ACADIA Pharmaceuticals Inc. (ACAD) Q1 2022 Earnings Report, Transcript and Summary

Good day, ladies and gentlemen, and welcome to ACADIA Pharmaceuticals First Quarter 2022 Financial Results Conference Call. My name is Crystal and I'll be your coordinator for today. [Operator Instructions] I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations at Acadia. Please proceed.

Good afternoon and thank you for joining us on today's call to discuss Acadia's first quarter 2022 financial results. Joining me on the call today from ACADIA are Steve Davis, our Chief Executive Officer who will provide an overview of our first quarter performance and a review of our business. Following Steve, Brendan Teehan, our Chief Operating Officer, Head of Commercial will provide updates on our commercial performance and initiatives; Dr. Serge Stankovic, our President, will then discuss our pipeline progress. Finally, Mark Schneyer, our Chief Financial Officer, will discuss our financial results and guidance 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 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'll will be making a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements including goals, expectations, plans, prospects, growth potential, timing of events or future results are based on current information, assumptions and expectations that are inherently subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially. These factors and other risks associated with our business can be found in our filings made with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date. I'll now turn the call over to Steve.

Thank you, Mark. Good afternoon everyone and thank you for joining us today. Please turn to Slide 5. The foundation of our business rests on three key elements. First to drive growth of the NUPLAZID franchise where we continue to outperform market comparators; second, advance our three late-stage opportunities in Alzheimer's disease psychosis, Rett syndrome and the negative symptoms of schizophrenia and third to develop the next wave of CNS breakthroughs with our early stage pipeline together with continuing to pursue strategic business development opportunities. For the first quarter of 2022, NUPLAZID achieved $115.5 million in net sales, representing an 8% year-over-year increase. While Brendan and Mark will go into more detail in a moment, I'd like to point out a few key components of our performance during the quarter. First, our operational performance in the first quarter was driven by 4% demand growth, a level of growth, similar to what we experienced through 2021 and which is also in line with our assumptions for our net sales guidance of $510 million to $560 million for the full year 2022. Second, following the Omicron variant surge as we exited the first quarter and now into the second quarter, we're seeing early signs of additional growth in total prescriptions and new patient starts both with NUPLAZID and the overall market as a whole. Just a bit of context here. Since the beginning of the pandemic in early 2020, the Parkinson's disease market has grown only 3% cumulatively over this two-year period. In comparison, during the two-year period prior to the pandemic, this market grew 9%. In addition, as we previously reported in-person patient visits to Parkinson's treating physicians are down approximately 20%. These conditions have resulted in fewer available patients being diagnosed and treated for their Parkinson's and subsequently for Parkinson's disease psychosis. However, as Brendan will speak to in both the community and long-term care channels, we've recently seen signs of the overall Parkinson's market stabilizing and slowly returning to growth. With mask mandates lifted and physicians encouraging patients to come back to the office, we are cautiously optimistic that we could see further improvement in these market dynamics throughout the spring and into the summer. Finally and most importantly NUPLAZID has continued to grow year-over-year outpacing the top brands and medications in the neurology segment, the PD market and in LTC facilities. We look forward to maintaining the strong performance and delivering on the long-term potential of NUPLAZID for PDP. Now let's turn to our three late-stage opportunities on Slide 7. First, I'd like to start by providing an overview of where we stand with our sNDA resubmission for ADP. This week, the FDA announced that they have scheduled an advisory committee meeting for June 17 to review our resubmission. For the meeting, we are focused on three key messages which point to the overall positive benefit risk profile for pimavanserin in this patient population, which include efficacy, safety and high unmet need. For efficacy, our package supports our position that pimavanserin provides a consistent and clinically meaningful improvement in the symptoms of psychosis and the reduction of relapse risk in Alzheimer's disease patients. On the safety side, we've demonstrated in clinical trials that pimavanserin has a favorable safety and tolerability profile and importantly is not associated with worsening of either cognition or motor function in Alzheimer's disease patients, a particularly challenging issue, which has historically hindered the development of therapies to treat this condition. And finally with regards to unmet need, today there are approximately 900,000 ADP patients being treated in the US, the majority of which take off-label multi-receptor acting anti-psychotics with marginal efficacy and known safety issues. In the large-scale CATIE-AD study, these off-label antipsychotics were associated with increased impairment of cognition in Alzheimer's patients, equivalent to about one year of disease progression. These medications are also associated with impairment in motor function, sedation, an increased risk of falls, fractures, hospitalizations and business. Today, with no FDA-approved treatment for Alzheimer's disease psychosis, healthcare providers will continue to prescribe these off-label antipsychotics despite all of their limitations, as families and caregivers many times are desperate to treat the debilitating psychosis these patients endure. We look forward to further making our case to the FDA at the upcoming advisory committee meeting that pimavanserin should be the first FDA-approved treatment for Alzheimer's disease psychosis. Please turn to Slide 8. Regarding our NDA for trofinetide, the pre-NDA meetings are complete and we are fully aligned with the FDA on the format and content for the upcoming NDA submission for trofinetide for the treatment of Rett syndrome. Our NDA submission will be primarily based on the pivotal Phase 3 Lavender study which delivered positive top-line results in late 2021. These results were recently presented at a late-breaker oral presentation at the American Academy of Neurology Annual Meeting or AAM. We plan to submit our NDA midyear and expect this to be a priority review with an action date most likely in the first quarter of 2023. Our commercial team is working hard on launch preparations, which Brendan will speak to in just a few moments. Moving now to our third late-stage opportunity, pimavanserin for the treatment of negative symptoms of schizophrenia. As we previously discussed, despite decades of attempts, today there is no drug approved for the treatment of the negative symptoms of schizophrenia. With pimavanserin, we have something that is rarely seen, a positive pivotal study in patients with negative symptoms that is our ADVANCE-1 study. With one positive pivotal study in the bank, we are currently conducting a second pivotal study, our ADVANCE-2 study and if this study is successful, we will file for approval. As an important reminder, the ADVANCE-2 study is almost identical to the ADVANCE-1 study with one important modification. In ADVANCE-2, we are evaluating the optimal 34-milligram dose, which as you may recall, had the most robust efficacy in the previous ADVANCE-1 study. We anticipate completing enrollment in this study around year-end with top line results in 2023. Please turn to Slide 9. Beyond our three late-stage opportunities, we are also developing several early-stage programs, including our ACP-044, novel non-opioid pain program currently in early Phase 2. Our M1 PAM program with our lead compound ACP-319 currently in Phase 1 testing and several earlier stage molecules, including those from our Vanderbilt and Stoke collaborations and additional molecules that build upon our learnings of pimavanserin. And finally, we continue to be highly engaged and focused on potential strategic business development to further expand our pipeline. I'd now like to turn the call over to Brendan to provide an update on our commercial efforts.

Thank you, Steve. Please turn to Slide 11. I'm pleased with our team's performance this quarter, delivering net sales of $115.5 million representing 8% year-over-year growth based on 4% year-over-year demand growth. Notably, this demand growth is in line with our first quarter plan and aligns with our assumptions for our 2022 net sales guidance range. As we look ahead, our ongoing HCP and patient caregiver campaigns continue to set us up well, reaching new physicians and patients, educating them on the importance of treating PDP early and the potential of NUPLAZID. As you all know, our relative outperformance in the PD and long-term care markets reflects our focus on the highest potential prescribers in the community and the top LTC facilities for treating PDP patients. Our teams, especially when they are able to have regular in-person contact with prescribers, a metric that is increasing month over month have made a measurable impact on overall prescribing behavior leading to more new patient starts. As Steve mentioned, the pandemic significantly impacted the growth of the overall PD market these past two years. Utilizing data from IQVIA, we see that the Parkinson's disease market as measured by treated patients grew only 3% since March 2020. Based on pre-pandemic growth rates, it should have grown three times this rate by 9% over that same timeframe. The biggest impact was in long-term care, especially in the first year of the pandemic. This makes sense as we know many facilities were hard hit by the pandemic with occupancy rates profoundly impacted by the spread of COVID-19 and many potential LTC residents remaining at home, as opposed to entering long-term care facilities. The good news is that we have recently started to see not only stabilization, but early signs of a return to growth in the PD market across channels. The growth of the NUPLAZID brand against this market backdrop gives us great confidence in our ability to accelerate as conditions continue to improve and normalize. In addition, when comparing our first quarter performance to pre-pandemic, in the office based setting, carbidopa and levodopa scripts declined 6% and the top 10 Parkinson's medications were down 12%. In direct contrast, NUPLAZID grew significantly up 19%, which was roughly four times that of the top 15 neurology brands, which averaged just 5%. In the long-term care channel, carbidopa/levodopa declined 9%, a reflection of a significantly lower LTC occupancy rates and the top 15 LTC brands were down an average of 13%. At the same time, NUPLAZID maintained growth up 2% over 2019 levels. This outperformance was fueled by meaningful increases in NUPLAZID's market share of new LTC patients, up almost 20% since the beginning of the pandemic. We are further encouraged that over the past few months, we have seen and heard from our field force early signs of a return to growth in several of the PD market dynamics that have hampered our growth, including a potential increase in physician visits by their PD patients. As the market normalizes and begins to return to its regular growth dynamics, we plan to further enhance our promotional efforts with more peer-to-peer live programing, speaker programs and potentially broader multi-channel physician, caregiver and patient engagement efforts to further grow the brand. Beyond PDT, we have two exciting near-term potential commercial opportunities. Let's start with a review of pimavanserin for the treatment of Alzheimer's disease psychosis on Slide 12. We have a significant potential opportunity ahead of us with pimavanserin for ADP, an indication that is approximately seven times the size of our current PDP market. Our teams are diligently preparing for the upcoming advisory committee meeting and subsequent commercial launch if approved. Key to our commercial messaging at launch for NUPLAZID in ADP will be both the products demonstrated efficacy and of equal importance, NUPLAZID's demonstrated safety profile. This is especially important for this patient population. NUPLAZID already has strong brand recognition as the first and only approved drug for PDP, and we look forward to potentially expanding this to ADP. Now let's turn to Slide 13 to discuss our opportunity with trofinetide in Rett syndrome. Towards the end of last year, we were very excited to announce positive Phase 3 results for trofinetide for the treatment of Rett syndrome, a debilitating disease that leads to severe impairments affecting nearly every aspect of life, the ability to speak, walk, eat and breathe easily. This community has waited a long time to see a positive Phase 3 trial in this neurodevelopmental disease and the results have been met with a lot of excitement. With the positive readout, we are focused on preparing for approval and the successful commercial launch of the first potential treatment for this disease. Today, we are laying the foundation for this launch through thoughtful collaboration and engagement with patient advocacy groups within the Rett community, centers of excellence and key opinion leaders on the best way to help identify, engage and educate Rett families. We've made meaningful progress on our commercial infrastructure and are investing appropriately throughout the year. A critical part of our launch preparation includes external stakeholder engagement with caregivers, physicians and payers to understand both their particular needs as well as the market opportunity for trofinetide. Our market research indicates a very high percentage of healthcare professionals who treat Rett patients today are interested in prescribing trofinetide when available for their patients. Many respondents say that trofinetide's potential efficacy in treating the core symptoms of Rett syndrome as a significant reason to look forward to prescribing it post approval. Not surprisingly, caregivers were also very excited about trofinetide's clinical results and expressed a strong interest in trofinetide for their loved ones. This feedback from physicians and caregivers of current Rett patients underscore our confidence in this treatment, the motivation for obtaining approval and the market opportunity ahead of us as we establish our presence in rare disease. I would now like to turn it over to Serge to provide an R&D update.

Thank you, Brendan. And good afternoon everyone. I would like to begin on Slide 15 by taking a deeper dive on our three late-stage opportunities. At this time, we are actively preparing for the upcoming advisory committee meeting to review our sNDA resubmission. Over the past several months, we have been working closely with the external key opinion leaders in multiple disciplines to help us prepare for the upcoming advisory committee meeting. We continue to refine our presentation to ensure we will be well prepared for an active discussion with the community on the benefit risk profile of pimavanserin for Alzheimer's disease psychosis. We see this as an opportunity to make our case that pimavanserin with its demonstrated efficacy and safety profile should be the first drug approved for Alzheimer's disease psychosis. And finally, I would like to reiterate a critically important point that Steve made earlier, there are real safety concerns with the off-label use of the multi-receptor acting anti-psychotics, which remain the current standard of care for ADP patients who are often frail and elderly. This significantly increase is the risk to these patients in the context of unproven and at best marginal benefit. Beyond the efficacy, we have demonstrated across multiple clinical studies and endpoint. We also have a tremendous amount of data on pimavanserin both in placebo-controlled clinical studies and six years of post-marketing pharmacovigilance data to support pimavanserin's well-characterized favorable safety profile at this at-risk population. Let me discuss our upcoming NDA submission with trofinetide on Slide 16. Rett syndrome is a serious and debilitating rare disorder, for which we estimate there are between 6,000 and 9,000 patients in the United States. There is no FDA-approved treatment for this neurodevelopmental disorder. Ultimately, Rett 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 Rett syndrome with statistically significant separation from placebo and clinically meaningful benefit on two 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, the efficacy results were consistent across all age groups and severity of disease. We have completed pre-NDA meetings with the FDA and aligned on the format and content of the upcoming submission. We plan to submit our NDA midyear and expect a priority review with PDUFA date most likely in the first quarter of 2023. Now let's discuss our negative symptoms of schizophrenia program on Slide 17. There are over 700,000 patients in United States who are currently treated for schizophrenia, but still have persistence and potentially debilitating negative symptoms such as social withdrawal, lack of emotion and blunted affect among others, and for which there is no FDA-approved treatment. As part of our advanced program, we have one positive pivotal study already ADVANCE-1 where we observed statistical separation on the primary endpoint overall, and even more robust results in patients receiving 34 milligrams of pimavanserin. As such, we are now evaluating all in the optimal 34-milligram dose of pimavanserin in our second pivotal study ADVANCE-2. And briefly, I wanted to mention that we continue to monitor the ongoing conflict in Ukraine and Russia and are doing everything we can to minimize any potential impact on enrolled. Given the multi-region multi-country design of the study, we believe based on current projections that we can still achieve our enrollment target of completion around year-end and top-line results available in 2023. Slide 18 highlights our early-stage pipeline opportunities. We are evaluating ACP-044 in both acute and chronic pain model. As previously announced, our acute pain Phase 2 study did not achieve statistical significance on the primary endpoint, even though a positive trend was observed in one of the two-dose regimens evaluated. As such, we are continuing to analyze the data to determine appropriate next step. Our Phase 2 study in a chronic pain model of osteoarthritis is ongoing and expected to complete in the first half of 2023. In addition, we are advancing compounds from our M1 PAM program with the lead compound HCP-319 currently in Phase 1 multiple ascending dose study. And we have multiple early-stage programs, we are advancing from our collaborations with Stoke Therapeutics and internally developed compounds, which build upon the learnings of pimavanserin. I'll now turn the call over to Mark to discuss our financial results.

Thank you Serge. Today, I'll discuss our first quarter 2022 results. Please turn to Slide 20. In the quarter, we recorded $115.5 million in net sales, an increase of approximately 8% compared to $106.6 million of net sales in Q1 of 2021. As Steve and Brendan both mentioned, our operational performance reflects approximately 4% demand growth year-over-year. This is consistent with our demand growth during the full year of 2021 and is one of our key assumptions underlining our guidance range for the full year 2022. In regards to revenue recognition, we observe essentially flat sell in volume compared to the first quarter of 2021. This is the result of two offsetting volume dynamics. First, as mentioned we grew demand by 4% year-over-year. However, this was offset by a larger in-channel inventory build in Q1 of last year as compared to this year. As you know in-channel inventory will wax and wane from quarter to quarter, but importantly, we achieved growth in demand, which ultimately drives our future revenue growth. Moving on, our gross to net adjustment for Q1 2022 was 25.1%. Year-over-year gross to net was higher to the timing of Medicare accruals between the first and the second quarter of 2021 and a greater portion of volume coming from 340B institutions in 2022 as compared to 2021. For the full year 2022, we are still projecting gross to net to be between 20% and 22%. GAAP R&D expenses increased to $128.9 million in the quarter compared to $57 million in Q1 2021. The difference was primarily due to the $60 million upfront payment for the stoke collaboration made in January and also from increased clinical spend and CMC costs. GAAP SG&A expenses decreased to $96.7 million dollars in the first quarter from $111.7 million in the first quarter of last year. The largest factors driving the difference in the prior year period were related to pre-launch expenditures for DRP in Q1 2021. And finally, our cash balance at the end of the quarter was $446 million. Now let's turn to Slide 21. As you can see on this slide, for the full year 2022, we are reiterating all of our previously announced guidance ranges. And now I'd like to turn the call back to Steve for closing remarks.

Thank you, Mark. Please turn to Slide 23. Today, we are executing on our promise to deliver new clients and patients with PDP where there is a significant long-term opportunity to continue to grow the brand. In addition, we are focused on the upcoming advisory committee meeting with the FDA as they continue their review of our sNDA resubmission for ADP. We are on track with our preparations to submit a new drug application for trofinetide for the treatment of Rett syndrome midyear. And we continue to advance our third late-stage opportunity with our ongoing Phase 3 study in the negative symptoms of schizophrenia with results expected next year. In closing, I would like to thank our employees for their accomplishments and their ongoing commitment and passion as we continue our mission to elevate life. I'll now open up the call for questions. Operator?

[Operator Instructions] Our first question comes from Charles Duncan from Cantor Fitzgerald. Your line is open.

Yes, Steve and team, thanks for taking our question and congrats on looks like a good quarter despite the challenging environment. My question is really related, I guess, to trofinetide since I'm going to hold it to one and then it is relative to upcoming NDA, would you anticipate an ADCOM for that drug given it's really first-in-class ever? And then if approved, would you be able to get a PRV? And then perhaps to extend the multipart, would that result in changes to the commercial infrastructure should it be approved?

Great. Thanks much for the questions, Charles. I'm going to ask Serge to respond to subparts one and two, and Brendan to subpart three.

Yes. Thanks, Charles. In relation to the anticipation of the Advisory Committee, of course, we are always thinking of that and preparing for such eventuality. Historically though, I would say that there is about half-half chances in this sort of situation with rare diseases, maybe even a little bit more on not having the Advisory Committee that at least from what we saw on the records that these occur. I would just say we do not see any our priorities substantive controversial issues that would immediately lead us, we think that we would have an advisory committee. But I would just say, it's a 50-50 chance.

Thanks Serge and Charles, thanks for the question. Just taking us back to when we had brought the program into ACADIA. We're very excited about what trofinetide means to us overall and it fits into our footprint very nicely. As you know, we already have rare disease experience in health. We expect to leverage synergies from internal operations but we will also make thoughtful adjustments to address a pediatric neurology community for the rare disease and I'm sure we'll go into further details on infrastructure the closer we get.

Charles and Steve, there was a second subpart. Could you just repeat that part?

Yes, I'm sorry. Is it possible that you would be granted a PRV if trofinetide is approved?

Yes. Sorry about that. Yes, having a pediatric orphan designation, we do anticipate it if approved, we would receive pediatric voucher.

Thank you. Our next question comes from Neena Bitritto-Garg from Citi. Your line is open.

Thank you for taking my question. I was just wondering about the ADCOM for Alzheimer's psychosis coming up in June. I guess any thoughts that you can share in terms of how typical of kind of a pediatric ADCOM you expect this to be or do you expect there to be any differences versus the historical channels versus the PDP ADCOM? Thanks.

Yes, thanks for the question, Neena. Serge, you want to take that?

Yes, thanks Neena. What I would say, as we've been saying all along. This is our response to the Complete Response Letter and the resubmission is not your typical application. We are making a fairly complex case following a very -- following a development that has been having its course for a while. So prevent perspective, the case we are making, we are trying to really present to the committee our full spectrum of the historical context of our application as well as the date. And really the data is the core of what we are trying to present in a comprehensive manner and offer them supportive evidence for substantial efficacy and positive benefit-risk in Alzheimer's disease psychosis but I would say the mechanics and execution of the Advisory Committee are fairly typical and I do not expect that in any way this would be outside of usual context of the Advisory Committee in any significant way.

Thank you. Our next question comes from Cory Kasimov from JPMorgan. Your line is open.

Thanks for the question. This is Tiffany on for Cory, just one more on NUPLAZID in ADP. We're just wondering how the go-to-market strategy might be different than for Parkinson's disease psychosis and if there's any synergies in terms of treatment centers, physicians, etc., I'm just kind of wanting to get your take on the commercial readiness and launch preparation as it relates to PDP. Thanks.

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

Sure. Tiffany, thanks for the question. As you undoubtedly know, we were getting ready for dementia-related psychosis a year ago and would have been right post launch at this point to plans were very much already in place, both in terms of strategy, our tactical execution and targets that we are going for in deployment. PDP is a subset of DRP and some of our target physicians for Parkinson's disease psychosis will absolutely be our targets for ADP as well, but we will thoughtfully expand to a broader audience that treats Alzheimer's disease psychosis which, just as a reminder, is 70% of that dementia-related psychosis audience. We will expand to cover more psychiatrists and there will be primary care physicians that are psych-like in their treatment and have demonstrated that in their ability to write for Alzheimer's medications and importantly have demonstrated the ability to prescribe atypical antipsychotics and in any event, we are prepared to address that broader audience.

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

Great. Thanks, Steve and team for taking the question and congrats on the progress. Maybe just following up a bit on the ADCOM in June. Very helpful to hear about maybe the mechanics and that maybe the typicality of it. I'm just curious, Steve, if you could provide some color on how important you think a vote of confidence is from the panel, especially in light of that unique situation that you've certainly endured and having the differences in the view on the initial package that led to the CRL. And maybe just related to -- and also related to just some of the history of ADCOMs and recommendations and how that leads to approvals or not. And maybe just a subpart, I'll throw one in as well. Yes, just respect to the potential scenarios of that outcome, but may be providing some color about how you're thinking about scenario planning based on the vote outcomes once you go from June until August? Thank you very much.

Yes. Thanks so much for the question, Greg. Serge, you want to take the first one regarding the importance of ADCOM of the confidence and I'll take the second part regarding potential scenarios.

Yes, thank you. Without a doubt, the vote on the advisory committee is very important, although this is the vote, an outcome of the Advisory Committee is not binding for the FDA. Statistics point out that in a great majority of cases, the FDA usually goes along with the recommendations of the Advisory Committee. Our own experience from the previous Advisory Committee on Parkinson's disease psychosis where we received overwhelming support from the Advisory Committee. And in respect of positive vote, certainly had a significant impact on the ultimate approval of the drug, as you know, initial reaction and the report from the FDA was not as favorable. So from that perspective, we certainly believe that it is important that we make a strong case for the Advisory Committee and obtain or receive support from the Advisory Committee for the case we are making.

Thanks Serge. And Greg, in response to the second part of your question, I think the way we think about it is, there are three principal buckets and maybe a little bit of space between the three buckets. You can come out of an Advisory Committee meeting with very significant opposition. So the math is heavily in favor of non-approval. You can come out the opposite end of the spectrum where the math is, the votes are heavily in favor of approval and then you come out with something that's more of a mid-point of that and then of course some variations between. And so I think for us and again we would just reiterating during the caveat as Serge mentioned that ADCOMs don't approve drugs, the FDA does, but the history tells us that the significant majority does not fall in ADCOM. And so in terms of how we think about this neuro planning impact it has on us, I'll just repeat what Brendan said earlier. We're in the very, very fortunate position. We did a lot of work preparing for DRP launch. We've got all that work and the benefits of that on the shelf. We're ready to pull it off and the precise timing of that and how we advance on that will be somewhat a function of the ADCOM in those three buckets and the good news is we have an action date that's scheduled for August 4, which is not too far down the road after an ADCOM. And so depending on how the ADCOM goes and kind of where we are in that spectrum of scenarios, we will be eager to be prepared for a launch.

Thank you. Our next question comes from Yatin Suneja from Guggenheim Partners. Your line is open.

Thank you for taking my question. Two real quick one for me. First one is could you confirm if you requested the ADCOM as part of the formal dispute resolution or was it proposed by the FDA? And then the second part is that both Phase 3 HARMONY and 019 study had a different study design and endpoints. So I'm just trying to understand how can they be supportive of each other when both are trying to answer a different question and the endpoints and studies and a completely different? Thank you.

Yes. Thanks so much for the question. I'll take the first one and Serge to respond second one. In terms of requesting an AdCom just to level set having AdCom entirely the discretion of the FDA. Early in our discussions with FDA after receiving the CRL, we did suggest that they consider having an AdCom and their response was simply it's premature for us to comment I think about that. Let's advance these discussions. Anyway we didn't discuss it any further with them. And then as we all know now they have determine they're having an AdCom. Serge, you want answer the second question.

Yes. Yatin, let me just make sure I understood the question that you broke up a little. Were you asking about the two studies as a part of our resubmission of 019 and 045 being studies in different patient population and with different outcomes and how that fits together in this application?

That is correct. Yes, not maybe the patient population, but just the endpoints are very different for both the studies.

Yes. That is correct. But we have been using in both studies measuring hallucinations and delusions, and the primary symptoms of psychotic breakdown, in one case more in severity sense and in other case measuring more in terms of relapse and recurrence of symptoms. But in any case, we do have, we can actually fairly reliably compare the data from both studies because we are measuring the same symptoms of the same disorder and from that perspective, they are, I would think of them more as a complementary rather than differential in terms of how we see. As a matter of fact, if you think about that is in the acute study of 019, what we demonstrated is acute efficacy of pimavanserin treatment in patients that are experiencing psychotic symptoms in short term six weeks paradigm. On the other hand Study 045 within the same symptoms has been evaluated, durability of effect in patients that respond to treatment. So from that perspective actually, there is just quite a bit of complementarity between two studies.

Thank you. Our next question comes from Salveen Richter from Goldman Sachs. Your line is open.

This is [Nel] for Salveen. First on NUPLAZID, could you share how in-person office visits in long-term care occupancy rates are tracking relative to pre-pandemic levels? And then on ACP-044, given that you saw a trend in acute pain, do you expect better results in chronic? Or do you view this is unrelated? Thanks a lot.

Yes. Thanks much for the questions. Brendan, you want to take the question on NUPLAZID and Serge on 044?

Sure happy to do that. What we've seen in the first quarter for in-person patient visits in the community reflects that they are still about 20% below pre-pandemic levels. With that said, I just want to point out in the visits to see customers, we see that clinicians are beginning to ask their patients to return for inpatient visits and not favor telemedicine over that. And then for LTC occupancy rates to further answer your question, we have two things going on. One is there are slight increases in LTC occupancy rates of late. From the base, they've returned to about 73% in the most recent data that we're seeing, so slightly up from where they were in the fourth quarter. And those are being driven by new residents entering long-term care facilities, which I think is encouraging for us because we understand if that trend were to continue that patients tend to be identified for PDP proximal to their being admitted to a skilled nursing facility. Thanks.

Yes. Nel, in regard to potential read-through from our acute model to chronic model of pain and the studies, as we have been saying throughout, we do not see a direct read-through from the results of the acute study. Of course, I would say we would love to see a very robust positive results of the acute study, rather than a signal that we have observed, but there is no direct connection. As far as the preclinical data and we've reported this previously, we see that ACP-044 has a positive activity in the animal models of those positive on both acute and the chronic models of pain. So from that perspective, we at this point not jumping to any premature conclusions in regard to the osteoarthritis study and the data will show us the best.

Thank you. Our next question comes from Sumant Kulkarni from Canaccord. Your line is open.

Good afternoon, thanks for taking my question. So, ahead of the ADCOM of convention for ADP, other than not having statistical significance for specific ADP subgroup and how many of what the FDA has already expressed on Study 019, what are some of the specific nitpicks or key sources of the pushback, if any, that your external KOLs or consultants might have on the data package they'd be putting together for the meeting?

Yes, thanks much for the question. Serge, you want to take that?

Yes. Actually, obviously we are preparing studiously and are looking forward to challenging feedback and question from our KOLs in order to prepare ourselves the best for the Advisory Committee, but I would say that overall, the feedback we are getting, we are getting quite a bit of a support from people in terms of understanding specific circumstances and the data and meaningfulness than consistency of the Alzheimer disease psychosis data that we have across the studies, across the end points and over time. So from that perspective, I think without getting into very specific details which you will understand, it's not really probably the most appropriate situation for us to do that at this point, I think that we are preparing to meet all of the scientific challenges that can be put in front of us in terms of the data and arguments and analysis that we are providing.

Thank you. Our next question comes from David Hoang from SMBC. Your line is open.

Thanks so much for taking the question. I just want to dig a little bit more on the recovery -- potential recovery of the PDP market this year. Can you just talk a little bit more and give a little more color in terms of what you're hearing maybe from your sales force and people in the field that gives you confidence that we should see both LTC and the office channel recover and then you mentioned spring-summer as maybe the time frame in which that happens. Is there anything that would potentially allow the recovery to happen faster?

Yes, sure. But let me just reframe the question a little bit and then I'm going to pass it to Brendan. So what we said is that we're beginning to see some evidence of slow growth. There has been a period of stabilization now and we will see some evidence of slow growth. We're seeing a little bit more in LTC than we are in the office-based setting, but we are seeing indicators in both sections and what we said is that we're cautiously optimistic that that will be able to grow on these and see these build in the course of the spring-summer. Brendan, do you want to answer the question more completely?

Sure. Thanks, Steve. And for the reframe, I think that's all very appropriate. A couple of the guide points to us that are encouraging are the new residents entering facilities. We've seen a slow but steady increase over the prior couple of months that is encouraging. Secondly, in terms of PD in-person patient visit, as I said before, the practices are more open from our experience to both seeing our representatives, which means we have an opportunity to tell our story face-to-face to them and our HCPs are really becoming advocates in asking their patients to come in for face-to-face consultations. This is a movement disorder and the subtleties of changes there coupled with neuropsychiatric symptoms make the HCP want to see both the patient and the caregiver face-to-face where possible. What we saw in the first quarter and what HCPs have told us is Omicron forced some hesitation in an elderly population to return to those offices, that coupled with any parts of the country where winter causes concern for falls also led to hesitation. So, as both of those things improve in the weeks and months ahead, there is at least cautious optimism that there will be some return to normalcy in seeing your clinician face-to-face. So those are really the key elements.

Thank you. Our next question comes from Marc Goodman from SVB Securities. Your line is open.

Thanks for taking my question. It is Rudy on the line for Marc. So, first congrats on the quarter. I have a question regarding NUPLAZID in PDP. So can you talk about the penetration rate so far in the PDP market and maybe provide more color on off-label use so far in other indications, including ADP. Thanks.

Yes, sure. Brendan, you want to take those?

Sure. Thanks for the question. First and foremost, I think Steve did a very nice job in prepared remarks talking about the PD market and how it's and impacted over the past couple of years. I think what's impressive is despite the fact that there have been fewer inpatient visits, fewer prescriptions written for the principal motor dysfunction medications, carbidopa and levodopa, we have seen NUPLAZID continued to grow total prescriptions over pre-pandemic levels. So that gives us great confidence, number 1, that our message is resonating and that we are being chosen more often in the first line position to treat Parkinson's disease psychosis and that's evidenced by what we've seen and increases in share both on the community side and encouragingly a new patient starts on in long-term care facilities.

Thanks.

Oh, I'm sorry, in terms of the question on off-label use that still continues to be a very, very, very small number for us. As you probably know, the vast majority of our prescriptions go through a hub, which requires a treatment form where you indicate specifically why you want to put a patient on NUPLAZID that has to be indicated as Parkinson's disease psychosis. And in our environment where payers are very careful about prior authorizations, we still see very low single-digit numbers of the product potentially used for something other than Parkinson's disease.

Thank you. Our next question comes from Chris Howerton from Jefferies. Your line is open.

Excellent. Thank you so much for taking the questions. I guess what I was wondering about with respect to the Advisory Committees both for ADP and the potential one for trofinetide, how important you believe patient advocacy groups to be as part of that conversation and how influential they might be? And if you would entertain a quick clarification follow-up, how do you derive the 900,000 patients treated with atypical antipsychotics in the ADP population? Thank you.

Yes, sure. Brendan, you want to take the second question first and then we'll be back to the first one.

Sure. Thanks for the question. When we speak of 900,000 patients being treated for ADP, about two-thirds of those would be expected to have been off-label atypical antipsychotics. There are also other mood stabilizers and anti-depressants used for a similar reason in that patient population, but that is still in our consideration of the addressable population for ADP.

And Chris, you were breaking up on line. Could you repeat the first part of your question around, I heard ADCOMs, I didn't hear what you said after that.

Yes, I'm totally sorry I guess maybe say more concisely is how important do you think patient advocacy groups are for your Advisory Committees either the ADP or the potential one for trofinetide?

Yes. Thanks so much. Well, first, let me just say patient advocacy groups advocate for patients. Right? So I mean, they are independent of us. But I think in both cases, they're very strong and passion advocacy groups pushing for therapies where there's nothing approved in both in Rett syndrome, as well as in Alzheimer's disease psychosis and so I think, they're very important, particularly in the circumstance where there is no drug approved and that's where the reasons we see them being very active in this space and making sure that they elevate the unmet need that they're living with and experiencing every day in the eyes of the FDA.

Thank you. Our next question comes from Vamil Divan from Mizuho Securities. Your line is open.

Hi, great, thanks for taking my questions. Most of them have been asked, but just a couple of things, just to clarify, so one on your assumptions around guidance, I just want to confirm that you're still not assuming anything in the sales or on the expense side related to ADP, I guess, on the SG&A side, assuming in ADP approval this year. And then on the 044 chronic data, is that still expected sort of by year-end? I think it used to be a 4Q 2022 event in clinical trials to cover this through December, but I'm not seeing it specifically mentioned in your slide. So, apologies if I missed it in your comments. Thank you.

Okay. Let's go to Mark for the first question and Serge for the second.

Hi, can you hear us?

We can hear you Mark. Go ahead.

Okay. Yes, sorry. There is something happening in the phone here. So just on the guidance question, as we said previously, there is nothing in our revenue or expense guidance related to ADP at this time.

Thanks. Serge?

In regard to the osteoarthritis study in spite of the headwinds that we all experienced, particularly in the these types of studies related to COVID, we continue to expect to complete enrollment around the year-end or the beginning of next year with the data as we said in the first half -- top-line results in the first half of next year.

Thank you. Our next question comes from Paul Matteis from Stifel. Your line is open.

Thanks for taking our questions. This is Alex on for Paul. Just one more on the ADP ADCOM. I was wondering maybe Serge you could talk a little about the importance of the black box discussion at the ADCOM. I guess is it your position that there should be no ADCOM on a potential approved sNDA for pimavanserin? How much evidence you have outside of PDP to maybe alleviate FDA's concerns around sort of the unknown mortality risk in this class. Thanks.

Yes. Alex, I think you meant to say presume that we would advocate for no black box.

Yes.

Yes. Yes, no worries. So Serge, you want to take that question?

Yes. What I will say without going with all of the details that the day that we had accumulated from the previous Advisory Committee and the previous application and approval with ADP is considerably larger, not only in respect to the controlled trial data, which we added hundreds and thousands of additional patients within this category or frail, the elderly patients, but also with the six years of post-marketing surveillance with about 40,000 and every indication in the day that we see is that we are gradually moving toward a much better balance and toward the balance in regards to the mortality data compared to previous data reported at a previous submission. So from that perspective, we definitely see a favorable trend and as well as what we are seeing in some real-life studies based on the Medicare data and recently reported, we had actually two reports where we are also seeing more favorable profile in terms of mortality when compare pimavanserin to other atypical antipsychotics that are used off-label in the Parkinson's disease psychosis. So from that perspective, we are very pleased with the data that we are seeing whether this data may be sufficient for removal of box warning, it is a different question because we still, as you know all the analysis on mortality with atypical antipsychotics included thousands of patients from the clinical trial. And from that perspective, the confidence interval is much more narrower than what we are seeing in the numbers that we have specifically for pimavanserin. So, we are not of an opinion that the total amount of data and evidence because of these numbers may warrant removal of the box warning, but I will just repeat the trends that we are seeing, the numbers and the data that we are seeing, we are very confident in the favorable profile of pimavanserin in this respect.

I just want to clarify one thing to Serge mentioned at the beginning of this answer, he referred to the previous ADP application and data set and what Serge mentioned as the previous PDP. So he is referring back to our initial approval and at that time, there was a very small numerical imbalance in mortality showing very small numbers, a little bit higher mortality on drug then placebo. Fast forward, we've now done multiple placebo-controlled studies in frail, elderly patients and that imbalance has now gone away. So when we look at our placebo-controlled studies, mortality on drug and placebo is equivalent in those kinds of populations. Serge also referred to the fact that we have a lot of pharmacovigilance data now having been on the market for several years. And so that data is also continuing to be very, very supportive and in fact, it is maybe highlighted by paper published by two members of FDA, two members of CMS and two academic members of Stanford University, a little over year ago, demonstrating that pimavanserin had a statistically significant improvement in mortality rates relative to other antipsychotics used in those population. So I think the final point that Serge was making is that to this is a Class 1, so it's not a pimavanserin box warning, it is a Class 1 that all antipsychotics have and typically to remove a class warning from your drug requires a very, very substantial body of evidence, however, with larger than the placebo controlled, the aggregate placebo-controlled data that we have today. So, but despite that as Serge mentioned, all of the data that we have from the time of our PDP approval until today continues to look more and more favorable as it relates to risk of mortality.

Thank you. Our next question comes from Jay Olson from Oppenheimer. Your line is open.

Thanks for taking the question. With regards to reimbursement, can you talk about where you see the longer-term steady state gross to net for NUPLAZID in PDP and whether or not the mix of 340B payers has stabilized? And then for trofinetide, any feedback from payer discussions you've had early on, which would be great. Thank you.

Great. Thanks much. Mark Schneyer, you want to take the first question and Brendan, the second?

Yes, sure. Thanks for the question. I think from a, yes I answer the second part first. So from a 340B standpoint, we still see growth and that growth is moderating. So I think as we'd go forward for this year and we continue to moderate for future years, we'll see how that trend continues to evolve. And then as far as long-term gross to net, that's not something that we forecast. We give it out on an annual basis and we'll continue to do so.

Thanks, Mark. Jay, for the second half of your question for trofinetide, obviously we've been excited to jump in with treaters, with the caregiver community and with payers to talk about the emerging Lavender results and their perception of value and what we see and it shouldn't be surprising is that payers view trofinetide much like they see rare pediatric medications. There is very little anticipated budget impact given the overall prevalence of the population. We expect that the product will be priced like other rare disease medications. And you can look at the gamut of rare disease pediatric drugs to get some sense for that and they would expect that it would have similar access issues in terms of what was the study patient population and potentially looking at sort of the broader Rett treatment community to make certain that access is appropriate based on clinical trial results. Those are the early findings.

Thank you. And we have time for one last question and our last question comes from Esther Hong from Berenberg. Your line is open.

Hi, thanks for taking my question. So, I just wanted to ask on trofinetide. If you could provide any details on the open label extension studies that are going on, maybe if you can speak about patients who have continued on treatment and what's been observed. Thanks.

Right. Serge, you want to take that?

Yes. Thank you. As you can imagine, we as part of our overall data presentation and analysis in the new direct application, we are including a long-term data from the open-label studies, particularly from the perspective of maintenance of effect that we saw in the short-term study in patients on drug as well as the changes in the symptoms for patients that are converted from double blind into open label study from placebo to active treatment. In both cases, we are experiencing further improvement or improvement for the former and improvement for the latter in the open label study that continues over the 40 weeks of treatment and beyond. So from that perspective, we are very pleased with that, the data and will be including that in our submission. In aspect from your second part of the question in terms of the retention of patients, what we are seeing in the open label study? We are continuing to see relatively good retention of patients with a somewhat lesser dropout rates that what we saw in the double blind period which is actually expected, even though you have to take in account, double-blind studies 12 weeks long while open label study around for many more weeks and from that perspective, those are longer studies that eventually results in the people dropping out to a larger extent. So, from both perspective, we are very pleased with the data and that data will be part of our submission.

Thank you. Mr. Davis, please proceed to closing remarks.

Thank you operator and thanks everyone for joining us today. We have a pretty full calendar over the course of the next 12 months plus 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.