ACADIA Pharmaceuticals Inc. (ACAD) Earnings Call Transcript & Summary

Great. Good morning from the 40th Annual JPMorgan Healthcare Conference. My name is Cory Kasimov. I'm the senior large-cap biotech analyst, and it's my pleasure to introduce ACADIA Pharmaceuticals and CEO, Steve Davis. [Operator Instructions] So with that, Steve, thanks for joining us today, and let me turn things over to you for an update.

Great. Thank you, Cory. Hello, everyone, and thank you for joining us today. I'm Steve Davis, CEO of ACADIA Pharmaceuticals. I need to just note that the business of pharmaceutical development and commercialization has certain inherent risks, so please refer to our most recent SEC filings for a description of the risks related to our business. I'd like to start this morning with a brief reminder of why we do what we do. What you see in this picture are faces of actual patients, their caregivers and family members and are the reason we work so hard. Whether it's a family member who's loved one has Parkinson's disease or Alzheimer's disease and are facing the additional burden of psychosis or a young family whose daughter is struggling with the harsh realities of Rett syndrome. These are just some of the faces of the people who deserve our very best as we seek to fulfill our mission to elevate life. Now please turn to Slide 4. In order to deliver on our mission, we are focused on 3 strategic pillars: First is to drive the growth of NUPLAZID franchise where we have continued to perform at a high level; second is to submit 2 new drug applications in 2022 for our late-stage opportunities in both Alzheimer's Disease Psychosis and Rett syndrome; and third is to develop the next wave of breakthroughs in the field of neuroscience through our internal development pipeline as well as through strategic business development opportunities. I think a prime example of our continued commitment and execution on this strategic pillar is the collaboration we announced yesterday with Stoke Therapeutics. Let's turn to Slide 6 for an update on our PDP commercial business. In 2021, we continue to outperform branded drugs in the space as NUPLAZID grew both total prescriptions and market share. Most recently, for the third quarter of 2021, we achieved an all-time high net sales of $131.6 million as a function of sequential and year-over-year volume growth. We did this despite far fewer in-person PD patient visits with their physicians and significantly lower occupancy rates in long-term care facilities. Let's look at our performance in each channel. In the office-based setting, NUPLAZID current script levels are up 28% when compared to pre-pandemic levels. This is nearly double the neurology segment branded average growth rate of 15%. During the same timeframe, the top 10 Parkinson's brands were down 7%. In addition, for carbidopa and levodopa, scripts were actually down 4% in the same timeframe. When under normal circumstances, we would expect them to be up 4%. This is particularly relevant as carbidopa and levodopa are essential PD motor medications and a reflection of the impact of fewer in-person visits in the overall PD market. Let's turn to the long-term care setting. Here, carbidopa and levodopa were down even further at 12%, a reflection of the significantly lower LTC occupancy rates. In the top 15 LTC brands were even further suppressed, they were down an average of 22%. At the same time, NUPLAZID was up 8%, despite significantly fewer patients in these facilities as compared to pre-pandemic levels. Let's now discuss our growth initiatives on Slide 7. Our strong performance underscores our team's ability to adapt and find new ways to grow the brand. This focus on growth includes the addition of 2 important campaigns we have launched in the second half of 2021: First, we launched a campaign targeting health care providers promoting NUPLAZID's unique safety and tolerability profile. This is especially important as we know the multi-receptor antipsychotics used off-label in PDP, block dopamine, the very thing Parkinson's patients need more of. This leads to impairment of motor function in these patients who are already motor impaired. These drugs also have other significant side effects that are particularly problematic in this frail patient population, including sedation and orthostatic hypotension. NUPLAZID, which binds to serotonin receptors, does not block dopamine and does not impair motor function. It carries an overall very favorable tolerability profile. In addition to this campaign for health care providers, in the fourth quarter, we also launched a new campaign directed at patients and caregivers. This direct-to-consumer campaign is aimed at closing the information divide between patients and physicians. The gap that has widened during the pandemic as the rate of in-person visits between Parkinson's patients and their doctors has declined by double digits. When Parkinson's patients are now seeing their doctors frequently, psychosis symptoms are less likely to be discussed, and doctors are many times reluctant to prescribe new medications when treating remotely. Our new television and digital ads are designed to help patients and their caregivers identify PDP symptoms and activate them to schedule an appointment and have that critical conversation with their doctor. Let's now discuss our 2 FDA submissions in 2022, turning to ADP on Slide 9. I'm going to start with the unmet need. There are over 6 million diagnosed Alzheimer's patients in the United States alone. This represents over 2/3 of the diagnosed dementia population. Approximately 30% of these patients are experiencing the symptoms of psychosis. So in sum, we estimate that there are approximately 900,000 ADP patients currently treated with off-label drugs in the U.S. The vast majority of these patients are on dopamine blocking multi-receptor antipsychotics. And just as a reminder, there is no FDA-approved drug to treat ADP today. The dopaminergic multi-receptor antipsychotic used label today offer little to no proven efficacy. These drugs unfortunately introduced a host of safety concerns, most notably an acceleration of cognitive decline. And it is not insignificant. In a very large study, dopaminergic multi-receptor antipsychotics were observed to accelerate cognitive decline in Alzheimer's patients by an amount equivalent to 1 year of disease progression. And of course, in this frail and elderly population, the last thing you want to do is exacerbate the primary symptom these patients suffer from, that is cognition impairment. Dopaminergic multi-receptor drugs are also known to impair motor function in ADP patients, another very significant side effect in this frail population. Importantly, we evaluated in our studies, if pimavanserin, which binds to serotonin receptors, could have similar safety concerns. And we look at pimavanserin across multiple clinical studies, we see no negative impact on cognition or motor functioning in ADP patients. Let's discuss our upcoming resubmission on Slide 10. Pimavanserin has the potential to be the first treatment approved for ADP, and we plan to resubmit our sNDA this quarter. We expect this to be a 6-month review cycle. Our resubmission will be focused primarily on additional analyses from 2 separate placebo-controlled studies, the HARMONY study and Study 019. In the HARMONY study, we observed highly statistically significant and clinically meaningful results in the overall dementia-related psychosis population. These results were recently published in The New England Journal of Medicine. As we previously reported, we and the FDA are now focused on assessing individual subgroups within that broad DRP population. And when we look at the Alzheimer's disease subgroup, we see a very clinically meaningful benefit in this prespecified analysis. These results were not statistically significant because the study was not designed or powered to show significance by subgroup. To further assess the response we see in Alzheimer's subgroup and address the question whether that clinically meaningful effect is a chance finding versus an effect of the drug, we've done significant additional analyses to explore the effect on Alzheimer's patients in this study. And when we look at the efficacy of pimavanserin across multiple cross-sectional analyses, you see described on this slide, we see a very high consistency of drug effect in pimavanserin. This is consistent across multiple analyses of HARMONY as well as when we compare to Study 019. Let's now turn to Study 019. During prior to running the HARMONY study, we did a separate study that was designed empowered to evaluate pimavanserin, specifically in ADP patients. In the 019 study, we showed both statistically significant and clinically meaningful results demonstrating the benefit of pimavanserin in ADP. As we previously stated in our CRL, the FDA expressed some concerns regarding the conduct of the 019 study. In response, we have conducted several analyses designed to address these concerns and confirm the positive conclusions of the study. In our latest meeting, the FDA agreed that they will review these analyses in greater detail in our resubmission. In both the 019 study and the HARMONY study, in addition to testing for efficacy, we also assessed measures of cognition. And as I noted earlier, importantly, we did not see any cognitive impairing effect with pimavanserin. So to recap, our resubmission package will include the results of Study 019, where we have statistically significant and clinically meaningful results, subgroup analysis from the HARMONY study where we met the prospectively defined endpoint in the broad DRP population. And when we look at the ADP subgroup, we see a clinically meaningful effect that is very internally consistent through multiple cross-sectional analyses. In summary, we believe when we look at the totality of our data, it supports the efficacy of pimavanserin in treating ADP, a very favorable safety and tolerability profile without impairment of cognition or motor function and an overall positive benefit risk profile. Please turn to Slide 11. In sum, we've had 3 productive meetings with the FDA following our CRL. At our last meeting with the FDA, they stated that they will review our resubmission which is focused on Alzheimer's disease psychosis, including all of our new analyses. This resubmission is our opportunity to make our case to the FDA that pimavanserin should be the first drug approved to treat ADP, addressing this very high unmet need. Let's now discuss our second NDA submission in 2022, trofinetide for the treatment of Rett syndrome, starting on Slide 13. Rett syndrome is a very serious and rare disorder for which we estimate there are between 6,000 and 9,000 patients in the United States and for which there is no FDA-approved treatment. This debilitating disorder occurs predominantly in females following apparently normal development for the first 6 to 18 months of life. Let me provide an overview of the core symptoms that impact the daily life of a typical Rett syndrome patient. These include loss of ability to communicate both verbally and nonverbally, [ gate ] abnormalities and repetitive and relentless hand moments, motor and autonomic impact and serious GI issues, especially constipation. Ultimately, Rett syndrome patients lose their ability to maintain independent functioning on a daily basis and require a round-the-clock support. Rett syndrome is a neurodevelopmental disorder as opposed to neurodegenerative and this means that the neurons actually remain intact. However, with Rett syndrome, there is a degradation of synaptic communication between neurons across the brain, which is why Rett presents with such a broad array of debilitating symptoms. Let's now talk about trofinetide's potential mechanism to address this on Slide 14. The mechanism of action of trofinetide is designed to treat the core symptoms of Rett syndrome by restoring synaptic dysfunction between neurons and in addition, reducing neuronal inflammation. As a result, we see in the positive and consistent results in our Phase III LAVENDER study shown here. We see broad efficacy across multiple end points. The LAVENDER study met both of its co-primary endpoints, demonstrating significant benefit on the Rett syndrome behavioral questionnaire, a caregiver assessment tool, as well as the clinical global impression of improvement, a physician assessment tool. We are very encouraged by the fact that in this study, trofinetide showed improvement across all 8 domains of the RSBQ, which aligns with our belief about how trofinetide works by improving synaptic communication. In addition, the study achieved statistical significance on its key secondary efficacy outcome, another caregiver assessment focused on the patient's ability to communicate. The meaningful effects, as here, can make a big difference for parents and their daughters whose lack of ability to communicate is a major issue that interferes with many aspects of their daily living. Importantly, the efficacy results were consistent across all age groups and severity of disease, which further reinforced trofinetide's proposed mechanism of action. Please turn to Slide 15. Trofinetide has been granted Fast-Track status, orphan drug designation and RPD designation, which means it's eligible for priority review and if approved, could be awarded a rare disease priority review voucher. We plan to meet with the FDA in the first quarter of 2022 and are planning for an NDA submission midyear. Our NDA will consist of the positive results of the LAVENDER study in addition to supportive efficacy data from the previous Phase II study and our ongoing open-label extension studies. As we look ahead, we are very excited for the potential of trofinetide and are committed to ensuring a successful launch from day 1. Turning to Slide 17. Beyond the significant opportunity in PDP, ADP and Rett syndrome, we're developing multiple programs in our pipeline, all of which address significant unmet needs in CNS. Let's start with a review of our negative symptoms of schizophrenia Phase III program on Slide 18. There are over 700,000 patients in the United States who are currently treated for schizophrenia, but still have persistent and potentially debilitating negative symptoms such as social withdrawal, lack of emotion and blunted affect, among others. Approved antipsychotics primarily address the positive symptoms of the disease, that is hallucination, delusion and agitation. But importantly, these drugs do not adequately control negative symptoms, which can have a profound impact on the lives of patients. Today, there is no FDA-approved treatment for the negative symptoms of schizophrenia, despite many efforts in the industry to address this unmet need. With pimavanserin, we've accomplished something not often seen with the negative symptoms of schizophrenia, and that is a positive pivotal clinical study. In our ADVANCE-1 study, we observed statistically significant and clinically meaningful results. The results of this study were recently published in The Lancet Psychiatry. We're now conducting a second pivotal study, our ADVANCE-2 study. This study is progressing well, and we expect to complete enrollment by the end of this year with the results available in 2023. Please turn to Slide 19 to discuss ACP-044. Let me start with the approach we are taking in this program to treat pain. ACP-044 is a redox modulator for pain, meaning this molecule is designed to intervene at a point in the pain signaling cascade, upstream of multiple [ CNS ] targets. We're excited about it for 2 reasons. This MOA has the potential to address a significant challenge in non-opioid pain management, and that is, if you block one pain pathway, many times another one activates. And second, this approach has potential utility in both acute and chronic pain. For acute pain, we have an ongoing Phase II study evaluating ACP-044 for the treatment of post-operative pain following bunionectomy surgery. This study is nearing enrollment completion, and we expect results around the end of this quarter. And for chronic pain, we have 2 -- we have an ongoing Phase II study, evaluating ACP-044 for the treatment of pain associated with osteoarthritis that is expected to complete by the end of 2022. Moving to Slide 20. Yesterday, we were pleased to announce a new collaboration with Stoke Therapeutics. This deal aligns nicely with our BD strategy of building out our pipeline with novel opportunities in CNS. Specifically, the Stoke collaboration extends our rare disease presence and leverages new modalities in genetic targets. The collaboration includes 3 new preclinical programs focused on SYNGAP-1 syndrome, Rett syndrome, which, of course, further strengthens our franchise there and one additional undisclosed target. We look forward to sharing further details on these programs as they develop. On Slide 21, I'd like to turn to our strategy to continue to build our pipeline through business development. On this slide are 4 examples of our execution of this pillar of our strategy: One, we licensed a muscarinic receptor program, our M1 PAM program from Vanderbilt University. Our lead compound ACP-319 is currently in Phase I multiple ascending dose trial. Two, we are excited about the collaboration I just described with Stoke Therapeutics. Three, we have multiple earlier-stage molecules, which are focused on different targets such as compounds which build upon the learnings on pimavanserin and other molecules that are focused on additional undisclosed CNS indications. And four, we continue to focus on expanding our pipeline with strategic business development. Slide 22 highlights our ongoing clinical programs and upcoming milestones. To recap what I've shared, we plan to make 2 new drug submissions to the FDA this year. In the first quarter, we expect to resubmit our supplemental NDA for pimavanserin for the treatment of ADP. Midyear, we expect to submit a new drug application for trofinetide for the treatment of Rett syndrome. We continue to advance our late-stage clinical pipeline and plan to complete enrollment of our pivotal Phase II study with results expected in 2023. And we have 2 ongoing Phase II studies for ACP-044 with topline results expected around the first quarter or end of the first quarter for our study for post-operative pain and by the end of the year in our study for osteoarthritic pain. I'd like to close on Slide 23, summarizing ACADIA's growth strategy. We will continue to grow our PDP franchise with NUPLAZID. This year, we'll submit 2 new drug applications in ADP and Rett syndrome. And we're excited about the opportunities represented in our growing clinical development pipeline as well as our early-stage programs. We are well capitalized to execute on our strategic priorities and fulfill our mission and we look forward to keeping you updated on our progress. And with that, I'll turn it back to Cory for the Q&A session.

Terrific. Thank you, Steve. Good job with that. [Operator Instructions] So I guess, for Q&A, I want to touch on a number of different subjects, but not surprisingly start on ADP. And I think when thinking about plans to resubmit the NUPLAZID sNDA, specifically for ADP, how much confidence do you have in the viability of this path forward, given your conversations with the agency versus being a so-called last digit [ tempt ], if you will, aside from your multiple meetings with the FDA, how much feedback were you able to gather from independent regulatory experts and physicians on this strategy? Because it doesn't seem like investors are giving are putting a lot of faith in this just yet.

Yes. Thanks much for the question, Cory. Let me start by just teasing a few things out here. So we've made the decision to resubmit based upon the merits of the data package we have, which we believe demonstrate a positive benefit risk profile for ADP. And of course, in putting together our data, we did extensive research and took careful counsel from many regulatory advisers as well as KOLs from the medical community. And where we stand today is, we've had 3 productive meetings with the FDA, and we've advanced the discussion significantly since the time of our CRL. In the CRL, it was clear that the FDA preferred to look at DRP on a subgroup basis as we've discussed, and they expressed their concern that the ADP subgroup did not demonstrate statistical significance. Again, it was something that the study was not powered nor designed to do. By contrast, now the dialogue at our last meeting was primarily focused on all the additional analyses we've done, which actually support a resubmission specifically for ADP. And as I've said, this resubmission is really our opportunity to make our case for ADP, and the FDA will now have the opportunity to do more in-depth assessment of all the analyses we've conducted since the CRL that support approval. I just want to note that, importantly, while we shared our new analyses with the FDA in our conclusions, the resubmission provides the FDA at the time to actually review these analyses in much greater detail and ultimately determine if they view it the same way we do. So I guess I would sum up by saying, we're confident in our data. We're confident that the data supports efficacy of pimavanserin in the treatment of ADP. It supports a very favorable safety and tolerability profile, and it supports a favorable benefit/risk profile.

Okay. And I have some questions here in the portal regarding ADP, so I'll try to work a few of these in. First one, have you addressed all the issues that were raised in the CRL? Or are there still some outstanding analyses that need to be conducted before refiling? And is there a gating factor to the refiling in terms of another FDA meeting?

There's no additional analyses we need to do, and we believe our resubmission will address all of the issues raised in the CRL.

Okay. And then the next one is, was an ADP-only indication previously considered with the original DRP filing? And if not, why not?

I got to take a little bit of running start at this. Of course, the Phase II program that we were in, the 019 study was a study in ADP patients. We head into Phase II meeting with FDA, where we describe the results of that study showed strong efficacy in Alzheimer's patients without impairing motor function and without impairing cognition and aligned with the FDA around the plan to run a broad-based DRP study, which, as we all know, is what we then ran. We ran exactly the Phase III program that we aligned around. After seeing our results, the FDA determined that they really want to focus on subgroups, and of course, as I mentioned, we -- the HARMONY study was not designed or powered to show significance on subgroups. So the answer is, yes. So certainly, at a certain point in time, after we finished the Phase II study, we considered running an ADP-only study. We felt like -- and honestly, we continue to feel like the best way to study this population is looking at a broad DRP population, but the FDA is not focused on it. They're focused on subgroups, and in our case, the subgroup where we have the most data and we feel like give us the strongest case for resubmission and potential approval without additional clinical studies is Alzheimer's Disease Psychosis. So that's where we're focused today.

Another portal question is, is there precedent or do you have examples of drugs that were approved in a subgroup of patients after receiving a CRL in a broader patient population?

Well, I'll start. Serge, feel free to jump in, if you like. It is a little bit of an unusual circumstance, right? We've all known in many circumstances where companies studied individual subgroups and then submitted an NDA seeking an approval for a much broader population using those subgroups as examples of why the drug should work across the broad population and the FDA coming back and narrowing the label to the subgroups that were studied. We have kind of the opposite situation. We aligned around a Phase III program and ran a Phase III program looking at the broad population that was never designed to or powered to show significance on subgroups. In that broad population, we have a highly statistically significant result. We're now focusing on subgroup. So this is a little bit of an unusual circumstance, I will acknowledge. I think at the end of the day, what really matters is what does the data tell us? And what we see is a statistically significant, clinically meaningful result and the 019 study focused specifically on ADP patients. And in the HARMONY Study, we see this overall highly statistically significant, clinically meaningful results in dementia-related psychosis, broadly speaking. In the subgroup, we see a clinically meaningful result that, as I mentioned in my remarks, raises the question, but it's not statistically scenic. So it raises a question, is this a chance finding? Or is this an effect of a drug? And to answer that we think the best way to probe that question is to look across multiple analyses to determine do we see a strong consistency of effect and what we see is a very consistent effect. So we believe this package strongly supports the utility of pimavanserin in ADP. We're eager to make that case with FDA.

What I would add as another element of difference from maybe other precedents that usually after the study in broader patient population fails, the sponsors look at the different subgroups trying to claim the efficacy in a particular subgroup. Our situation is very different in that, that our broader population study is positive, and we are now looking for evidence of consistent benefit within the particular subgroup. So that's a little bit different from the examples because we are working within the context of overall positive study in the broader population.

Okay. And then another portal question here is, given that you successfully submitted an application before, can we assume the likelihood of a refusal to file is minimal? Or is there still some risk based on the new strategy?

Well, so in a resubmission, a little bit like with an sNDA, you don't have all of the same steps involved in that you have with an NDA. And in a resubmission, there's not a formal filing of the resubmission by the FDA. What they typically do is, a month or so after the resubmission, if they feel like they've got issues with the resubmission, they will let you know that. So it's not a formal process like the 60-day clock that we're all familiar with on filing of an NDA. And so -- but more precisely to your point, as I said, we've had 3 very productive meetings with the FDA. In the last meeting, we really spent the -- almost the entirety of the meeting talking about the resubmission, and they very clearly expressly stated that they will review our data in the resubmission.

Okay. And then does NUPLAZID impact both hallucinations and delusions relatively equally in the ADP population?

Serge, do you want to take that?

Yes. Well, there are some differences in respect to the frequency of hallucinations and delusions across different dementia subtypes in patients. We have been consistently seeing a positive benefit on both hallucinations and delusions across different type -- subtypes. In actually, our HARMONY study, even the prevalence of hallucinations and delusions was relatively equal in the sample that we have in the study. So the answer is, yes, we do see a positive benefit at the equal extent in both on hallucinations and delusions.

Okay. And then another portal question. Were the initial positive results driven by a particular subgroup of ADP patients?

Cory, the question you asked by a particular subgroup of ADP patients. Is that what you said?

Yes.

Well, within -- the answer is no, not within ADP. So within ADP, the results that we see are uniform and consistent. Now again, we've talked about the fact that we initially studied broad DRP population and are now focused on ADP. But within ADP, it is really quite compelling, in our view, how consistent the data are across ADP patients and between the 019 and the HARMONY study when we look at the ADP subgroup.

Okay. And then the last inbound question, I see for now is, do you still have a Breakthrough Designation in DRP? And does that carry over to ADP?

So the answer is, we still have Breakthrough Therapy Designation as we previously announced, and we were not surprised when the FDA indicated they were considering withdrawing Breakthrough Therapy Designation for DRP because as we've said, they're now focused on individual subgroups within dementia. We had a meeting to discuss that. We ended the meeting with them saying that they've not made a determination and they will get back to us, and we've not heard anything more on that topic since.

Okay. And then why not start or run a concurrent study in ADP and potentially, other DRP subtypes while the review is ongoing?

Yes. So it's a good question. So let me -- this is a multifactorial consideration. So let me describe some of the considerations. So of course, with any investment in this industry, we want to be mindful of the amount of patent life that we have. And second, immediately, we juxtapose against that, what's the amount of time and money that it will take to get to an answer. And in this case, there's a significant amount of uncertainty regarding the time that it would take to enroll a study in this very elderly at-risk population, and particularly with the most recent way with Omicron, we just don't have a sufficient amount of clarity on how long it would take to do that study. So that's kind of one set of considerations. And then another important consideration is, I've mentioned this, we've not talked a lot about this, but it is an important consideration for us. We do have earlier-stage molecules that we're advancing that build on the learnings of pimavanserin. And these include a variety of profiles ranging from molecules that are designed to leverage the -- about chemical profile of pimavanserin more closely and other molecules that for competitive reasons, I won't go into, but have profiles that are even further differentiated. And of course, all these molecules have much longer patent lives. So there's an opportunity for us to pursue -- fulfilling this very high unmet need with molecules that might have much longer patent life. So again, as -- I'm going to end where I started and that is, it's a multifactorial consideration. We made the determination not to commence additional studies at this moment in time and instead focus on our resubmission.

Okay. And could you remind us what the latest is on the patent life like what the book-end scenarios are here?

Sure. So with pimavanserin, we have composition of matter patents that will take us into the second half of 2030. We -- there are 2 approved forms of the drug, 34-milligram capsule dose and on that form of the drug, we have multiple formulation patents that go into 2038. And then the other approved form of the drug is a 10-milligram tablet that's used for patients that are taking potent 3 and 4 inhibitors. And those -- that's a small single-digit proportion of the population, and we have a method of use patent on that form of the drug that goes to 2037. We're highly confident in the strength of our patents in all cases.

Okay. And then a quick follow-up from the investor on the breakthrough question. Do you still currently enjoy the typical benefits of Breakthrough Designation such as streamlined communication with the agency while they're making their determination? And I would follow up, at this stage, does Breakthrough Designation matter all that much when you're out to file?

Well, I think the last thing you mentioned is really the point. Breakthrough is designed primarily to open lines of communication while you're developing the drug so that you can get as much clarity as possible. It doesn't really benefit you that much once you get to the registration process. So -- and I think in our case, as evidenced by 3 significant meetings we had with FDA, we feel like the lines of communication are very strong. We've been very pleased that in all 3 of these meetings, we were able to not only meet with the division of psychiatry, but also the office of Neuroscience was represented at these meetings. And that's given us an opportunity to really, I think, have these very 3 productive meetings.

Okay. We only have a few minutes left, but I want to make sure we touch on trofinetide and Rett syndrome. So can you just -- can you speak to your confidence in the ability to file with the FDA on the basis of LAVENDER alone, maybe some -- I know you're meeting with the FDA later this quarter, but some -- the earlier regulatory interactions you may have had?

Sure. So this is with the neurology division, and I'm going to ask Serge to answer this question.

Yes. Thank you. Well, I'll start by first expressing our level of -- that we are very confident in the strength of our trofinetide data. And in regard to the discussions with FDA and the expectation, yes, I want to remind you that the LAVENDER study design and co-primary endpoints were agreed with the FDA upon at the end of Phase II meeting. In fact, the FDA recommended we made both the caregiver assessment, Rett syndrome behavioral question as well as physician assessment, CGI-I as a co-primary end points in the study in order to provide the level of internal validation of the meaningfulness of the results and both were statistically significant. Therefore, we feel very confident and are planning to further reiterate what will be included in our submission at an upcoming pre-NDA meeting with the FDA, which we expect to hold this quarter. And I would say that actually we also had a pre pre-NDA meeting, which we also discussed even in advance of the LAVENDER study results, discuss the package for the NDA. So we had a very good ongoing dialogue with the FDA and are looking forward to our submission midyear.

Okay. And then, Serge, probably for you. You have the acute pain readout later this quarter. Going into that, what are you hoping to see? What would be a promising result that would justify advancing the asset?

I would say that in terms of the post-operative pain, this is a pretty straightforward study. We, of course, are looking for, first of all, favorable tolerability and safety profile of the drug and the efficacy side, we would want to see separation of the dose of ACP-044 from placebo in the reduction in pain intensity within the -- or before 72 hours post dose. So this is a Phase II study. We are looking for positive efficacy, separation from placebo and primarily, also a good tolerability and safety in order to obtain this program further. Similarly, in the osteoarthritis chronic pain model, I would offer the same answer. We're looking for favorable tolerability and safety profile along with separation from placebo on the -- at least one of the dosing regimens that we will be studying in the 4-week study on the pain rating scale.

Okay. Perfect. Well, with that, I believe we are out of time. So thank you guys very much. A very busy year coming up, so best of luck to you.

Thank you very much, Cory.

Thank you very much.