ACADIA Pharmaceuticals Inc.

Press star followed by zero, and a coordinator will be happy to assist you. I would now like to turn the presentation over to Mr. 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 second 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 Q2 2021 financial performance and a review of our business operations. Also joining us today 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 Sankovich, 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 Presentations 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 meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, timing of events or future results, are based on current information, assumptions and expectations, that are inherently subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially. These factors and other risks associated with our business can be found in our filings made with the SEC. Your caution not to place undue reliance on these forward-looking statements, which are made only as of today's date. I will now turn the call over to Steve.

Thank you, Mark. Good afternoon, everyone, and thank you for joining us today. I'd like to start with a review of our commercial performance, followed by some important company updates. Please turn to slide four. For the second quarter of 2021, New Placid achieved $115.2 million in net sales, representing a 5% year-over-year increase driven by sequential and year-over-year volume growth. As a result of a slower pace of pandemic recovery and a higher-than-expected gross-to-net, we are projecting net sales for the year at $480 to $515 million. Elena will discuss the gross-to-net dynamics in greater detail in her section. Let me speak to the continuing impacts of the pandemic, which impacted our growth in the second quarter. In the office-based channel, Parkinson's patients visits in the quarter were down 20% from pre-pandemic levels. This is important because many physicians are hesitant patient on a new therapy without diagnosing them first in person. So while we still grew new patient starts in the quarter, the rate of growth in the new patient starts was significantly impacted by reduced Parkinson's patient visits. In the long-term care channel, occupancy rate facilities are currently approximately 15% below pre-pandemic levels, and new admissions are down approximately 17%. For many of our patients, being in or admitted to a long-term care facility often coincides with a PDP diagnosis and thus a new patient start on new plans in. The reduction in both ongoing occupancy rates and new patient admissions continue to impact our ability to start new patients on New Plaza in the LTC setting. Despite these impacts of the pandemic on patient population, we've grown our new patient starts and our business overall. Our ability to grow despite these headwinds is further reinforced by our strong relative performance compared to other branded products in the long-term care channel. Visits long-term care facility admissions and less in-person detailing were headwinds that slowed our growth in the second quarter. These headwinds are, of course, temporal. Going forward, despite these headwinds, we expect to continue to grow our business, including sequential volume growth and new patient starts. As pandemic conditions for the Parkinson's community improve, we expect these headwinds to become tailwinds, further accelerating our growth. In addition, we have commenced several PDP growth initiatives that Amanda and Charmaine will speak to in a moment. Let's move to an update on our DRP program on slide five. We recently completed a Type A end-of-review meeting with the FDA to discuss the issues raised in the complete response letter that we received in April. Today, we'd like to share the key takeaways from that meeting. First, the FDA reaffirmed their stated position in the CRL that Pimivanserin should be studied by individual subgroups of dementia and advised us that the best path forward to conduct an additional clinical study and each of the subgroups for which we seek approval. In the meeting, we highlighted the consistent and clinically meaningful efficacy observed in the DRP population overall, as well as across individual dementia subgroups, Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease dementia, and patients with mixed pathologies. As a result of these discussions, the FDA indicated that they are open to discuss additional analyses from the HARMONY study and the 019 study, that may support a potential resubmission without conducting an additional study. We're planning to discuss analyses with the FDA at a meeting later this year. In parallel with preparations for this meeting, we will also prepare for all potential outcomes that may come from this discussion. In addition to DRP, let me highlight clinical updates as we turn to slide six. We recently completed enrollment from our phase three program for trofinetide and Rett syndrome and are on track to deliver top-line results by the end of the year. Our Phase III program for Pimivanserin for the negative symptoms of schizophrenia continues to enroll well. As a reminder, the Pivotal Advance II study was started in the third quarter of last year. Earlier this year, we initiated a Phase II study evaluating ACP-044 for postoperative pain associated with bunionectomy cert, and expect top-line results later this year. Furthermore, in the second quarter, we initiated a Phase II study evaluating 044 for pain associated with osteoarthritis. Business development continues to be a key priority for our strategy to expand our pipeline for 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 second quarter commercial performance and growth initiatives.

Thank you, Steve. Today I'd like to review our second quarter performance and our long-term expectations for new plazids in Parkinson's disease psychosis. Please turn to slide eight. In the quarter, we delivered net sales of $115.2 million with sequential volume growth of 3% across both the office-based and long-term care channels. This quarterly performance was primarily driven by new patient starts and continuing patients, which demonstrated strong patient adherence and compliance. Although new patient starts are consistent with pre-pandemic levels, they are not yet accelerating at our expected rate. We believe the reasons for this is that growth of new patient starts are dependent upon Parkinson's patient office visits and new admissions and occupancy rates within the long-term care channel, both of which have slowed due to the continued impact of the pandemic. The challenges related to the pandemic have disproportionately affected the patient population which we serve. To give you further color on this, as shown in the graph on the left, Parkinson's patient visits within the office-based setting were still approximately 20% below pre-pandemic levels in the quarter. We know physician-patient visits are highly correlated with new patient starts, and therefore we are confident that as patients return to their physician offices, new patient starts will increase, resulting in greater New Plaza demand, which will drive market penetration. Despite office-based visits being down, new patient starts in total have remained at pre-pandemic levels, as highlighted in the graph on the right, reflecting our team's ability to execute in a challenging environment. We've been able to accomplish this through our HDP messaging, which elevates PD psychosis symptom identification and highlights the efficacy and safety of New Plaza's and the urgency to treat psychosis early. Please turn to slide nine. Now turning our attention to the long-term care channel. As you can see from the graph on the top right, occupancy levels have been slowly improving at half a percent to 1% each month. However, they are still 15% below pre-COVID levels. For many patients, the identification of hallucinations and delusions resulting in a diagnosis of PDP often occurs in a long-term care facility and may coincide with a new resident admission. As new admissions increase and occupancy levels return to normal, we fully expect our momentum to translate into accelerated growth within the LCC channel. As shown in the graph on the bottom right, long-term care bottles began growing sequentially in the second quarter as a result of our enhanced marketing and promotional messaging and a modest increase of patients within long-term care facilities. Overall, we are encouraged as New Plaza's growth outperformed foundational Parkinson's medications, including Carbidopa-Levodopa, as well as a market basket of branded LCC products across multiple therapeutic areas. This performance indicates strong brand support and positions us to accelerate growth within this setting. In the near term, our ability to accelerate growth will be largely dependent on the pace of recovery of patient office visits, LTC new admissions, and face-to-face engagement. Regardless of this, we have implemented new growth initiatives, which Charmaine will now highlight.

Thanks, Amanda. Please turn to slide 10. Let's discuss our new growth initiatives, which will position us well in the second half of the year to capitalize on improvements to the leading indicators that Amanda just discussed. These initiatives incorporate new market research insights, specifically as it pertains to awareness of New Plaza's safety and tolerability profile and in light of other important medical considerations when treating Parkinson's patients. Our growth initiatives leverage important clinical data newly available for New Plaza promotion to highlight New Plaza's safety benefits. New Plaza's safety profile is a distinct advantage. We are elevating that advantage to increase diagnosis and capture a higher percentage of new PDP patients. Today, less than 50% of patients with a PDP diagnosis receive treatment. And also, our market research indicates that 37% of physicians delay PD psychosis treatment because of safety concerns associated with off-label antipsychotics. In addition, a key concern in Parkinson's patients is falls. And another is motor impairment. Our communication to HCPs highlights that Nuplavit has no warnings for orthostatic hypotension-related or sedation-related events. Cognitive impairment is another concern for physicians, especially for Parkinson's patients who've been diagnosed with comorbid dementia. Our promotion materials will now include the SAPS PD efficacy data in the cognitively impaired subset of patients with MMSE scores ranging from 21 to 25 from our pivotal PDP study. Beyond efficacy, we will also communicate that there are no safety differences across age, gender, and cognition with New Plaza treatment. After being presented with our new safety messages, approximately 77% of physicians stated that they would be more willing now to prescribe New Plaza to treat PD psychosis earlier than before. Please turn to slide 11. Our promotional messaging highlights the efficacy and safety of New Plaza and amplifies our improvement without impairment strategic vision. The new messaging will be executed across all promotional channels, including our field teams, in the second half of the year. We continue to see strong brand support for New Plaza and high engagement of our promotional presentations at medical congresses, with over 2,000 HCPs attending a branded New Plaza program in Q2. Additionally, we continue to amplify our message through digital and non-personal promotion efforts to reach our target healthcare providers. We've increased our efforts with caregivers and patients to drive more patient identification. Our consumer programs educate patients and caregivers about the signs and symptoms of PD psychosis and why it's important to talk to your doctor. While our DTC and digital platforms activate those patients to request new positive by name. Our initiatives will increase patient identification and our promotional messages with a focus on safety, set us up well to accelerate new patient starts in the back half of the year, and drive long-term prescription growth of new classes. Now I'll turn it over to Serge to share our pipeline progress.

Thank you, Charmaine. Good afternoon, everyone. Please turn to slide 13. As Steve mentioned, we had a constructive dialogue with the FDA at our end of review type A meeting. While we still do not have alignment with the FDA on what it would take for a resubmission, we are encouraged by the agency's openness to continue the discussion and allow us to present additional data analysis to further support a resubmission without an additional clinical study. Accordingly, It will take some time for us to prepare and for the FDA to schedule the meeting. As such, we will have an update on the outcome later this year. Furthermore, consistent with the views expressed in the CRL regarding individual subgroups of dementia, it appears the Division of Psychiatry at the FDA has changed their view on breakthrough therapy designation for dementia-related psychosis and have notified us that they are considering rescinding the DRP designation for Pimavanserin. We will be meeting with the FDA in the coming months to discuss further. In the meantime, our new publications in both DRP and PDP continue to be received very well by the medical and scientific community. Let's discuss further on slide 14. I'm excited to share that the positive results from our Phase III Harmony Study were published in the New England Journal of Medicine. We are pleased to be able to share these important findings that clearly demonstrate three main takeaways regarding primavanserin as a potential treatment for DRP. One, in the open label portion of the study, Pimavanserin treatment clearly demonstrated a meaningful reduction of the symptoms of psychosis. Two, continuation of Pimavanserin treatment in a double-blind portion significantly reduced the risk of relapse of psychosis by almost three times. And three, importantly, Pimavanserin was not associated with a decline in cognition or motor symptoms, and was well tolerated in elderly patients with dementia-related psychosis. Also in July, Acadia hosted a disease awareness symposium to further discuss the high unmet need in DRP at this year's Alzheimer's Association International Conference. The symposium was highlighted by key experts in the field discussing whether dementia subtypes matter when it comes to treating psychosis and the urgency for awareness and appropriate management of hallucinations and delusions across dementias. The discussion among the experts was both consistent and supportive of our view that dementia-related psychosis is most appropriately studied broadly. In June, Results from the open label extension study, which highlight the sustained Pimavanserin response in patients with PDP were published in Parkinsonism and related disorders. This data further demonstrate the utility of Pimavanserin in PDP. Let's move to our development stage pipeline starting on slide 15. with an update on our tropinotide program for Rett syndrome. As Steve mentioned, we have recently completed enrollment in the Phase III Lavender Study and are on track to announce top-line results in the fourth quarter of this year. Turning to slide 16, our Phase III program evaluating pimavanserin for the treatment of negative symptom schizophrenia includes two pivotal studies. our positive ADVANCE-1 study, and ADVANCE-2, which we initiated in the third quarter of last year. Enrollment continues to progress well and is on track. Please turn to slide 17 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 in both acute and chronic pain models. The Phase II study evaluating ACP044 for the treatment of postoperative pain following banyonectomy surgery is enrolling well, and we expect results in the fourth quarter of this year. Furthermore, we recently initiated a Phase II study for patients suffering from pain associated with osteoarthritis. Slide 18 highlights a brief summary of our ACP319 M1 PEM program for the potential treatment of schizophrenia and cognitive impairment in Alzheimer's disease. As part of our transition, we're completing some additional non-clinical work and we'll be progressing our phase one program with the initiation of a multiple ascending dose study in the fourth quarter of this year. Slide 19 summarizes our ongoing development timelines. Most notably, in the fourth quarter, we look forward to announcing top-line results from our Phase III tropinotide study in Rett syndrome and top-line results from our Phase II study for HCPO44 in postoperative pain. We look forward to keeping you updated as we advance our pipeline. With that, I will turn the call over to Elena now.

Thank you, Serge. Today I'll discuss our second quarter 2021 results and our updated 2021 financial outlook. Please turn to slide 21. In the second quarter 2021, we recorded $115.2 million in net sales, an increase of approximately 5% compared to $110.1 million in net sales in Q2 of 2020. This was driven by 5% volume growth year over year. The growth to net adjustment for Q2 2021 was 18.4% compared to our expectations of mid-teens. Weeks of inventory in the channel at the end of the second quarter were relatively flat quarter over quarter and still at the high end of the range. The question of demand in Q2 outpaced reported growth due to inventory levels slightly increasing in Q1 and then remaining stable in Q2. Moving down the P&L, GAAP R&D expenses decreased to $56.9 million in the quarter compared to $64.3 million in Q2 of 2020. GAAP SG&A expenses increased to $96.8 million in the second quarter from $84.3 million in the second quarter of last year. Non-cash, stock-based compensation expense during the quarter was $22 million compared to $19.5 million for the same period in 2020. Our cash balance at the end of the quarter was $556.9 million. Please turn to slide 22. As we look ahead, our Q2 demand growth, commercial initiatives, and leading indicators give us confidence in driving volume growth in the second half of the year. From a growth-to-net perspective, we've observed a shift in our payer mix this year with a greater proportion of volume from 340B institutions who are eligible for statutory discounts. As a result of this shift, we now expect growth to net for the full year to be approximately 20% versus our previous estimate of high teens. We are reducing our net sales guidance for the year to be in the range of $480 to $515 million as a result of the continuing impacts of the pandemic and a higher growth to net. On the expense side for 2021, we are decreasing our GAAP R&D guidance to be between $250 and $270 million for the full year from the previous range of $280 to $300 million. This includes approximately $25 million in stock-based compensation expense. We are reiterating our GAAP SG&A between $385 to $415 million for the full year. This includes $50 million of stock-based compensation expense. And with that, I'll turn the call back over to Steve.

Thank you, Elena. Please turn the slide. In closing, On the commercial front, we continue to execute in a challenging environment. In the short to intermediate term, expect to continue to grow despite these conditions. Looking from the intermediate to long term, we're fully confident in the potential of Nuclasid and are committed to getting it to the PDP patients who desperately need it. Regarding DRP, we look forward to continuing our discussion with the FDA to align on a potential path to a resubmission. We're focused on advancing our development pipeline with two clinical data readouts in the fourth quarter of 2021, while continuing to pursue attractive business development deals. Finally, I would like to thank our employees for their passion to our mission to elevate life. I'll now open up the call for questions. Operator?

Certainly. Ladies and gentlemen, if you have a question at this time, please press star then one on your touchtone telephone. If your question has been answered, and you'd like to move yourself from the queue, please press the pound key. Our first question comes from the line. Corey Cosimo from JP Morgan. Your question, please.

Hi, this is Gavin on for Corey. Thanks for taking our question. Just curious, does the FDA clarify what particular analysis needs to be completed to convince them, or what do you think you can show them to be convincing? Thank you.

Yeah, thanks for the question, Gavin. Serge, do you want to take this?

Yes. Thanks, Gavin. We brought to the Type A meeting a number of additional analysis that, you know, we looked at the meeting as an opportunity for us to address some of the questions and concerns expressed in the CRL as we didn't have opportunity prior to this to So the analysis that we brought and were of quite a bit of interest to the FDA could be summarized in a couple of buckets. One is as it relates to the clinical characteristics and features of psychosis among the different dementia subtypes. We analyzed specifically, we analyzed and looked at psychosis rating scales and did a variety of different cluster analysis, item analysis, characterizing this clinical picture of psychosis among different subtypes, whether before treatment, in the course of the treatment, as well as following withdrawal of successful treatment, essentially showing a very similar pattern of clinical characteristics and behavior among these different subtypes. So that's one bucket of analysis. The other bucket is related to the meaningful, clinically meaningful response, not only overall among patients with dementia-related psychosis, but also when you look at a pattern of response and the meaningfulness of the response among different subtypes. Particularly when you look at the response to Pimavancer in treatment, we see quite a bit of similarity and meaningfulness in that clinical response. So we perform a number of different analysis demonstrated that as well. So those were kind of the main features of the analysis that we perform and present it to FDA and we'll continue to discuss as we move forward with our discussions.

Okay, thank you very much.

Thank you. Our next question comes from the line of Nina Petrito Garg. Your question, please, from Citi.

Hey guys, thanks for taking my question. So just on the BRP indication as well, I guess, have you gotten a sense from the FDA around, you know, if you are able to kind of move forward with some additional analyses of the existing data, would a refiling or a resubmission kind of be for the broad indication, or do you think it would be for specific subtypes only? Thanks.

Thanks so much for the question. Serge, do you want to address this?

Yes.

Well, Nina, thanks for the question.

When we look at the discussions that we have and the potential paths, there are essentially boils down to three pathways that we can pursue. One is that additional analysis and the discussion and review of the data results with the alignment that the existing data is sufficient for approval of the broad DRP indication. The other option is that the data that we have for the subtypes, particularly for some of the larger subtypes that we have, like Alzheimer disease psychosis, along with the study in Alzheimer disease psychosis that we have, with the analysis and data that we present, we aligned that that data is sufficient for the approval of individual indication, individual subtype, without additional clinical work. And finally, the third part would be that if FDA remains steadfast with their position that they would want to see additional clinical data, then additional work in individual indication would be required to move forward. So that's how we see. Obviously, our position is for the first or the second option, and I think the data that were presented received some traction and we're continuing discussion and we're happy to have that opportunity.

Perfect. This is Steve. I don't know if others heard this, but there was some skipping when Serge was talking, so I just want to clarify. So, as Serge mentioned, there's three potential ways this could play out. First is our position that our existing data supports a broad DRP label. We made that case in the type A meeting we have, and we determined that we need to continue the discussion on that front. So, that's one possibility. Another possibility is to resubmit based upon one or more individual subtypes. As Serge mentioned, Alzheimer's disease psychosis is where we obviously have the greatest amount of data. It was the largest group in the study. We also had very compelling data in dementia with Lewy body. So a second potential outcome here is that we resubmit, again, without additional clinical work, based upon one or more subtypes. The third possibility, of course, is that the FDA, and this is their current view, requires that we do additional clinical work and submit on individual subtypes. Now, having said that, again, here, too, they said, this is what we suggest you do. We think this is your best path forward, but we're willing to have a further discussion with you about the possibility of submitting without additional clinical work. That's where things stand today. Those are the three potential outcomes as we see them.

Great. Thank you.

Thank you. Our next question comes from the line of Jess Hunt from Morgan Stanley. Your question, please.

Thanks for taking the questions. Just to clarify, for the follow-up meeting with the FDA, is this the meeting where the agency will make a final decision on whether to allow for the resubmission without the additional clinical study, or is there potential that this could go on to multiple additional meetings? Do you have a follow-up on that?

Yeah. Serge, do you want to take that?

Yeah. Just to clarify, I mean, type A meeting that we already had with the FDA, 60-minute meeting, and obviously we brought a a lot of information and data to that meeting and in the briefing documents. So the extension of this meeting that we will have in the next scheduled meeting is essentially continuation of the discussion that we already have. They already started and had with the FDA. We do anticipate that we will come to a certain point of alignment with the FDA or a certain point of understanding what will be necessary along the three different pathways that we just discussed at that next meeting and obviously are hoping that the data that we're bringing and the discussion at the meeting will support our position and proposals how to move forward.

Okay, thanks. And if I can clarify, so then, can you provide a little more color on the FDA reiterating their position and being open to having another meeting? Like, was that more that they're pretty firm on their position, but they'll hear you out, or does it seem like they're more open to an actual discussion?

I'll start, and then I'll let Serge add additional color if you'd like. I don't think they would have suggested, you know, we're open to having another meeting if they weren't interested in hearing more of the analysis that we're doing, that we did for the Type A meeting and we're continuing to refine that. So I think they're being genuine when they agreed to have a further dialogue. As Serge mentioned, the Type A meeting was only a 60-minute meeting. We only covered so much ground in that meeting. Having said that, again, I just want to be clear. They said, we believe your best path forward is to do additional clinical work and do an additional clinical study for each subtype that you want to pursue. But we're open to having a further discussion. That's as much clarity as I can give at this point. We need to have the next meeting in order to try to get further clarity. Thank you.

Thank you. Our next question comes from the line over to Beryl from Cowan. Your question, please.

Hi, thank you. This is Lila Onferi, too. Thanks for taking the question. Maybe just to follow up on DRP, for the meeting that you plan to have with the FDA later this year, now is that expected to be with the same reviewers, the same members of the FDA you've been interacting with, or is there any potential that it might escalate to more senior members of the division? Thank you.

Serge, you want to take that?

Yes. Let me just say that we, first of all, we were very pleased to have a strong FDA representation and presence at our type A meeting along both from the division as well as from the Office for Neuroscience. At the meeting, you know, obviously the psychiatry division director, Tiffany Faccione, was present, but also the director of Office for Neuroscience, Billy Dunn, was present at the meeting. So we anticipate, as we continue this discussion, to continue to have that strong presence from the FDA side as well and continue our constructive dialogue.

Thank you for clarifying.

Thank you. Our next question comes from the line of Charles Duncan from Cantor Fitzgerald. Your question, please.

Yeah, hi. Thanks for taking the question. I had one additional question on DRP and then a commercial question, and that is regarding DRP, I guess I'm wondering if you're contemplating actually initiating a trial with one of these patient subgroups. And then given the kind of perspective that you got from AAIC, I'm wondering if you can provide any additional color on why you think the psychiatry division is contemplating, you know, there being differences in psychoses across these degenerative disorders.

Sure. Do you want to take this question? Yeah.

Yes, let me try to address the first part of the question, second part of the question, and that is, you know, we received quite a bit of support from the medical community out there in regard to interpretation of the data and the results of our Harmony study, and the overall data that we submitted as a part of our supplemental NDA. So there is indeed, as you are pointing out, a little bit of a discrepancy in the way how Division of Psychiatry looked at the data and how the wider medical and scientific community look at the data. We were very, as I mentioned, very pleased with the fact that we also had published the data in the New England Journal of Medicine and received also a positive editorial in regard to the overall data we have. But it remains a debate within the community about how to study dementia-related psychosis, to study it as a single entity. clinical entity, which is positioned where we had, and we had an agreement to that effect, or to studies by dementia subtypes. And I guess that the Division of Psychiatry, on the basis of available data to them and the data that we presented, came to conclusion that that way of studying psychosis by dementia subtypes was is an appropriate way to study dementia-related psychosis. But that's the best that I can say.

Charles, I think you also were asking about running an additional study. Yeah. Go ahead, sir.

Yeah, we are obviously preparing for all possible alternative outcomes of our discussion. We do not want to prejudge the discussion, but we are prepared for all possible outcomes and alternative actions that we would be taking as we move forward with it. So that's how we look at things.

Okay, quick commercial question then. And I know that you don't, you know, promote off-label, but I'm just wondering if you're able to detect any change in the use of Pima Vanserin off-label as a result of the agency decision and the visibility around that. I don't even know if there is off-label use, but I'm wondering if that – if there is, if that dynamic changed over the course of the second quarter.

Yeah, thanks for the question, Charles. From the time we've launched in PDP, we've had very little off-label use. We can't track every bottle. We don't know the final destination of every bottle, for instance, that goes into long-term care. But the majority of our sales of our bottles come through our hub, and we know what the diagnosis is on every bottle, every prescription that comes through our hub. And When we look at those prescriptions, the amount that is off-label has consistently been in the low single digits, so more than 95% of prescriptions are on-label. It's difficult to get the drug off-label, as it is many drugs. It's possible but difficult, and so for that reason, a very high percent of our bottles are on-label. That has not changed throughout the life cycle of the product, and we're not seeing any differences in that today.

Okay. Thanks, Steve, for the added color.

Yeah. You bet, Charles. Thank you. Our next question comes from the line of Tazeen Ahmed from Bank of America. Your question, please.

Hi. Good afternoon. Thanks for taking my question. Guys, I just wanted to maybe clarify on the comment that you made in your prep statement about breakthrough status. I guess why would it be the case that FDA might be reconsidering breakthrough? And who's going to make that decision as you kind of have these meetings, your next meeting? Is anybody in that committee going to be involved in determining breakthrough status? And if and when it's determined what the future path is going to be, let's say the best case, you don't have to do another study, you can resubmit, does the chance now go up that it would be for regular review given the breakthrough status might be revoked? Thanks.

Yeah, sure. Serge, you want to take this? Yeah, a couple of things here. First of all, just a clarification. We received this notification from the FDA prior to our type A meeting. And the breakthrough designation at this point, you know, the reason we believe this is consistent with their CRL is it's very consistent with their position that the data did not substantiate approval for this particular indication. And at this point in the life cycle of the development, really that the regular therapy designation does not have an impact as otherwise would have. So from that perspective, this is something that we are not surprised to see. To your question, the division makes a recommendation for the breakthrough therapy designation and it's then approved by the higher levels with the agency. And in regard to the review, which is an important point, in case of resubmission, that resubmission goes either to, depending on whether it's a labeling resubmission or its additional data, which in this case would probably be, would take six months review cycle. So it doesn't go in a manner like original submission.

Okay. Got it. Thank you.

Thank you. Our next question comes from the line of Jason Butler from JMP Securities. Your question, please.

Hi, thanks for taking the questions. Just on DRP, was the Phase II ADP study discussed at all or any of the FDA's comments in the CRL relating to that study discussed? And then just on the commercial side, in geographies where the case rates of COVID have remained lower. Are you seeing a better return to physicians' offices or occupancy levels in LTC that are closer to normal? Are you seeing different things across the country, or is it still depressed across the country? Thanks.

Serge, why don't you take the first question?

Yes. Thanks, Jason. The FDA invited us to bring additional data and analysis. The point that we brought to the meeting in the discussion as far as the Phase II ADP study goes is that the positive conclusions of that study remain regardless of how you look at the data and analyze the data and independent on any concerns that the division expressed in regard to some quality issues with that study, single-center study, and so on. So from that perspective, they did invite us to bring that additional analysis and data validating the overall conclusion of that study because it is important studying the overall package of the data we submitted.

Right, thanks so much. Amanda, you want to take the geography question?

Yeah, thanks. I'll take the second question. Thanks, Steve. So specific to are we seeing, you know, differences across the U.S. as it relates to the pandemic? And we do see regional differences across the U.S., but what I will say is that we have seen, you know, from the beginning of the year until this year, we've seen a return of our face-to-face engagements with our reps and our physicians. And we've seen LTC new admissions continue to grow, although still at pre-COVID levels, as well as PD patient office visits. So we'll continue to track those leading indicators and continue to optimize with our engagements with our HCPs as we navigate the pandemic.

Got it. Thanks for taking the questions.

Thank you. Our next question comes from the line of Mark Goodman from SVB LERINK. Your question, please.

Yes, hi. So, Steve, to confirm, if the FDA ends up saying, okay, you need another study, you're willing to do another study in one of these subgroups? Is that confirmed?

Yeah, no, I appreciate the question, Mark. I think the honest answer is we need to know what would be required for a and approval in any of the individual subgroups, or for that matter for DRP generally. And we just haven't had, we're not at that point in the discussions yet. So we need to understand what that path looks like. Obviously if it's a path that, if we ultimately determine that we need to do additional clinical work to get an approval, if the path is one that we feel like is appropriate, it's scientifically valid, we still have a lot of patent life and we'll be eager to pursue it. If the path forward is one that we feel like is just not feasible, it would be very difficult to enroll or take a very, very long time to enroll, then you'll want to take that into consideration. But, you know, next step's next. The next thing we need to do is have a further discussion with FDA.

So basically at the meeting they told you that you should do another study in a subgroup to get that particular subgroup, but they didn't give you any guidance on that type of study at all. There was no discussion about what it would be.

We did not have a discussion on what that would look like. That's correct. We spent the majority of the meeting talking about the new analysis that we had done and had a dialogue around that. And, you know, again, as I said, I want to be really clear, they said we think your best path forward is to do additional clinical work. However, we're willing to have a further discussion with you to further consider the analysis that you've done.

Right. And, Serge, your comments, somewhere in the comments you used the term some traction. We got some traction. So I was just curious, what part of the discussion was it that you got some traction? Thank you.

Well, I would just directly say the buckets that I described, both sets of analysis that we were discussing were received with quite a bit of interest. This was a new information, new data that we brought, a new analysis, and there was quite a bit of interest and discussion, and finally encouragement to see more of that analysis and continue discussion in that. That is the reason that I characterized as attraction. but really relates to both buckets of the analysis.

Thank you. Mark, I might just add one additional comment. You know, any time you get a CRL, and we were very clear about this before the TAFE meeting, you know, you would expect that going into that meeting, because they just issued a CRL, that their view would be that you should do additional clinical work. So I would say we're very pleased that both Dr. Farcione and Dr. Dunn were at the meeting, and we had an opportunity to present the analysis that we did. And as Serge mentioned, I think there was very meaningful interest in the analysis, and we had a very constructive dialogue. So I think coming out of that meeting, with the recognition that this warrants further discussion, I think is what Serge is referring to when he said, you know, we've got some traction and feel like we had a productive discussion and now we need to continue that dialogue. Thanks.

Thank you. Our next question comes from the line of Salveen Richter from Goldman Sachs. Your question, please.

Thanks for taking our question. This is Andrea on for Salveen. Elena, maybe one for you. With respect to the lowered guidance there, can you help us understand What proportion of that reduction is due to expected continued impact from the pandemic versus gross to net?

Sure, Andrea. So about half the reduction is a result of the slower pace of recovery due to the pandemic, and about half of it is due to the growth to net.

Great, and then Serge, one question on ACP044 for the data that you're expecting in the fourth quarter of this year. Can you help frame expectations for that and what is clinically meaningful?

Yes, we are conducting, just as a reminder, a study in post-surgical pain, bunionectomy surgery, about 240 patients study and expect the results before the end of the year. In that study, the primary outcome measure is pain intensity measured over 24 hours. We are testing two kind of dosing regimens in the study at the highest dose level. And, you know, it's a placebo-controlled study, so we would be very pleased to see significant separation in the pain intensity or reduction in pain intensity with treatment. Over placebo, of course.

Thank you. Our next question comes from the line of Joseph Stringer from the company. Your question, please.

Hi, everyone. Thanks for taking our questions. First one, commercial on PDP. Just following up on an earlier question on sort of regional difference, just curious if you had any data or info on hesitancy amongst vaccinated PDP patients, whether it be returning to And I know in the long-term care, it's a little bit different dynamic. You mentioned occupancy and new admissions were down, but is there a different sort of effect for each of those settings? And then the second question is just on RET. Can you remind us again what to expect for a clinically meaningful change in RSPQ and CGI endpoints? Thank you.

Yeah, sure. Amanda, you want to take the first question and Serge the second?

Sure. Thanks for the question, Joseph. So let me kind of separate my question into two kind of, or my answer into two distinct categories when we think about, you know, regional differences and how we think about the business. But it really boils down to two things, and it's either the face-to-face physician and patient visits or the face-to-face physician and rep interactions. And specifically with the face-to-face physician and patient visits, This is important because we know HCPs are more effective diagnosing PD psychosis, and they have an increased willingness to prescribe a new product during an in-person patient visit. And so currently, in-person patient visits, as I shared, are about 20% below pre-COVID levels. So regardless of this, though, we've maintained our new patient starts pre-pandemic. The second thing we look at, both regionally and nationally, is when we look at face-to-face physician and rep interactions. And so what we know is that when we engage with our HCPs in person, we're just more effective than we are when we interact virtually. And so currently, more than two-thirds of our physicians and rep interactions are in person, which is a significant improvement from the beginning of the year. But it is still at pre-COVID levels. So Throughout our growth initiatives, you know, the temporal headwinds, you know, turning those into tailwinds, we do expect to see an increased demand for new plazid. And we do expect that to kind of vary regionally, but those are really the ways we look at it from both a regional and national perspective.

Yes. About the terfinetide red phase three study, As a reminder, the study has two co-primary measures. One is Red Behavioral Symptoms Questionnaire, which is a caregiver-completed questionnaire across symptoms of Rett syndrome. And the second is Clinical Global Impression of Improvement, which is a physician rating scale. So in itself, the study has sort of internal validation of whether the rating scale changes that are observed in individual patients correlate with the improvement, meaningful improvement that the physician characterized on the scale, on their rating scale. So from that perspective, since we need to reach both separation from placebo on both co-primary measures, there is an internal validation of meaningfulness of the results whenever we separate from placebo. I will remind you that in the Phase II study that was positive, there was about a 15% reduction on the scale, and obviously that was meaningful separation, particularly in the context of the broad assessment of the broad symptoms across patients Rett syndrome, as well as that there are no other available treatments at this point.

Great. Thank you.

Thank you. Our next question comes from the line of Jay Olson from Oppenheimer. Your question, please.

Oh, hey. Thanks for the update, and thanks for taking the questions. I was wondering if you could share any thoughts on Cerevel's data. for their M4 PAM and any read across that you might see to your M1 PAM. And then maybe if you could please provide an update on your latest thoughts about potential indications to pursue with your M1 PAM and when we should expect to see phase one data. Thank you.

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

Yes, let me start with our thinking around what potential indication for the M1M that we are currently developing. You know, we are taking, as we mentioned, in a broad stroke, we are looking at schizophrenia and the cognition and cognitive symptoms in dementia. When we talk about schizophrenia, obviously, one can pursue acute symptoms of schizophrenia, but also negative symptoms and cognitive symptoms of schizophrenia. We will be, what they say, following the molecule, listening to the molecule as we are developing it and conducting our phase two, because there are some indications, there are some those that believe that M1 is more targeted toward and successful in the treatment of cognitive symptoms while they aim for maybe more successful in treating the acute symptoms. I would say that we, as much as we believe in that law, we would also, there are data that suggest different, and we would like to evaluate as we further move with the development of M1PAM. As far as the M4 data from Cerevel, I would say it's an impressive data. It is an acute, short-term, acute treatment of positive symptoms of schizophrenia. We looked at that data. First of all, we do need better treatments for schizophrenia, so we are very pleased to see such positive results. as a cerebral reported, but I would also say that we are seeing that as a validation of muscarinic receptor as a target for schizophrenia and are very, very pleased that we also have a program in development in that area.

Great. Thank you.

Thank you. Our next question comes from the line of Gregory Renta from RBC Capital Markets. Your question, please.

Hey, Steve and Tim. Thank you very much for taking my question. Steve, just on the Type A meeting, I know coming into that meeting, you were really striving for an understanding of why the FDA appeared to have changed their position there. I'm just curious, coming out of that now, if you've felt as though you've reached that understanding, and as you allude to kind of the alignment path forward, what that means for getting on firmer footing with the next steps. And then just secondly, on a separate topic just related to BD, just curious if you could update us on sort of your criteria there, especially as maybe the wider industry has been prompted to rethink assets and development plans following the adecanumab approval. Thank you very much.

Yeah, sure. Let me take them one at a time, and I'll answer the first question, and then, Serge, again, feel free to adding a different color. Look, I think this is a situation where reasonable minds can differ. And we believe our position and the way to look at DRP broadly as one indication is supported by the data in the medical literature in terms of the way physicians think about this indication. most importantly in terms of the way it presents and the way it responds to treatment. So we feel like we've got a very strong case there. We think our data from our Harmony study is consistent and supports that position. As Serge mentioned, when you look at the drug-treated group in the randomized withdrawal portion of the study, between subgroups the response is very similar. It's also very similar in the open label portion of the study. So, however, we respect the fact that the FDA, particularly the Psychiatry Division, has a different position. And, you know, this is not to say that we're right and they're wrong or vice versa. They just have a different position than we do. So recognizing that, our objective is to accomplish two things. One is we want to get this drug to patients who desperately need it as fast as possible. And two, we want to get it to the broadest group of patients that can benefit from it. So as we go forward, we're going to focus on where we can try to find alignment to accomplish those two objectives, recognizing that we just have a reasonable difference of scientific opinion. Serge, anything you want to add to that?

Oh, I think you summed it up quite well.

Okay. And then to your second question regarding BD, you broke up in, I think, a key part of the second question. Could you repeat that?

Sure, Steve. I'm just curious if you could just update us on the criteria that you're applying when you look at external assets and just curious if some of the adecanum have approval while it's prompted others in the sector to maybe rethink how to look at assets and development programs, if that applies to you as well. Thank you.

Yeah, thanks. Thanks much for the question. You know, I would say our strategy on business development is unchanged. We built a presence in both neurology and psychiatry with very strong franchisees that both on the R&D as well as on the commercial and medical affairs fronts. And we're going to continue to pursue that. Is it really specifically to edutainment? I would say that has not had a meaningful impact in terms of our view of assets and the development paths forward. Having said that, I'll say, you know, we obviously, there's a topic of great discussion in the general press. There's, you know, probably political points of view and social points of view and medical points of view that relate to how the FDA is currently thinking about the accelerated approval pathway, and we'll continue to stay very much on top of that. But I would say when I step back and think about the things that are most impactful to our strategy on business development, this does not create a sea change or a significant difference.

Thanks, Steve.

Thank you. We have time for two more questions. Our next question comes to the line of Danielle Brill from Raymond James. Your question, please.

Hi, guys. Thanks so much for the questions. This may be a follow-up to the one just asked, but So maybe just if you could clarify a bit. Steve, it seems like there's nothing gating to having another meeting with the FDA. So I guess, can you just walk us through exactly what the next steps are from here to get that meeting scheduled? And then on the commercial side, I'm curious if you have any insights as to why PD office visits were down more in 2Q than 4Q or 1Q when the pandemic was at all-time highs. Thank you.

Yeah, thanks. I'll ask Amanda to answer the second question in a second. as it relates to the, I'm sorry, Danielle, could you repeat the first question?

Yeah, I'm just wondering, like, what the steps are from here to having that follow-up discussion with the FDA.

Yeah, got it. Okay, sorry. So, let me just cover it kind of mechanically first. So, mechanically, we need to submit the request. And then, depending on whether it's a type A, B, or C meeting, it'll be a 30-, 60-, or 75-day clock on the meeting, and then we need to submit a briefing document 30 days before the meeting. So, it's just the mechanical rules that are in place with FDA. We are working very diligently on the material that will be needed to be included in the briefing document, and we have that clearly within our sites before making the request. So that's coming. And just as a little bit of additional context, I would say, you know, as we reported previously, we unfortunately didn't get an opportunity to learn of the FDA's concerns in DRP that led to the CRL until we got the CRL. So we're very thankful and appreciative of the opportunity to have the type A meeting that we had and respond to those concerns. And so as we continue this dialogue, we want to make certain that we are very responsive to their concerns and responsive to the dialogue that we're having. And so in order to do that, Now that we know those concerns, we've had an initial discussion with them, it's important to get this right for the next discussion as well. So that's, of course, our number one priority. Okay. I'm sorry, Amanda, you want to take the second question?

Yeah, sure. Thanks, Steve. Thanks, Danielle, for the question. Specific to PD office visits, I just remind you that, you know, we serve a PD patient population that is elderly. So, you know, as the pandemic, you know, continues, this is an elderly patient population that we serve.

Understood. Thanks, guys.

Thank you. And our final question for today comes from the line of Emil Devan from Mizzou Securities. Your question, please.

Great. Thanks for squeezing me in, and thanks for all the details today. So maybe just one on the commercial side again, I guess for Elena, just the comments around gross to net. Maybe I know it's too early to kind of give formal guidance for next year or beyond, but can you sort of talk about, as you're talking about the higher gross to net this year, is this sort of more the range you'd expect sort of generally speaking going forward, or is this more of an unusual situation this year where things will kind of settle back down as we look at 2022 and beyond? Thank you.

Hi, Vamil. So as I mentioned in the prepared remarks, we've seen the volume from 340B institutions grow this year. It was pretty stable last year in the low single digits, and it increased this year to mid to high single digits. This is a trend that's been seen more broadly in the industry, so I wouldn't expect it to reverse. So, as I mentioned, we expect for this year, gross net to be about 20%, and we'll provide guidance for next year on our 4Q call in the February timeframe.

Okay. All right. Thank you.

Thank you. This does conclude the question and answer session of today's program. I'd like to hand the program back to management for any further remarks.

Great. Thanks, Operator, and thanks so much to each of you for joining us today. We look forward to updating you on our progress as we move forward.

Thank you, ladies and gentlemen, for your participation at today's conference. This does conclude the program. You may now disconnect. Good day.