ACADIA Pharmaceuticals Inc.

Welcome to Acadia Pharmaceutical's first quarter 2021 financial results conference call. My name is Mary and I will be your coordinator for today. At this time, all participants are in a listen-only mode. We will be facilitating a question and answer session towards the end of today's call. If at any time during the call you require assistance, please press star followed by zero and a 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.

Thank you, Mary. Good afternoon, and thank you for joining us on today's call to discuss Acadia's first quarter 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 Q1 2021 financial performance and a review of our business operations. Also joining us on today's call is Amanda Morgan, our Chief Revenue and Customer Officer, and Charmaine Likens, Global Product Planning and Chief Marketing Officer, who will provide updates on our commercial performance. Dr. Serge Sankovic, our President, will discuss our pipeline progress, and our Chief Financial Officer, Elena Ridloff, will then discuss our financial results in more detail before turning it back to Steve for final remarks and opening the call-up for your questions. I would also like to point out that we are using supplement slides, which are available on the events and presentation section of our website. Before we proceed, I would first like to remind you that during our call today, we will be making a number of forward-looking statements within the meanings 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.

Thank you, Mark. Good afternoon, everyone, and thank you for joining us today. Please turn to slide four. We remain steadfast in our commitment to our mission and to executing on our three strategic pillars to create long-term growth. First, driving continued growth of Nuplizit for patients with Parkinson's disease psychosis or PDP. Second, delivering on the dementia-related psychosis or DRP opportunity. And third, developing the next wave of breakthrough therapies by advancing our development pipeline and acquiring new assets. Let's review our Q1 results in greater detail, starting on slide five. For the first quarter of 2021, Nuplizit achieved $106.6 million in net sales. This represents an 18% year-over-year increase driven by strong year-over-year performance in the office-based setting. During the first quarter, sales and appliances were negatively impacted by the post-holiday spike of COVID-19 and ongoing conditions relating to the pandemic. As we look ahead, we observed improvements related to the pandemic in the latter part of the first quarter and into the beginning of the second quarter. And based on these indicators, we are projecting continued growth throughout the year, and reiterating our net sales guidance for fiscal year 2021 at $510 to $550 million. Let's move to an update on our DRP program on slide six. We remain committed to bringing PIM of answer into the DRP patient community. In April, we announced that the FDA issued a complete response letter, or CRL, regarding our supplemental new drug application for dementia-related psychosis. We look forward to a constructive dialogue with the FDA in our Top A meeting, where we plan to discuss the CRL and a potential path, approval path, for PIM of answering. We're prudently planning and preparing for multiple scenarios based on what we learn at this meeting. I want to remind you of the significant unmet need that remains in this disease. Current treatment of DRP involves the use of off-label antipsychotics, which carries significant risks for this often frail and elderly patient population, including worsening of cognition, and impairment of motor symptoms. We've heard both publicly and privately from many physicians, caregivers, and concerned family members who have made their voices heard on this critically important matter. We're further encouraged by the public statements made by patient advocacy groups such as Us Against Alzheimer's, the Lewy Body Dementia Association, and Alzheimer's Association. We all recognize that without an FDA-approved treatment, the burden of DRP remains significant. In addition to DRP, we're focused on developing and expanding our pipeline of innovative new programs across multiple therapeutic areas, as shown here on slide seven. Our phase three program for terpenetide remains on track to deliver top line results by the end of the year. And our phase three program for pimevanserin for the negative symptoms of schizophrenia continues to enroll well. We recently initiated a phase two study evaluating ACP044 for postoperative pain following bunionectomy surgery. and expect top line results by year end. In the second quarter, we plan to initiate an additional phase two study evaluating ACP044 in pain associated with osteoarthritis. Business development continues to be a key priority of our strategy to expand our pipeline, fuel long-term growth, and bring new therapies to patients with high unmet needs. I would now like to turn the call over to Amanda and Charmaine to discuss our first quarter commercial performance and growth initiatives.

Thank you, Steve. Today we'd like to review our first quarter performance and our long-term expectations for New Placid and Parkinson's disease psychosis. The strong base of PDP patients continuing on New Placid, improvements in the conditions related to the pandemic, and our focus on growth initiatives will enable us to deliver double-digit revenue growth in 2021. Please turn to slide nine. NUPLAVI continues to transform the standard of care for patients with PDP. In the first quarter, we delivered net sales of $106.6 million, representing an 18% year-over-year increase. Performance in the quarter was driven largely by new patient starts and growth of our prescriber base within the office-based channel. As Steve mentioned, New Plaza's performance in Q1 was negatively impacted as a result of the post-holiday spikes in COVID-19 cases, resulting in a decline in patient office visits. However, as we exited the quarter, we observed overall visits returning to traditional levels, including an increase in face-to-face interactions, all of which are related to improving conditions of the pandemic and an increase in vaccination rates. While continuing patients on new classes remained high, we faced a unique temporal dynamic in the first quarter as payers reverted to pre-pandemic guidance of 30-day refills versus the ability to obtain a 90-day fill. This policy reversal temporarily interrupted our average bottle per continuing patient and impacted our Q1 net sales. Within the long-term care channel, after showing several months of stability, In the first quarter, we observed an additional decline in census. However, we are now starting to see census, and more importantly, admissions, improve in March and into April. For both the office-based setting and the long-term care channel, our leading indicators and overall market conditions are steadily improving. As we come out of the pandemic, the timing and pace of recovery in face-to-face interactions, PD patient office visits, and LTC new admissions will be key drivers to our 2021 performance and where we land in our reiterated fiscal year 2021 net sales guidance of $510 to $550 million. Please turn to slide 10. We have recently started to see early indicators pointing towards a return to growth in the LTC channel, including an increase in new long-term care admissions and modest growth incentives. The following key points highlight this observation. First, more facilities are allowing family members to visit loved ones, which previously was a major impediment to new resident admissions. And second, in the first quarter, both large and small LTC provider groups shared that rapid vaccination of all residents was prioritized over other areas of care. There are now high vaccination rates among residents and staff, which has led to a greater than 90% drop in COVID-19 cases since December 2020. And finally, our data shows that new resident admissions is a highly correlated leading indicator of new patient starts within the long-term care channel. We are encouraged by these improving market conditions within the long-term care market that support a return to growth. I'll now turn it over to Charmaine to discuss our focus on sustainable growth for the overall PDP business.

Charmaine, I believe you are on mute.

Thank you. Thanks, Amanda. Please turn to slide 11. We've tailored our marketing channel mix to maximize response to the underlying market conditions as we begin to emerge from the pandemic. We've continued to amplify our healthcare professional and consumer campaigns, both digitally and in person, and we expect that these initiatives will drive growth throughout the remainder of the year. This means strong engagements with virtual CME and speaker programs, and leveraging virtual promotional booths at several key medical Congresses across the country. In April, our virtual New Plaza product theaters at the American Academy of Neurology and the American College of Physicians were very well attended, and we will continue to leverage our virtual Congress presence throughout the rest of this year. In addition to that, we are executing an on-air DTC an online campaign to support that DTC campaign in order to activate patients and caregivers to request Duplazid specifically. Our current DTC campaign is exceeding our reach targets and working synergistically with social media and other digital tactics that we have out there to grow the breadth and depth of the prescriber base. The market opportunity for Duplazid remains large. Most patients today are prescribed off-label antipsychotics, which carries significant safety risks, including the potential for worsening of motor symptoms. We're focused on growing our share of the PDP market, and our new patient share continues to exceed our overall share. This is a key indicator of future growth and penetration. In recent weeks, we've started to see growth across our business, which is supported by the improving market conditions. And importantly, as we exited the quarter and into April, we have started to observe a recovery in face-to-face interactions, in-office patient visits, and long-term care and new admissions. Our commercial team's expertise has positioned us well, with strong performance during the pandemic and the ability to grow future business as we emerge from it. We are well positioned to drive long-term prescription growth of new positive in PDP. And now I'll turn it over to Serge to discuss our pipeline progress.

Thank you, Charmaine. Good afternoon, everyone. Please turn to slide 13. In regards to DRP, our team has been diligently preparing a briefing package which outlines our perspective on SNDA, the positive Phase III Harmony study results, and provides a template for discussion and future interactions with the FDA. This document is almost complete now and will be included in the request for a Type A meeting. Our objectives for the Type A meeting are to discuss the CRL and identify a mutually agreeable path towards approval with the FDA. We are confident in the science, the data, and benefit-risk profile of pimavanserin in DRP described in our SMDA and are committed to achieving FDA approval and make Nuclasid available to patients caregivers, and their families who suffer from DRP. As we've said before, we believe that the prospectively agreed development program and the design of the Pivotal Harmony Study is scientifically the most appropriate way to evaluate efficacy and safety of Pimavanserin as a treatment for DRP. Our position is informed by the following. The Pivotal Harmony Study met its pre-specified primary and key secondary endpoints with highly statistically significant and clinically meaningful results. Consistent with these results, in the double-blind portion of the study, Pimavancerin demonstrated meaningful separation from placebo on the measures of severity of psychotic symptoms, such as hallucinations and delusions, or on a global clinical assessment. And all this with a notable effect size. Furthermore, in the open label portion of the study, over 60% of patients met very rigorous treatment response criteria while on Pimavanserin demonstrated meaningful and sustained reduction in the symptoms of psychosis consistent across patient subgroups. The consistency of the above described results in our Pivotal Harmony Study further informs our view on the benefit-risk profile of pimavanserin for DRP. We would like to better understand the division's position in hopes that we can align on an efficient plan towards resubmission. We look forward to keeping you updated on our progress. Beyond DRP, we are advancing our pipeline of innovative treatments for areas of high unmet need, with ongoing clinical trials across five disease areas. Let's briefly review the rest of our pipeline starting on slide 14 with Rett syndrome. Rett syndrome is a rare neurological disorder with debilitating symptoms including severe cognitive, emotional, sensory, and motor impairment. Patients often lose spoken communication and purposeful hand use leading to a loss of independence. Our Phase III program continues to progress well, with top-line results expected from our lavender study in the fourth quarter of this year. Please recall that the lavender study uses the same validated endpoints as the positive Phase II study, which are designed to show improvements on the core symptoms of Rett syndrome. Turning to slide 15. There are over 700,000 patients in the United States who are receiving treatment for schizophrenia but still experience the debilitating negative symptoms including social withdrawal, lack of emotion, restricted speech, and blunted affect. These symptoms can lead to long-term disability and significant caregiver burden. As a reminder, Our Phase III program, evaluating pimavanserin for the treatment of negative symptoms of schizophrenia, includes two pivotal studies, our positive ADVANCE-1 study and ADVANCE-2, which we initiated in the third quarter of last year and is currently enrolling patients. Please turn to slide 16 for an update on our ACP-044 program. ACP-044 is a novel, first-in-class, orally administered non-opioid analgesic that is being studied for both acute and chronic pain. I'm pleased to announce that we recently initiated a Phase II study evaluating ACP-044 for the treatment of postoperative pain following bunionectomy surgery. The study is a randomized, double-blind, placebo-controlled study enrolling approximately 240 subjects and evaluating the efficacy and safety of ACP-044. The primary endpoint of the study is average pain intensity score measured by a numeric rating scale from first dose on the day of surgery through 24 hours. We anticipate top line results from this study before the end of the year. Furthermore, We plan to initiate an additional phase two study for patients suffering from pain associated with osteoarthritis later this quarter. Slide 17 highlights a brief summary of our ACP319 program for the potential treatment of cognition and schizophrenia. Transition and continuation of the phase one program is progressing well, And we look forward to providing more detailed updates on this program in the future. Slide 18 summarizes our ongoing development timelines. In the first quarter, we initiated phase two study for ACP044 for postoperative pain. In the second quarter, we plan to initiate a phase two study of ACP044 for pain associated with osteoarthritis. And in the fourth quarter, we expect to announce top line results from our phase three tropinotide study in RAF syndrome. We look forward to keeping you updated as we advance our pipeline. And with that, I'll turn the call over to Elena.

Thank you, Serge. Today I'll discuss our first quarter 2021 results and our updated 2021 financial outlook. Please turn to slide 20. In the first quarter of 2021, we recorded $106.6 million in net sales, an increase of approximately 18% compared to $90.1 million of net sales in Q1 of 2020. This was driven by 4% volume growth year over year. Importantly, this comparison is challenging because last year's first quarter was pre-pandemic. Despite this, we delivered increased demand year over year. Our performance was led by the office-based channel, with year-over-year growth impacted by fewer patient office visits and a decline in average bottles per patient in the quarter, as Amanda described. In the long-term care channel, demand declined year-over-year, driven by a further decline in census levels in LPC facilities in the first quarter of 2021, following several months of stabilization in the second half of last year. However, we started to see patient office visits and office-based channel increase and census levels and our demand improve in LTC as we exited the first quarter and into April. The growth to net adjustment for Q1 2021 was 22.3%. As a reminder, growth to net is typically highest in the first quarter due to the annual reset of the donut hole for Medicare Part D patients. Weeks of inventory in the channel at the end of the first quarter were slightly higher than year end. Moving down the P&L, GAAP R&D expenses decreased to $57 million in the quarter compared to $72.6 million in Q1 2020. GAAP SG&A expenses increased to $111.7 million in the first quarter from $102 million in the first quarter of last year. Non-cash, stock-based compensation expense during the quarter was $13.2 million compared to $22.3 million for the same period in 2020. Our cash balance at the end of the quarter was $577.8 million. Please turn to slide 21. For the full year 2021, we are reiterating our new PLASID revenue guidance of $510 to $550 million. Given the impact of the pandemic we observed in the first quarter, we could land in the lower end of the guidance range. Just where we finish will be a function of the timing and pace of recovery in face-to-face field interactions, patient office visits, and LCC new admissions. On the expense side for 2021, we now expect GAAP R&D to be between 280 and $300 million for the full year, from a previous range of $300 to $320 million. This reflects some optimization in our development expenses and includes approximately $25 million in staff-based compensation expense. We are reducing our SG&A guidance to reflect the reduction of expenses associated with the delay in a potential VRP launch. We now expect GAAP SG&A to be between $385 and $415 million for the full year from a previous range of $560 to $590 million. The revised guidance range includes approximately $50 million in stock-based compensation expense. And with that, I'll turn the call back over to Steve.

Thank you, Elena. Please turn to slide 23. In closing, we are confident in our long-term commercial outlook for PEP. We are committed to bringing PIM advancement to patients and caregivers struggling with DRP, and we are focused on investing in our clinical programs and business development opportunities. I would like to thank our employees for their unwavering passion to our mission to elevate life. I'll now open up the call for questions. Operator?

Thank you. Ladies and gentlemen, if you wish to ask a question, please press star followed by one on your touchstone 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 one to begin. Please stand by for your first question. Your first question comes from the line of Rita Baral from Cohen. Your line is now open.

Hi, guys. Thanks for taking the question. I wanted to ask about the path forward for DRP. I guess the first very quick housekeeping question, have you formally requested the Type A meeting at this point? And then two, the broader question here is, I guess, if the main issue has to do with the 011 study and potentially records kept around that, is there any way to sort of address those recordkeeping quality issues with those clinical trial records that are worth discussing at the Type A or beyond?

Yeah, thanks much for the question, Ritu. I'm going to answer the first part of your question. I'll let Serge answer the second part. So the answer is we have not yet submitted the request. So in order to request a Type A meeting, you first have to prepare a briefing document which outlines your position and provides a template for discussion. And it's important to get this right and lay the right foundation and template for the benefit of future interactions. We believe we have very strong arguments to discuss with the FDA and want to be diligent in preparation before submitting the formal request. And this includes input from expert counsel and outside advisors. The document is almost complete and will be included in our official request for the Type A meeting again very soon. And as a reminder, the Type A meeting will be scheduled by the FDA within 30 days of our request. Serge, you want to take the second part of Ritu's question?

Yes. Ritu, I'll just reiterate first what Steve mentioned earlier, and that is that our principal objective in this meeting is really to understand the concerns and issues raised by the division in the complete response letter. Considering that a part of those issues were related to the study O19 that you mentioned, we certainly in our briefing document will be addressing all of the issues point by point that were raised in the complete response letter in detail and extensive manner in a hope that we can provide additional information that will be helpful to the division to understand the context of those concerns and issues and to address them.

Got it. Thanks.

Next question comes from the line of Charles Duncan from Cantor Fitzgerald. Your line is now open.

Yeah. Hi, guys. Thanks for taking the question. Good quarter on the top line. I had a follow-up question on the DRP indication. I guess I'm wondering if, you know, maybe this is jumping the gun, but are you willing to pursue a dispute resolution or do you need to learn more information before you determine strategy? And could you imagine refiling with a more limited label based on some diagnostic criteria?

Thanks much for the question, Charles. So if following the type A meeting, we can't agree on the appropriate path towards resubmission, there is baked into the FDA process an official appeal process that could be pursued. At this time, we don't think it's productive to speculate on that appeal process until we've actually had the meeting with FDA and have a sensible and gather information about that meeting. So, that's the next step and we'll be focused on that. And I'm sorry, Charles, there was a second part of your question that's escaping me now.

Yeah, that makes sense. Thanks, Steve. Regarding a limited label based on some diagnostic criteria.

Yeah, I remember now. Look, there too, we need to have this type A meeting. We need to learn what we can learn there, and I don't want to speculate about potential avenues beyond the type A meeting. We've obviously done a lot of scenario planning, but we just need to have the meeting first.

Okay. Thanks for taking the question.

Next question comes from the line of Kari Kazimov from J.P. Morgan. Your line is now open.

Hey, this is Turner on for Corey. Thank you for taking my question. Just curious, what are your latest thoughts on your European strategy? Does the DRP delay in the U.S. impact how you think about Europe, and is it possible to potentially take this package to European regulators along with PDP? Thanks.

Yeah, thanks much for the question. So as we previously indicated, we've frame-shifted our European filing strategy, and this is really a – just a reflection of the very, very dramatic difference in pricing that drugs like this, this is not unique to Pinnacle Cancer, but drugs like this get in Europe versus in the United States. So in other words, the vast majority of the value pie for a drug like this is in the United States. And because the pricing is so dramatically different, we felt it was important to play out the work that we're doing in other indications in an attempt to try to get multiple indications into a common 10-year data-exclusive degree. So we don't have anything more to say on that at this juncture. We'll continue to assess as we go forward. But I just want to remind you that Valley 5 is in the U.S. There is a few outside of the U.S., and we certainly want to make sure we secure every every bit of value with PIM of answering, but at this juncture, we don't have anything more to say about timing of filing in other jurisdictions. Thanks, that's helpful.

Next question comes from the line of Jason Butler from KMP Securities. Your line is now open.

Hi, thanks for taking the question. Just had one on the thinking about PDP opportunity moving forward. It's I guess just looking a little into the future midterm as we exit the COVID headwinds, how do you see the opportunity for growth in the office-based channel versus long-term care? Which one has the larger opportunity for growth? And if you could just remind us of your views on the market size in each channel, how deeply penetrated in each you are today in that context. Thanks.

Yeah, thanks so much for the question. Charmaine, I'm going to ask you to answer that.

Yeah, sure. Thanks, Steve. Well, first of all, when you look overall about our opportunity for growth in PEDP, we're committed to accelerating growth across all the channels, both office-based and long-term care. And we're going to do this through several means. Namely, our commercial initiatives have demonstrated positive effects across both channels over time. And we're going to continue to provide resources to deliver information to patients and caregivers to activate that caregiver and that patient to request new plasma. and also establishing NUPLASID as the only FDA-approved treatment out there for Parkinson's disease psychosis. Beyond that, we're educating the medical community, which has an impact both in the office-based business and the long-term care setting on important data on Pima-Vansarin and the benefits of NUPLASID through virtual promotional booths at several congresses that we've already actually participated in and virtual speaker bureaus throughout the year. In addition to that, we've got a fully integrated consumer awareness program which is executing with social media, both on the HCP side and on the consumer side. And we continue to see strong results coming from our digital platform across both HCP and consumer, regardless of setting. I think I would say, overall, we continue to perform or outperform, actually, the market basket in long-term care, the market basket of products that we benchmark ourselves against. which I think further underscores the effectiveness of these tactics that we're executing on today. So we're very optimistic of our growth prospects, not only in the long-term care channel, but also in the office-based channel.

Okay, great. Thanks for taking the question.

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

Hey, Steve and team, thank you for the update and thanks for taking my question. Steve, I just wanted to focus a bit on the near-term outlook for PDP. It sounds like you had an encouraging exit first quarter metrics and the reiteration of the full year guidance. I'm just curious if you could just touch a little bit more on those factors. If I heard Elena correctly, I think she indicated maybe a lower end of the range. So just curious if you could maybe unpack that a bit, maintaining that guidance versus, you know, perhaps narrowing that or lowering it just in light of the commentary you added. And then just lastly related to that, just curious to what degree, if any, was the DRP opportunity this year a potential potentiator for PDP penetration in the market? Thank you very much.

Yeah, thanks so much for the question. I'm going to answer the second question first, and I'm going to ask Elena to answer the first question. So from the time we've launched this drug, we've had very, very low off-label use. We can't see every bottle in all channels, but the significant majority of scripts come through our hub, and we know exactly – the percent of scripts that are on label, and it's always been in the high 90% range. That hasn't deviated. So I don't see any impact on first quarter from changes in off-label, present off-label use in PDP. In addition, just as a reminder, obviously, as you know, Our overall results in DRP were very, very compelling. And of course, the results in PDD patients, or Parkinson's disease dementia patients that have psychosis were also super compelling. So I just don't see any connectivity between DRP and PDP first quarter models. Lainey, you want to take the first question?

Sure. Greg, we are confident in our guidance range. I did comment with regards to the low end of the range just to remind you and folks that when you lose patients in the first quarter or have fewer new patient starts than expected, that has an impact on the continuing bottles for those patients for the remainder of the year. As we talked about, we, in both March and April, have seen improved trends in both the office-based setting and the long-term care channel, and we expect to see continued growth in both those channels. So we are confident in the guidance range that we reiterated today.

That's great. Thank you very much, guys.

Next question comes from Nina Betrito-Garg from CDE. Your line is now open. Okay.

Thanks for taking my question. So I guess just another question on kind of next steps in DRP. I guess can you elaborate a little bit more on, I guess, just the timeline to us kind of hearing the outcome of the Type A meeting, and is that something that you do plan to communicate or right after the meeting, or would you wait until after a few minutes from that meeting? If you could just talk a little bit more about that, that would be great.

Yeah, thanks so much for the question. So the meeting under the FDA's structure should happen within 30 days of the request, and they usually are right at 30 days. Once we have the meeting, as we would do in most meetings of this sort, whether it's an end-of-phase two meeting, a pre-SMDA meeting, or in this case, a top-A meeting following the CRL. We would typically wait until we get minutes from the meeting before speaking publicly on it, and that's our plan in this case as well.

Great. Thank you.

Next question comes from Jeff Hung of Morgan Stanley. Your line is now open. Thanks.

Hey, everyone. Thanks for taking the question. For DRP, should you go down the path of appeals? I know it's really early, but are there any precedent cases you can highlight where companies went through the appeals process and the CRL was overturned? And any similarities or differences that you would highlight from those cases to PIM of answering in DRP? Thanks.

Well, first, just one kind of just to make sure we're all level set. There's no overturning of a CRL, per se, because once you get a CRL, you have to resubmit. So the question always is, what do you need to do to resubmit? And in some cases, you can resubmit without doing additional clinical work, and in other cases, you need to do additional clinical work. This was S-NDA, or Supplemental New Drug Application, and so the decision on issuing a CRL was made by the psychiatry division, and that is the division with whom we'll have the Type A meeting. And so as we Once we've had that meeting, we'll be in a position, as indicated earlier, to comment further about plans forward, and of course it will then inform our view of what the next steps will be.

Thanks for the clarification.

Next question comes from Salvin Richter of Goldman Sachs. Your line is now open.

Thanks for taking the question. This is Andrea on for Salvin. Maybe some questions on the pipeline. Serge, maybe if you could speak a bit more on the mechanism of action for ACP044, and if there's any reason to believe the drug may be more effective in acute versus chronic pain. And as you look at those two opportunities, if one is more of a low-hanging fruit. And then I have a second.

Yes. Very interesting mechanism of action. First of all, we are particularly excited about having a non-opioid mechanism of action. This compound has ability to accelerate elimination of peroxynitrite, which is in the development of pain, it's an underlying upstream mechanisms for sensitization of multiple pain mechanisms. And that's really what is particularly attractive. This is also a peripherally restricted compound, so the risks of any potential dependence abuse liabilities is not present. So from that perspective, we are very excited about the drug. In regard to the question whether we anticipate a better benefit in the acute versus chronic pain models, you know, so far we have only indications we have are from the preclinical data that we have. And in those mechanisms we saw quite a bit of efficacy displayed in a variety of different pain models, whether acute or chronic. And in some extent, we saw an efficacy that is quite unpar or better with the opioids. So from that perspective, we are quite bullish in terms of our anticipation of possible ability to demonstrate benefit both in the acute models of pain as well as chronic models. And that's why in the phase two trial, we are pursuing both models. Obviously, looking forward to the clinical data for the confirmation.

Got it. And then with your M1, Pam, if you could just speak on what the status right now with that phase one, the nature of that, and when we could start to see some of the data emerge. That would be helpful. Thank you.

Yes, as I said, we are quite progressed in the process of transitioning and continuing the phase one work. This compound already is in a phase one. We need to continue through the expanding the exposures as we move forward. And that's actually the stage where we are right now, both from the perspective of providing appropriate toxicology covering so that we can be increasing those exposures in humans, as well as doing the human work. But we are in the phase one right now. And as we As we complete this work, we will be reporting, obviously, and updating you on the future plans moving forward.

Great. Thanks so much, Serge.

Sure. Next question comes from Paul Matiz of Stifel Financial. Your line is now open.

Hey, thanks a lot for taking my question. I know there's a lot of moving parts in OneQ, and we've heard from NERF about changes in compliance and refill rates, I guess. I wanted to try to simplify it. Did you exit first quarter with more patients on drugs than you had at the end of last year? And I guess what do you kind of see now that things are reopening in terms of the cadence of the patient ad rate for the rest of the first half? Thanks.

Yeah, thanks so much for the question. Elena, you want to take that?

Yeah, thanks for the question. As we talked about ending Q1, we did see growth in both the office-based setting and the long-term care channels. So we are exiting Q1 in a good place. I also just want to comment on the continuing bottles. We had strong continued bottles for the majority of our patients. There was a small portion where a single-digit percentage of patients that started to receive 90-day fills, which Amanda spoke about in her prepared remarks, that historically pre-pandemic was about 5%. It grew to about 8% in the pandemic. And in Q1, we saw that reverse to 6%. And now in April, it's back to 5%. So we expect, starting in Q2, to see a more normal trend as far as average bottles per continuing patient.

Okay. Thanks so much.

Next question comes from Brian Milas of Jefferies. Your line is now open.

Hi, everyone. Thanks for taking my questions. So maybe a few follow-ups on 044 and acute postoperative pain. So if possible, can you speak to the PK profile? Maybe it's estimated half-life and onset of action. And then as a follow-up, can you outline the dosing strategy? I know there's a high and a low dose, but is this once daily or as needed? And then finally, maybe you could talk about what rescue medications are allowed and how that's going to be handled in the primary endpoint. Thanks.

Sure. Do you want to take those questions?

Yes. You know, as a matter of fact, this study that we are conducting right now, one of the important questions that we want to answer is what is the optimal dosing regimen for the drug. So we are essentially testing the same daily dose, but in two different dosing regimens. So the trial has three arms, two active arms and one placebo. And that's essentially one of the objectives for us because we would definitely want to better understand both from the pharmacokinetic but also pharmacodynamic perspective behavior of the drug and potential for analgesic coverage in that respect. I'm not sure that I addressed your second part of your question, if you want to.

Yeah, just about rescue medications, how they'll be handled for the primary and if they're allowed.

Yeah, we don't go into that level of details in the protocols and all that, but obviously the design of this trial is very, very... it's a classical acute pain design, and, of course, we do make records. There are certain medications that are prohibited that interfere with this, but we are, you know, there is, in terms of the primary measure, we are measuring pain intensity, and there are certain restrictions in terms of the rescues.

Okay, thank you.

Next question comes from Yatin Sinha of Guggenheim. Your line is now open.

Hey, everyone. This is Eddie for Yatin. Thanks for taking my question. So on the lavender study, given the phase two is only six weeks and you're upping it to 12 weeks, and in the phase two the drug arm was still decreasing when that study stopped, how much additional benefit do you think you can get on those clinical endpoints with that added time? And then in the phase three, you're enrolling slightly older patients. Was there any age or severity of disease-related differences in that phase two data that led you to add older girls to the study? Thanks.

Yes. Our view on the data and discussion with the experts that we had, as well as vis-a-vis the mechanism of action of terfenotide, led us to a conclusion that actually the shorter trial did not provide a full opportunity to display the benefit. And the additional benefit based on the symptom, changing symptoms over time, would have been potentially obtained. So therefore, we have decided to design the trial in the way how it is designed, and we do expect that additional benefit will be verified. Of course, we did not want to go with an overly extended period for the trial, but we believe that we are at the right timing for the duration of this trial. In terms of the specific characteristics, I mean the important point with this particular patient population is that we have a patient population that is within the span of the school age where the patients are receiving also a number of rehabilitation measures that are applied in this, and that patients that are older than that may have a different disease course or may be more stagnating from that perspective. So, similarly, we did not include in this trial very young patients. We are doing that in a separate separate clinical trial, but for the group that is included in this trial, we do not anticipate that there will be significant variability in terms of the symptoms across the group. I mean, some variability is always present, but we do not expect it to be significant and substantive.

Next question comes from Jay Austin from Oppenheimer. Your line is now open.

Thanks for taking the question. Maybe just to follow up on Trophinatide. Can you talk about the target product profile for Trophinatide and any work that you're doing to prepare for the launch and how you're thinking about the ultimate market potential for Trophinatide? Thank you. So do you want to

take the target product profile, and Charmaine, you want to take the question regarding preparation for launch?

Yeah, I think that the important point I would like to underscore here talking about trofinetide is that trofinetide targets core symptoms of RAD disease, meaning Multiple. As we know, multiple symptoms. As we know, RAD disease manifests itself in a variety of different systems, as I mentioned, cognition, motor, communication, neurological symptoms, including seizures. And so far, our data suggests that the benefits seen with trofinetide are seen across different symptoms clusters. And that is something that is relatively unique so far from the perspective of the treatments that have been tested or applied in this patient population. As you know, we have some development programs where people were mostly targeting respiratory symptoms. Others were targeting seizures and so on. So I think that's one distinguish characteristic out there at this point, at least that we're not aware of programs that are targeting a broad array of the core symptoms of RAD syndrome, astrophenotide, and I think that's where obviously there is nothing else available. for treatment and there's broad target of symptoms is certainly the most salient characteristics of, characteristic of Trophinatide.

And from a commercialization perspective, as we look to prepare for launch, being seen as this is a rare disease, of course the caregiver is very, very important and a high touch relationship with those caregivers and those patients is also going to be very important for launch. Some of the things that we're working on are strong relationships with advocacy, particularly RettSyndromeFoundation.org or RettSyndrome.org, as well as looking to understand the patient journey and the diagnosis to Rett initially and then how that patient is managed throughout the course of their disease and where we might find an opportunity for Trufenatide at launch to help those patients manage their disease. So it's a lot of the early core research foundational brand strategy types of deliverables that we're working on with an extra emphasis on the caregiver and the patient knowing that this is a rare disease.

Great. Thanks for taking the question.

Next question comes from Vamil Devan of Mizuho Securities. Your line is now open.

Hi, great. Thanks for taking my question. So I guess this one's for Steve. I asked this question to you previously, but I'm just curious, given the or delay here with DRP, how that may be impacting your thoughts around the overall corporate strategy. I'm sure you want to get through the Type A meeting and kind of really get more clarity on the outlook there. But just as you think about business development or other steps you could take, whether to diversify the story or what, has anything sort of evolved in your thinking over the last couple months since you first got that notification that there are some deficiencies? Any updated thoughts would be helpful. Thanks.

Yeah, thanks much for the question. Look, we're obviously very disappointed in having the setback here in DRP. It doesn't change the strategy. We're equally committed to capitalizing on the opportunities we have of very attractive revenue growth going forward in PDP. We're determined to meet the unmet need in DRP patients and we will continue to have business development be a key pillar of our strategy. As it relates to business development, what I've said previously, and this continues to be the case, I just want to make sure I've reiterated, you will see more deals. Second, we have a strong foothold both in neurology and psychiatry today. We have a presence both in chronic indications with significant unmet need as well as rare disease, as we go forward, you will likely see the shift on the types of deals that we do evolve in more neurology and rare disease and more on the specialty front. Just to be completely clear, there's still very, very interesting opportunities in psychiatry and neurology, very interesting opportunities in broad symptomatic relief, chronic therapies, as well as in rare disease. So you'll see things evolve in that direction. So, again, business development will continue to be a very, very important part of our business. And as I've said before, you'll see more deals from us.

Okay. Thank you.

Next question comes from Daniel Beal of Rima James. Your line is now open.

Hi, I've got another Tricinitide question. Could you remind us what we should be looking for in the Lavender data set later this year with respect to what do you consider to be a clinically meaningful outcome for the two co-primary behavioral endpoints, the RSPQ and the CGI? Thanks.

Yeah, it's a little bit sort of difficult to describe that in the context of two co-primary measures. As you mentioned, we have a red behavioral symptom questionnaire, which is a parent-assessed outcome, and then clinical global assessment, or the improvement, which is the clinician assessment of the changes. We obviously being a co-primary we have to separate statistically on both of these measures in order to declare the trial positive and I think in itself that's a high threshold but achievable threshold because both of these measures separated significantly in our smaller phase two trial so we have a reasonable expectations that we will be able to replicate. These are a difficult trial. I will say in absence of the substantively beneficial treatments out there, the improvements that we would see on both of these scales, even if on a lower end of the effect size, would be tremendously valuable to patients and their families. And that is, although we expect to repeat relatively robust results that we have in Phase II, we would not be disappointed with a win on both primary measures. Great, thanks.

Next question comes from David Wong of SMBC. Your line is now open.

Hi, team. Thanks for taking the question. So, I just had a couple. So, first one, have you talked to much KOLs following FDA's issuance of the CRL and DRP? And just kind of wanted to get a sense, are prescribers still excited to, you know, use Pimavanserin and DRP? Is there any concern or hesitancy on their part in terms of willingness to prescribe after the agency's decision?

Yeah, so I'll take that, Serge, if you want to add any additional color, please feel free to. So the answer is yes, we continue to talk to KOLs even after the CRL is issued. I want to just take a little bit of a running start at this and to describe kind of what those interactions have been like from the time we initially announced the results of the Harmony study. So when we announced those results, we convened a panel of 15 KOLs around the time of the CTAD meeting and went through all of the data with them, and they were extraordinarily excited about the data. That has not changed. So we've had regular dialogue with a broad array of KOLs in this space. We've gone through all of the data. and they continue to be very impressed with both the efficacy that we observed in this study. We get strong support in the medical community that they believe this is the right way to study this population. The subtypes are very tricky to diagnose. There's often mixed etiology. They're frequently misdiagnosed, and about 40% of dementia patients don't get a subtype diagnosis because of the challenges associated with that. On the safety side of the equation, the KOLs, and I would say the medical community in general that we've consulted with along the way, have been very excited about the fact that this drug, as we've observed clinically, does not impair cognition. And that's not what you see with the dopaminergic antipsychotics. You see that they, in a very large study, very well established that they impair cognition. It's not insignificant. is equivalent to about one year of disease progression. So the very unfortunate situation in using those drugs is that when you use them in this patient population, you actually make, you may help on the psychosis, although it's very debatable whether they're even getting any benefit there. But you certainly have to compromise because they make the cognitive impairment that these patients have worse. So as we've continued to advanced toward our type A meeting. We continue to have dialogue with a broad array of medical and scientific experts and continue to feel very, very confident in our data.

Got it. Thanks for sharing that. Anyway, just one quick follow-up.

I'm sorry, we lost you. Yeah, I think we lost you. Operator, maybe you can get back in the queue. I think we've lost the connection there.

Sorry, David Wong. Your line is now open again. You can go ahead.

Hi. Hi. Are you able to hear me?

Yeah, we can do. Yeah, go ahead.

Okay. Great. Thanks. Just a second quick question. In terms of the Phase III Harmony Study, can you just remind us which subgroup sold the greatest magnitude of benefit there?

Sure, sir. Do you want to take that? Yeah, the greatest magnitude that was observed was with Parkinson's disease dementia patients with psychosis. Following, of course, that's if you obstruct dementia Lewy body patients because we just simply could not calculate their due to small numbers, but it was also a notable difference. Actually, there was one relapse in... in a placebo while no relapses on drug. The next in line with this substantial number of patients is Alzheimer's disease psychosis subgroup, and in that subgroup we observed approximately 40% reduction in risk of relapse, which is clinically very meaningful and notable and in line with all of the data that we are aware of the clinically meaningful results and statistically significant results from different randomized withdrawal trials.

Okay. Appreciate the input.

There are no further questions at this time. Mr. Davies, you may proceed on your closing remarks.

Great. Thanks much, Operator. Thanks, each of you, for joining us today. We look forward to updating you on our progress.

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