropinotide. I know you asked a question about 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, you know, 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, you know, if we get a positive approval, and we'll reflect kind of later in the year how to give guidance as appropriate at that time.
spk09: Got it. Thank you. Thank you. Our next question comes from the line of Tazeen Ahmed from Bank of America. Your line is now open.
spk08: Hi, guys. Good afternoon, and thanks for taking my question. Can I just ask about the upper end of guidance that you've 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, you know, for doctors already prescribing, you need them to prescribe to more patients than they do? Thanks.
spk03: Steve, I think you're on mute. 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. 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 as a society, and 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 Dazeem's specific questions are about things in particular that may drive that upper end of the pandemic that, or excuse me, the upper end of our guidance that would reflect an improvement in pandemic conditions. I'll let you add additional detail in color.
spk02: I think, you know, while we have, as always, a variety of of assumption that comprise our range, really the principle assumption underlying the range is what Steve reflected is really the underlying market dynamics. So I think Steve explained it well, and it, you know, just at the higher end of the range, as I mentioned earlier, would reflect an improvement in market conditions from what we've seen, you know, last year and recently.
spk08: Okay, but by market conditions, are you saying more interactions with physicians?
spk02: I think it's staffing, right, at both long-term care facilities and in office settings, more in-person patient visits with their doctors, and a continuation because we've seen improvement recently in our ability to visit physicians in person. Brendan, do you have anything else to add to that?
spk16: Brendan, I think you're on mute. Sorry, thanks. Yes. Tazin, thanks for the question. I just wanted to add to that. Yeah, 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.
spk08: Okay, that's helpful. Thank you.
spk09: Thank you. Our next question comes from the line of Corey Casimo from JP Morgan. Your line is now open.
spk14: Hey, good afternoon, guys. Thanks for taking the question. I wonder if you have any insight from the agency yet as to whether or not you should expect an adcom for New Plaza in ADP. Is that Is that something you would have 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? Thank you.
spk03: Yeah, thanks so much for the question, Corey. Serge, you want to take that? Serge, you're on mute.
spk04: Yes, Corey, thanks for the question. In respect to the advisory committee, this is a decision for the FDA. 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 returned following our submission. But, you know, we would anticipate considering a six-month review cycle that fairly soon we should learn about that. You know, all I can say is in regard to advisory committee, we will be ready to make our case to the FDA advisors as well. We look for every opportunity to make the case of the efficacy and safety of primavanserin in treatment of Alzheimer's disease psychosis. But, you know, we'll just wait for the ultimately decision of FDA in regard to whether or not they will move toward the advisory committee.
spk14: Okay. Thank you.
spk09: Thank you. Our next question comes from the line of Ritu Baral from Cowen. Your line is now open.
spk07: Hi, guys. Thanks for taking the question. It's on trofenetide for RET. Have you guys discussed functional unblinding analyses as part of the FDA meetings? 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 that PMC meeting, for that submission? Thanks.
spk03: Thanks for the question, 3-2. Serge?
spk04: Yes, thanks, 3-2. As a part of our briefing documents for the meetings, we have submitted a detailed information on the results from our pivotal trial and from the results of the trial. So a complete and full both efficacy and safety information was available to the FDA in preparation for the meeting. To your question whether this potential functional unblinding was discussed, the answer is no. That question was not raised in the meetings and contacts that we had with the FDA, so we did not discuss that at all.
spk03: Do you want to just recap the analyses that we've done on this one? Sorry, Ricky.
spk08: Go ahead.
spk04: I'm sorry, you were both speaking.
spk03: Maybe you could just give a very high-level recap of the analysis that we've done on that point.
spk04: Oh, yes. I mean, you know, we did a very detailed analysis, both evaluating the efficacy data for patients with and without diarrhea on either of the co-primary outcome measures. We also looked at the scatter plots. We looked at the responder analysis. So we did look, we did perform very detailed analysis and all of them point in the same consistent conclusion that there is no indication of any bias in terms of the assessment of efficacy in regard to diarrhea as an adverse event. But as I said, that question was not raised and there was not discussion on that question at all in the meetings.
spk07: Got it. Were those analysis, Serge, were those analysis pre-specified and submitted as part of the statistical analysis plan?
spk04: Those analysis will be part of our submission, NDA submission, but obviously statistical analysis plan is always submitted prior. to unblinding the data. So there wasn't, these analysis were not part of the statistical analysis plan because there wasn't any information or based on which you could anticipate those analysis.
spk09: Got it. Thank you. Thank you. Our next question comes from the line of Jeff Hong from Morgan Stanley. Your line is now open.
spk13: Hey, thanks for taking the question. For your collaboration with Stoke and Rett, can you just remind us of how that may be differentiated from Trophenotide and how different might the patient population be than those that you could treat with Trophenotide?
spk03: Sure. Serge, you want to take that question?
spk04: Yes. Stoke technology addresses about one-third of the patients that display genetic hypomorphism. So that's not the entirety of the population, but rather, as I said, about 35 to potentially 40% of the overall population of the patients. And the difference in technology is that based on this intervention, the increase in the protein is actually on the gene that is performing suboptimally. So from that perspective, it's a completely different approach than what in general is approached with terfenotype.
spk03: I think maybe just to add a couple of annotations there. One is with true phenotype wave rights to North America and under the Stoke Collaboration, our rights are worldwide in that program. And then the short version is with the approach that we're taking in collaboration with Stoke, there's a greater potential for disease modification. So potential for an even greater or more profound effect with that type of approach. So we think that program is a very, very nice complement to the franchise that we're building around for phenotype. Thank you.
spk09: Thank you. Our next question comes from the line of Mark Goodman from SVB Layering. Your line is now open.
spk11: 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, you know, how the second study is going to report out later this year. Thanks.
spk04: Yes, thanks, Mark. This is, you know, the bonyonectomy study is a first phase two study evaluating ACP044 for treatment of post-operative pain following bonyonectomy. So it's an acute model. The study, just as a reminder, is a randomized double-blind placebo-controlled, enrolled about 240 patients, so it's appropriately powered. But the objective of this study is really to evaluate safety and efficacy of ACP-044 in the targeted patient population and to evaluate efficacy compared to placebo in pain control in analgesia. And from that perspective, we would consider success of the study if we have a statistically significant separation from placebo in terms of the pain control and have acceptable safety and tolerability profile for the drug. Related to your question, we are doing the chronic model, osteoarthritis study. That study will take a little longer to complete, so results will be sometimes next year. But, you know, obviously the mechanism per se, theoretically, but also on the basis of the preclinical animal models, the drug was active, the molecule was active both in control of acute and chronic models of pain. And from that perspective, our anticipation would be that success in one model should indicate potential success in the other model. I will remind everybody the pain studies are notoriously sensitive to placebo response. They are difficult to conduct, and from that perspective, I think that read-through is not automatic, and we should be always very careful in interpreting and translating the results of one model into another model.
spk09: Thank you. Our next question comes from the line of Jay Olson from Oppenheimer. Your line is now open.
spk10: Oh, hey, this is Matt on for Jay. Thanks for taking our questions. The first question we had was just on your M1PAM program, just in terms of data timelines. And as a corollary, if you would ever plan or imagine doing a combination trial of your M1PAM with Pimavancerin, If you could imagine any combination 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. Thank you.
spk03: Okay. I've got a few questions in there. I'm going to start with an answer on the combination, and then I'll turn it over to Serge for further color on the M1 PAM program, and then Brendan on tryptophan. So in relation to the combination, I'll just simply say for competitive reasons, we don't talk a lot about opportunities we're interested in in terms of of additional things we're doing that are early in the pipeline or things that we might have an interest in pursuing. So I'll just simply say that, you know, the potential applications for 319 we find very interesting. And there are things that we've learned through the development and commercialization of PIM of Answering that we think give us insights to further leverage with new molecules, including combinations, going forward. Serge, you want to speak more to 319, and then Brendan, you want to take the truffin attack? Yeah.
spk04: Just as a reminder, Matt, our ACP390 M1 PEN program is for the potential treatment of cognition, cognitive impairment in Alzheimer's disease and negative symptoms and cognitive impairment in schizophrenia. We, as we announced, we initiated multiple ascending dose phase one study last year. It's currently ongoing. It's a multi-phase study and we look forward to providing additional updates later this year on the study. Even in these early development phase one studies, we will be evaluating target engagement to try to better understand where are the 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, you know, it's to some extent understandable considering that so far there haven't been successful late stage programs with in rat syndrome for treatment of symptoms of rat syndrome. So from that perspective, there is quite a bit 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 approvals.
spk16: Thanks, Serge. And I just want to echo Serge's comments. The RET 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 RET diagnoses, 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 RET, so we have access to databases that will show us physicians and numbers of patients that they have that are already diagnosed with RET. 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 MEK P2 testing and then looking at potential partnerships to have confirmatory MEK P2 testing for suspected RET patients post-launch.
spk10: Okay, got it. Extremely helpful. Appreciate all the input.
spk09: Sure. Thank you. Our next question comes from the line of Ami Fadia from Needham. Your line is now open.
spk05: Hi. Thanks for taking my question. I had two questions. Firstly, just with regards to the PDP indication for new closets, has something changed structurally with regards to the market because of which we may not see recovery and 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, you know, being able to tap into that market relative to PDP? Thanks.
spk03: Brendan, you want to start? I'll add color. You can unmute, Brendan.
spk16: My apologies. Ami, thank you so much for both questions. In PDP, no. I don't think that there's anything fundamentally restructured around PDP as a market. With the abating Omicron trends, we would expect that in-person PDP patient visits will improve. We've already seen from some of our top physicians that type of dynamic has taken place. Patients that we're not seeing in December, they are beginning to see more readily in the first quarter. So I think there are pandemic-related headwinds that as those abate will improve for us. in long-term care, as you had suggested, the census rate has been suppressed. Steve spoke to staffing challenges in long-term care facilities. Again, in this environment, we're seeing selective improvements where staffing is improving. When staffing improves, new residents become potentially available to us. So, again, I would call these temporal types of changes for us to adapt to in the near term. but we are hopeful that as pandemic conditions abate, so will these begin to return as well. Your second question was around ADP. This is a tremendous opportunity for us. It has about seven times the number of addressable patients that we have in PDP. We've quoted a number of about 900,000 patients treated today. This is a line extension for an already existing and very well-known brand in New Plaza launched back in 2016. The core reasons to treat are very similar as they are for PDP, and there's an overlap in the types of treaters that are addressing ADP that also have treated PDP. We will expand, obviously, to address a broader audience of psychiatrists and psych-like PCPs that will also address ADP, but this is an opportunity for us to be first to market by a significant margin with a product that would be the first to treat ADP.
spk03: Just add one quick thought to Brendan's point on PDP. So the question was, do we see any evidence of a structural change in the market? As Brendan mentioned, The impact that we're seeing, the principal leading indicator, it's multifaceted, but the principal leading indicator is not infection rates, but it's staffing. It's staffing both in long-term care as well as in office-based settings, both shortages of staffing as well as significant staffing turnover. And so in addition to particularly in long-term care where occupants' rates are just down, the staffing turnover both have an impact, on new patient stars. In all other aspects of the franchise, we continue to see very, very solid results. Our refill rates have not wavered, so we continue to see very high refill rates. Our conversion rates, when scripts are written, quite frankly, climbed during this timeframe. But the impact of the pandemic, particularly as it relates to staffing rates and as it relates to Parkinson's patients seeing their physician in person, have more of an impact on starting new patients. And so as we, that's why we say as we see conditions normalize and those dynamics shift, we'll see a increased opportunity to start new patients. And as Brenda mentioned, we continue to grow share during this time frame. So as these conditions normalize, we expect that they'll get significantly after our growth rates.
spk05: So if I could just sort of follow up. I mean, it seems that you've resumed a comparable volume to last in your guidance at the midpoint of your guidance. Is that sort of conservative? And as you see the trends evolve, you know, you would sort of review that. Is that how I should think about it? Or is it something else you've seen, you know, which has sort of guided you to think about a – you know, because of which you're sort of giving a guidance range where it's sort of a flat volume versus loss.
spk03: Mark, do you want to respond to that?
spk02: Yeah. So just to clarify, I guess the midpoint of the gain is similar volume growth to last year, not flat volume over last year. So there is underlying growth, just not, you know, as high as we've seen in the past. And that is, you know, as we live through, you know, still living through the pandemic. And then the higher end of the range is coming out of the pandemic and getting back towards, you know, higher growth, and hopefully over the long term, that trajectory and above. So I think that's kind of where we stand now. I wouldn't, you know, I would just say, listen, we're, you know, it's in the third year of the pandemic. I think we're getting better at forecasting I wouldn't use the word conservative. I would just say we have confidence in the range. We still are living in a pandemic, so that is influencing this range. But we hope and expect to exit that in the near term and then continue on with investment and growth in the brand.
spk03: And Mark spoke to the midpoint of the range and the upper end. Just for the sake of completeness, of course, when we – Provided guidance range, we model a number of scenarios. At the lower end of the range, we're reflecting the recognition that it's possible that we're going to have another variant besides Omicron, or it'll 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 see 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.
spk09: That's very helpful. Thank you. Ladies and gentlemen, if you wish to ask a question, please press star followed by one on your touchtone telephone. If your question has been answered or you wish to withdraw your question, press the pound key. Please limit yourself to one question. I repeat, please limit yourself to one question. Our next question comes from the line of Paul Matias from Stiefel. Your line is now open.
spk01: Hey, thanks for taking our question. This is Alex. I'm for Paul. Just one question on the Advanced 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? Thanks.
spk00: Sure.
spk04: Serge, you want to take that? Yeah. Let me just remind you first that ADVANCE-2 is a multinational study and is being conducted in 12 countries across multiple regions, Western Europe, Eastern Europe, and South America. So from the perspective of impact of the current geopolitical situation in Russia and Ukraine, I think that although there will be some impact locally, we certainly expect that considering the setup of the study that no single country or geography would have a prevailing impact on the overall recruitment or conduct of the study. In regard to the data, we have, through the COVID pandemic, made a number of adaptations in terms of the remote data collection and interruptions in the programs So we have in place mechanisms to deal with this sort of situation as well. Having said all of this, I do also want to express a grave concern for the Ukrainian people and, you know, the suffering that they're going through with this unprovoked attack. But, you know, as far as our, and I wish that the situation obviously gets resolved as fast as possible to the constructive resolution for Ukraine. But I will say as far as our trial is going, we do not expect a dramatic impact.
spk09: Thank you. Our next question comes from the line of Gregory Renza from RBC Capital Markets. Your line is now open.
spk12: Hey, good evening, Steve and team. Thanks for the update, and thanks for taking my question. Maybe just a quick one, Steve, in the event that I missed it. 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 New Plaza and PDP as we've come out of the gate, not just with 2021, but exiting January and also exiting February to that extent. Thank you very much.
spk03: Yeah, 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, continuing 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, it appears, of the Omicron wave. We don't know what the impact will be from reduction of mask requirements and 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 or reflected in the scenarios that we've run. And again, the two underlying currents 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 need a little bit of time to see this play out through the year.
spk12: Great. Thanks for the caller.
spk09: Thank you. We have time for one last question. Our next question goes to the line of Jason Butler from JMP Securities. Your line is now open.
spk15: Hi. Thanks for taking the question. Just wondering if you can speak to the commercial prep work you'll be doing in RET this year. Obviously, assume the infrastructure outbuild will mainly be, you know, towards the end of the year and into next, but from a medical education perspective, just a, Can you walk us through the work you're going to be doing to get the market ready for the drug? Thanks.
spk03: Sure. Brendan, you want to start? Brendan, I think you're on mute.
spk16: 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 3 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 healthcare community, which has helped us to understand where we're going to find our RET 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 MEKP2 tests will also be available for suspected patients with Rett at any of their HCPs.
spk15: Great. Thank you.
spk09: Thank you. Mr. Davis, please proceed to closing remarks.
spk03: Thank you, operator, and thanks to each of you for joining today. We appreciate your time and attention and support and look forward to updating you as we go forward.
spk09: Thank you for your participation in today's conference call. This concludes the presentation. You may now disconnect. Good day.
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