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

Good day, ladies and gentlemen, and welcome to ACADIA Pharmaceuticals conference call. My name is Towanda, and I will be your coordinator for today. [Operator Instructions] I would now like to turn the presentation over to Mark Johnson, Vice President of Investor Relations of ACADIA. You may proceed.

Thank you, Towanda. Good afternoon, and thank you for joining us on today's call to discuss the positive top line results from the pivotal Phase III LAVENDER study evaluating trofinetide as a potential treatment for Rett syndrome. On today's call, Steve Davis, our CEO; and Serge Stankovic, our President, will provide some opening remarks. Following Serge, we will hear from Dr. Dominique Pichard, Chief Scientific Officer at the International Rett Syndrome Foundation, who will discuss Rett syndrome and the unmet need in greater detail. Then Kathie Bishop, our Chief Scientific Officer and Head of Rare Disease, will walk us through the LAVENDER results. Finally, Steve Davis will provide some closing remarks, and then we will conduct a Q&A session. In addition to our speakers today, Brendan Teehan, our Chief Operating Officer and Head of Commercial; and Mark Schneyer, our Interim Chief Financial Officer and Chief Business Officer, will be available for Q&A. I would also like to point out that we are using supplemental slides, which are available on the Events & Presentations section of our website. Please turn to Slide 2. 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. 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 Davis, CEO of ACADIA.

Thank you, Mark. Good afternoon, everyone, and thank you for joining us today. We are thrilled to be sharing with you the positive results from our pivotal Phase III LAVENDER study evaluating trofinetide for the treatment of Rett syndrome. Serge will provide a quick overview of trofinetide before turning the call over to 2 very important speakers. Let me introduce them to you now. First, we are honored to be joined today by Dr. Dominique Pichard, the Chief Scientific Officer at the International Rett Syndrome Foundation, or IRSF, who will provide a deeper understanding of the challenges of Rett syndrome. For those of you who are not familiar, IRSF is a leading Rett syndrome research and advocacy organization, building on its nearly 40-year commitment to breakthrough discoveries and life-changing advancements in research to treat Rett syndrome in addition to supporting families affected by this very debilitating disease. Dr. Pichard has focused her career on patients with rare disorders and complex medical needs. Prior to joining IRSF, Dr. Pichard held a joint appointment at the Department of Pediatric Oncology and Department of Dermatology at the National Institutes of Health, where she worked as a clinical investigator. In addition, as the parent of a daughter with Rett syndrome, Dr. Pichard is committed to identifying research breakthroughs for Rett syndrome. Following Dr. Pichard's presentation, we will hear from ACADIA's Chief Scientific Officer and Head of Rare Disease, Dr. Kathie Bishop. Kathie has more than 20 years of experience in leading translational research and drug development with a focus on novel therapeutics for the treatment of neurological and rare diseases. Kathie will present in greater detail the results of the LAVENDER study. I'll now turn the call over to Serge.

Thank you, Steve. I would like to start with a few brief remarks regarding Rett syndrome, patients suffering from this devastating disease and the Rett community. Rett syndrome is a rare neurodevelopmental disorder that leaves its victims, predominantly girls, without the ability to maintain independent functioning on a daily basis and consequently require round-the-clock support. We are grateful to have with us today Dr. Pichard to help us understand better just how severe and distressing this disease is and the tremendous need for an effective relief. Over the course of development -- developing trofinetide, we have observed firsthand the burden this disease places on patients and their caregivers. That is why it is so important to have a potential therapy that can treat Rett syndrome. Currently, there are no FDA-approved treatments, representing a serious unmet medical need. In our efforts to develop trofinetide for the treatment of Rett syndrome, we have been fortunate to have strong encouragement, support and cooperation from the Rett community. Without incredible dedication and perseverance of patients, their parents and caregivers as well as the medical and scientific community, we would not be able to advance trofinetide as a potential new treatment. For this, I wanted to express our deepest appreciation and thanks to all of those involved with trofinetide clinical studies. Slide 5 is an overview of trofinetide and its proposed mechanism of action. Trofinetide is an orally available novel synthetic analog of the amino-terminal tripeptide, or IGF-1, designed to treat the core symptoms of Rett syndrome. Rett syndrome is neurodevelopmental disorder as opposed to a neurodegenerative disorder, which means the neurons are still intact. However, their communication has been compromised with lack of synaptic functioning. It is thought that trofinetide acts by improving synaptic function and restoring synaptic structure by inhibiting overreaction of inflammatory microglia and astrocytes and by increasing the amount of IGF-1 in the brain. From regulatory and IP perspective, trofinetide has Orphan Drug status and is protected by a method of use patent for the treatment of Rett syndrome, which provides exclusivity with expected Hatch-Waxman patent extension to the end of 2035. Please turn to Slide 6. I'm really excited to share with you today that our pivotal Phase III LAVENDER study met both of its primary endpoints, achieving statistically significant separation from placebo on both the Rett Syndrome Behavioural Questionnaire, or RSBQ, a caregiver assessment tool; and the Clinical Global Impression of Improvement, or CGI-I, a physician assessment tool. In addition, the study achieved statistically significant separation from placebo on its key secondary efficacy outcome, another caregiver assessment focused on the patient's ability to communicate. Importantly, the efficacy results were consistent across all age groups and severity of disease. Based on the LAVENDER study results, we plan to meet with the FDA at the pre-NDA meeting in the first quarter of 2022. I'm now pleased to hand the presentation over to Dr. Pichard to further discuss Rett syndrome.

Thank you, Serge. I look to start on Slide 8. Rett syndrome is a rare neurodevelopmental disorder, affecting 1 in 10,000 female babies and affecting males at much lower rates. Rett syndrome impacts nearly every aspect of daily living. There's a period of normal development followed by a loss of skills, leaving a typical child with Rett syndrome unable to use her hands, walk, eat or even breathe easily. Medical complications include seizure, scoliosis, breathing issues, pneumonia, sleep disruption and gastrointestinal disturbances. Despite this complex, very involved disorder, many individuals with Rett live into adulthood requiring 1-to-1 care for all aspects of their day for their entire lives. There are no treatments for Rett syndrome. This is a tremendous unmet need as the treatment for many issues in Rett syndrome do not adequately address the symptoms they are intended to treat. Next slide, please. Rett syndrome looks like all of these disorders listed on the right in one child. The impact is across virtually all body systems and leave those with Rett syndrome trapped in a body that won't let them do what they want to do and often ravaged by the medical issues that I mentioned. Next slide, please. Rett syndrome, caused by mutation on the MECP2 gene, is diagnosed by meeting a set of clinical criteria. As you can see on the slide, there are 5 necessary criteria as well as 2 criteria of exclusion. The supportive criteria are useful in the diagnosis of a typical Rett but are not sufficient nor necessary for the diagnosis of classic Rett syndrome. On the next several slides, I will briefly touch on some of the main signs and symptoms of Rett syndrome. Next slide. The repetitive hand movements or hand stereotypies are characteristic of Rett syndrome. Individuals with Rett cannot use their hands for any intentional use as they are mostly in a stereotypic pattern. This leaves them fully dependent on adult to do everything for them. Next slide, please. Sleep is very commonly disrupted in Rett syndrome. Some individuals have difficulty falling asleep, and many cannot stay asleep, waking up in the middle of the night, sometimes for hours at a time. This is disruptive not only to the individual who has Rett and does not get appropriate rest but to the entire family. Next slide. Seizures are very common, presenting in approximately 80% of individuals with Rett syndrome, usually in early childhood. The seizures can be very difficult to manage, often requiring more than one antiseizure medication, sometimes even 3 or 4 medications and maybe an implantable device in addition. The results are mixed, often leaving the individual with less frequent or shorter seizures, but not complete control of the seizure disorder and several side effects from the medication cocktail. The seizures can result in many hospitalizations over the course of a lifetime. Next slide. The breathing abnormalities in Rett syndrome include breathing too fast or hyperventilation as well as stop in breathing or breath-holding, both of which are very disruptive. The breathing abnormalities interfere with everyday functioning and can be as severe as requiring supplemental ventilation, as seen in this photo. Next slide. Anxiety can be a significant issue in Rett and may be more noticeable in those who have more preserved function and can demonstrate their anxiety compared to those with less abilities, but it is no less significant. And this can significantly interfere with the ability to leave the home and integrate into the community or school setting. Next slide. Issues of the gastrointestinal tract are near universal in Rett syndrome, from dysfunctional chew and swallow to failure to thrive, resulting in the need for a feeding tube to chronic constipation. It is rare for an individual with Rett syndrome to not be touched by at least one GI symptom. In particular, the constipation can be something that life of the family had to revolve around. Medications and procedures required to maintain regular stooling and prevent impaction are part of routine life in order to decrease the need for hospitalization due to this constipation. Next slide, please. Many individuals with Rett syndrome develop scoliosis, one of the most common orthopedic issues in Rett, often requiring a spinal fusion to correct a significant deformity that is quite debilitating. Next slide. Individuals with Rett are mostly nonverbal, although not noncommunicative. They have the intent and intellect to be able to communicate, but they cannot communicate verbally and cannot use their hands to type or write. Therefore, they require technology and people around them who learn their body language and nonverbal communication system. Now that I've provided a deeper dive into many issues that are part of daily life in Rett syndrome, I want to briefly touch on the Rett Syndrome Behaviour Questionnaire, which was used as one of the co-primary endpoints in the LAVENDER study. Next slide, please. As Serge mentioned, the RSBQ is a rating scale completed by the caregiver of the study participants. As we just reviewed, an individual with Rett syndrome is not able to complete their own rating scale. So in Rett syndrome, we depend on the caregiver to report for the individual they care for. This scale has 45 items, which cover 8 domains. The ratings reflect severity and frequency of the symptoms in Rett syndrome. Each of the 45 items is scored as 0, 1 or 2 to report an item is not true, sometimes true or often true. Previous studies have demonstrated that the RSBQ has been correlated with functioning as well as quality of life in Rett syndrome and has been characterized across the range of ages in Rett. To provide context of the rating scale, one example is the item spells of inconsolable crying for no apparent reason during the night. So for an individual for whom this is a 2 or often true, this impacts them and their caregiver in a significantly negative way. These spells with no known treatments are a driver for negative quality of life. A change in 1 point would mean this individual went from having these episodes often to having them sometimes, or a change in 2 points would mean this individual does not have these crying spells overnight at all. For disorder with no FDA-approved therapy, these seemingly small changes can mean a big change in quality of life for that individual and their entire family. I'll now turn the presentation over to Dr. Kathie Bishop at ACADIA.

Thank you so much, Dr. Pichard, for your perspective and spending time with us today. We appreciate all that you do for the Rett syndrome community. First, I would like to echo Serge in thanking the caregivers and patients, the investigators and clinical study teams for all their hard work, especially given the world we have been operating in over the past couple of years. I am really excited about these results and what it means for patients and their family members who have put their trust in us to deliver on the promise of trofinetide. Today's LAVENDER results represent a clear step forward to potentially delivering Rett syndrome patients and their caregivers an FDA-approved treatment option. Let me first walk you through the study design on Slide 21. The LAVENDER study was a pivotal, randomized, double-blind, placebo-controlled study in 187 girls and young women ages 5 to 20 with Rett syndrome. Patients were randomized 1:1 to placebo or trofinetide and then evaluated for 12 weeks using the co-primary endpoints of the RSBQ and the CGI-I. After week 12, all patients have the opportunity to continue treatment with trofinetide by rolling over to LILAC, our open-label extension study, until week 52. Following LILAC, patients have the option to continue to receive treatment in our additional open-label extension study, LILAC-2, until trofinetide is potentially FDA-approved and commercially available. Let's quickly review the baseline characteristics of the subjects in the study on Slide 22. The average age of patients in the study was approximately 11 years old, with about half of the patients being in the 5- to 10-year-old group and about 25% in the 11- to 15-year-old group, with about 20% in the 16- to 20-year-old group. There was a good balance between placebo and trofinetide and the severity of the disease at baseline, and enrolled patients generally presented with moderate to severe Rett syndrome. Please turn to Slide 23. As Serge mentioned, statistically significant separation from placebo was achieved for both of the prespecified co-primary endpoints in this study. At week 12 for the RSBQ, the p-value was 0.0175, with an effect size of 0.37. As a reminder, the RSBQ is a validated caregiver-completed rating scale assessing a wide range of neurobehavioral and neurodevelopmental core symptoms known to be impaired in Rett syndrome. Trofinetide patients improved an average of 5.1 points on the RSBQ from baseline in 12 weeks. In addition, at week 12, for the CGI-I, the p-value was 0.003, with an effect size of 0.47. The CGI-I is a clinician-completed assessment of how much the individual's illness has improved or worsened relative to baseline, scored using a standardized rubric that is specific to the clinical features of Rett syndrome. Furthermore, in the study, statistical significant separation from placebo was also achieved on the key secondary efficacy endpoint. The Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist-Social composite score is designed to assess the communication skills of the patients. Although initially designed for infants and toddlers, this scale is applicable and has been applied to older age groups for patients with neurodevelopmental disorders. Lack of ability to communicate verbally and nonverbally, as Dr. Pichard mentioned, is a significant challenge for Rett patients and their families. On this endpoint, at week 12, the p-value was 0.0064 with an effect size of 0.43. The consistency of these results was observed across all age groups in the study and severity of disease. In addition, these results are very consistent with what was observed in the Phase II study. Please turn to Slide 24. I'd like to briefly show graphs that demonstrate patients' improvements on trofinetide in the study compared to placebo on the co-primary endpoints. This graph demonstrates the change in RSBQ from baseline in the trofinetide and placebo arms through week 12. As you can see, in the placebo group, there is an initial improvement at week 2 that then dissipates, whereas in the trofinetide group, there's continued improvement with a clear separation from placebo at week 12, an improvement of 5.1 points at that time point. As Dr. Pichard mentioned, even a small point change on the RSBQ can make a big difference in the daily lives of Rett patients and their families. Let me give you some further examples that illustrate this to help you better understand the context of these results. A 1-point change on the item of uses gesturing to obtain desire objects or using gaze to convey feelings, needs and wishes would mean that the girl goes from doing this never to sometimes and a 2-point change from never to often. Similarly, a 1-point change on the item of expressionless face would mean that the girl goes from often to sometimes and a 2-point change from often to never. Thus, the 1- or 2-point changes I described can represent significant and meaningful changes for these patients. As shown on Slide 25, the RSBQ has 8 subscales. These include general mood, breathing problems, hand behavior, repetitive face movements, body rocking and expressionless face, nighttime behaviors, fear and anxiety and walking/standing, whose ratings reflect severity and frequency of symptoms. The trend was in favor of treatment with trofinetide on each of these subscales, and the overall effect on the RSBQ was not driven by just 1 or 2 individual domains. Please note that the study was not designed to test significance for the individual subscale. But together, they represent a very consistent effect on core symptoms. Slide 26 shows a graph of the CGI-I scores calculated at each visit. At week 12, you can see a clear and significant separation from placebo. These results are meaningful as CGI-I as a co-primary endpoint and physician assessment further validated the findings from the RSBQ score, a caregiver assessment. With both being statistically significant -- with significant effect sizes, it certainly implies a meaningful and consistent benefit. Let's move on to review the safety and tolerability findings of LAVENDER starting on Slide 27. Regarding safety, there were no areas of significant concern with trofinetide. Serious adverse events were low at approximately 3% in both the trofinetide and placebo groups. About 17% of patients on drug discontinued due to an adverse event compared to 2% of placebo patients. The most common adverse events were GI in nature, which we will discuss on the next slide. As shown in the table on Slide 28, the most common adverse events were diarrhea and vomiting, the vast majority of which were characterized as mild to moderate, not in [Audio Gap] 12% of patients discontinued due to diarrhea in the trofinetide group in the LAVENDER Phase III study. As Dominique -- Dr. Pichard noted, I'd like to point out that the majority of patients with Rett syndrome have GI issues, which can include severe constipation, for which they may be taking anti-constipation medications. Using learnings from the study and expert advice, we have developed a management strategy for the diarrhea, which includes withdrawal of these anti-constipation medications. So far, this seems to be making a positive difference. We have observed this towards the end of the LAVENDER study and have continued into our open-label studies, and we will continue to optimize and implement this diarrhea management protocol as we move forward. Notably, over 95% of the completers of the LAVENDER study elected to roll over to the LILAC open-label extension study. And with that, I'll turn the call back over to Steve.

Great. Thanks, Kathie. Let's turn to Slide 30. Today, we shared a little bit about Rett syndrome and the positive results from our pivotal Phase III LAVENDER study. So what's next? First, as a reminder, trofinetide has been granted Fast Track Status and Orphan Drug Designation for Rett syndrome, making it eligible for priority review. In addition, trofinetide has been granted Rare Pediatric Disease, or RPD, designation by the FDA and could be awarded a Rare Disease Priority Review Voucher if approved. We plan to meet with the FDA at a pre-sNDA meeting in the first quarter of 2022 and have already started to plan towards an NDA submission around midyear. Our NDA will consist of the positive results announced today from the LAVENDER study in addition to supportive efficacy data from the previous Phase II study. The NDA will also include longer-term exposure data from our ongoing open-label extension studies. So far, the observed safety profile in the open-label studies is consistent with what we observed in the Phase III study. Please turn to Slide 31. Today's positive LAVENDER study results for trofinetide are a very meaningful step forward for Rett syndrome patients and their families, especially in light of the high unmet need and lack of currently available treatment options. These positive results underscores ACADIA's commitment to investing in therapies to address high unmet needs in CNS. I want to echo everyone's comments and thank all of the patients, caregivers, family members and physicians for all of their hard work in getting us to where we are. I would also like to thank our partner, Neuren Pharmaceuticals, for the great collaboration along the way; and our ACADIA employees, their commitment to our mission to elevate life. Now let's open up the call for questions. Operator?

[Operator Instructions] Our first question comes from the line of Yatin Suneja with Guggenheim Partners.

Just a couple of questions for me. With regard to the average age in the study was 11, can you just talk about how the drug performed across the 3 subgroups that you highlighted, up to 20 years of age? Basically, how the drug works in kids versus the adults? And the second part of the question is, can you just talk about the missing data? Like how was that imputed or handled? And what was the main reason for discontinuation?

Sure. Thanks much for the questions. Kathie, do you want to take this?

Yes. Thanks. And first, I would just like to start and remind everyone that Rett syndrome is not a neurodegenerative disease, but it is a neurodevelopmental disease. And what that means is that neurons are intact. They stay intact through the lifetime of the patient, but there's a loss of synaptic function and some synaptic -- loss of synapses themselves. What trofinetide's mechanism of action is, is to restore that synaptic function and reduce inflammation so that synapses do not continue to be lost. So with that, we would expect, based on that [Audio Gap] As I was mentioning, Rett syndrome -- I just want to remind everyone, it's not a neurodevelopmental disease, but it's a -- sorry, not a neurodegenerative disease, but it's a neurodevelopment one in which the neurons stay intact through the lifetime of the patient, but they lose their synapses and synaptic function. Based on the mechanism of action of trofinetide and based on preclinical data from animal model, it is possible to restore that synaptic function at any point within the disease course of these patients. Consistent with that, when we analyze the Phase III data, looking at the age group of 5 to 10 years of age, 11 to 15 years of age and 16 to 20 years of age, we see a very consistent effect across both the RSBQ and the CGI-I, with improvements in all age groups. I apologize, I've forgotten the second question.

Got it. Yes. The second question was, how was the missing data imputed or handled? And what was the main reason for discontinuation?

Okay. Thank you very much. So we did have a few discontinuations due to COVID during the trial. We carefully took accounting for missing data in several different methods to look at the missing data as part of our sensitivity analysis. We are very happy that all of the sensitivity analysis we conducted both for the RSBQ and the CGI-I were all statistically significant at a p-value less than 0.05, indicating that the missing data did not have an effect on the results and the results are robust. As mentioned, the main reason for discontinuation in the trofinetide group was due to the adverse event of diarrhea, and that rate was about 12% over the 3 months of the study.

Got it. Just one final question. I'll get back in the queue. Can you just talk about your confidence on filing based on just one study? Did you have any prior agreement with the FDA that one study should be sufficient to file?

Sure. Thanks much for the question. Serge, do you want to take that?

Yes. We had prior discussions even at the time when we were at the end of Phase II meeting and laying out the program for approval. And we do have alignment with the FDA that a positive LAVENDER study with a positive data on both co-primary outcome measures would be sufficient for filing and approval.

And I'll just add on to that briefly that for the trofinetide Rett program, we are working with the neurology division of the FDA. And in my experience, they have very good experience dealing with rare diseases and are very familiar.

Our next question comes from the line of Charles Duncan with Cantor Fitzgerald. [Operator Instructions]

Yes. Steve and team, congratulations on this positive readout. I'll ask a 2-part question. One is on diarrhea and vomiting. In terms of the timing and severity, can you -- if you could provide a little bit more color on that, did the diarrhea occur early or late in the 12-week period? And do you think that it could have had any impact on finding? And the second part of the question is regarding the 8-item scale. Body rocking and fear and anxiety look to be the biggest, call it, difference or improvement driven by trofinetide. And I guess I'm wondering if that squares with what you think is the mechanism. And is that -- are those 2 items the most, I guess, highly burdensome to caregivers? And is that where you'd want to show clinical benefit?

Great. Thanks much for the question, Charles. Kathie, do you want to take those?

Charles, thanks for the question. With regard to the first question on the diarrhea, we've done a careful analysis both of timing and severity. Just a reminder that 97% of the -- or 96% of the cases of diarrhea were mild to moderate. We do not see this as a safety issue. It doesn't lead to dehydration or hospitalization in the trial. It generally -- and I'd say most patients occurs within the first couple of weeks of starting trofinetide, but there are some later cases as well. And there is some variability in how long it lasts in these patients as well. Regarding the question about diarrhea and/or vomiting potentially affecting the efficacy results and unblinding, that's an excellent question and one we asked ourselves as soon as we got the data. We've analyzed the data, looking at this in several different ways, and feel very confident that the answer is no, it did not unblind the study. For example, when we looked at response in patients with and without diarrhea and/or [ vomiting ], in all cases, the trofinetide patients performed better than placebo patients. And we don't see a consistent effect where diarrhea is driving the clinical response. Another example of the type of analysis we did is that we looked at clustering of effects with and without diarrhea and see a consistent response across patients with no clusters based on diarrhea. With regards to the RSBQ subscores, I think what reassures us is that all of the subdomains are moving in the direction of a positive response with trofinetide, showing that the effect was very consistent. We just got the top line results -- sorry, digging deeper into a little bit on the response and the difference of domains, so I don't think I have an answer on what's driving the response for some of them yet.

Sounds good. Congrats.

Our next question comes from the line of Cory Kasimov with JPMorgan.

I'll stick to just one. Can you -- I know you said you started to evaluate the removal of the anti-constipation medications that most of these patients are on to help deal with the diarrhea issue you've seen. Can you provide any more color in terms of some of the early, even if anecdotal, kind of feedback you're getting from doing that?

Sure. Kathie?

Okay. Thanks. So good question. First of all, I'd like to mention that this is a Phase III trial where patients were randomized either to placebo or trofinetide. So there was -- it makes it more difficult to ask the parents to remove those anti-constipation medications when they know that their girl may get randomized to the placebo. So it sort of was near the end of the trial and as we move into the open-label trial that we're able to do a lot more in terms of removal of the anti-constipation medications or other things such as change in diet or increase in fiber that may help lessen the diarrhea. But what we have done working with some of the clinical trial sites and also consulting GI effort is developed a diarrhea management plan that we implemented late in the study and now in the open-label studies that seems to be having an effect. What we hear anecdotally is that through these measures, the diarrhea changes from a watery explosive type to more like soft-serve ice cream, which is much easier for the caregivers of these patients to manage. We did see an effect late in the LAVENDER trial, where implementation of this plan led to fewer discontinuations near the end of the trial due to the diarrhea. We are -- now that we have these exciting Phase III results, our goal is to bring the treatment to patients. And as part of that, we'll continue to optimize and implement measures to help control the diarrhea.

Maybe if I could just ask Dr. Pichard to comment on how [Audio Gap] diarrhea in the context of this disease and the impact on utilization.

Yes, absolutely. So as I mentioned in the presentation, the constipation is a significant issue around which family life can revolve at times. And so a shift over to diarrhea can also create a problem unless there's some sort of management that controls this symptom. And so it alleviates the risk of impaction and the hospitalizations and the downstream issues that can happen as a result of the chronic constipation. And with appropriate management, the diarrhea can often be controlled in a population that is largely in diapers at baseline and, therefore, able to manage in all settings.

Our next question comes from the line of Neena Garg with Citi.

Congrats on the data. I was just wondering if you could talk a little bit about kind of the results that you saw by baseline kind of disease severity. I know you gave the breakdown based on CGI-S at baseline. So maybe if you could talk a little bit about that. And then also, I didn't see the baseline Rett Syndrome Behavioural Questionnaire number. So if you could share that, that would be great, too.

Sure. Kathie?

Yes. Thanks. So in addition to looking at the age groups, as I mentioned, we also looked at the response on the efficacy endpoints according to baseline severity using that cutoff on RSBQ of less than or equal to 35 and greater than 35. And just as we saw across the different age groups, we see a really consistent response across the severity levels of Rett syndrome on both the RSBQ and the CGI-I. With regards to the baseline scores, on RSBQ, they were well balanced between each groups and were approximately 44, 45.

Our next question comes from Vamil Divan with Mizuho.

This may be tied and similar to the prior question, but just around the baseline characteristics and specifically on the CGI, what you show on the slide here. It looks like it's maybe a little bit more skewed to markedly ill or severely ill patients in the trofinetide arm. I know the numbers are pretty small, but the whole study is pretty small. So I'm just wondering if you did any sort of adjustment for the baseline imbalances due to the CGI-I or anything else that you have to adjust for in the trial.

Yes. So definitely, our primary analysis model takes into account the baseline score of each patient in the model and adjusts for that. So that's accounted for in the -- all of the efficacy endpoints.

Okay. And maybe if I could just squeeze in one more then, just a quick follow-up. Just curious, I think a lot of questions we've been getting from investors around how to think about potential pricing for a product in this market. I know probably a little bit too early to say too much. But since we have some data now to react to, I don't know if Steve or anyone from the team want to just maybe share initial thoughts on how you're thinking about pricing for the product.

Brendan, do you want to take that?

Sure, Stephen. Thanks for the question. And I think it was a bit asked and answered. I think it's premature today for us to be talking about pricing. While we're still working through the details of the strategy, I would say similar to NUPLAZID, we will look to price the drug based on the value we believe it imparts to the patients suffering with Rett syndrome. And that will be the main factor determining our ultimate price.

I think I would just -- just to remind, Rett syndrome is a rare disease, and so you should expect pricing that would be in the -- that would be commensurate with the way drugs are priced in that space. And as Brendan mentioned, we always seek to price based on the value we're delivering. In this case, we believe with no drug approved for the treatment of Rett syndrome, given the very, very debilitating nature of this disease, we think that we have the potential of having a very significant impact on the lives of these patients, their families and caregivers.

Our next question comes from the line of Marc Goodman with SVB Leerink.

I was curious, what kind of label do you get as far as age here? I mean do you get a full label for anyone with Rett? Or do you expect it to be 5 to 20 years old? And if it is, what percent of the Rett syndrome patients does 5 to 20 make up? And then I just want to follow up on one thing to try to understand the previous questioning on the CGI-I. So I understand that's a 7-point scale and you go from improved or you're getting worse or whatever it is. But there are specific features that you're asking about, right? Are you more attentive? Can you communicate better? Is your functioning better? Like do you ask those questions? Like can you tell us like what part was getting better there? Because we noticed that you had a full slide on what was happening with the RSBQ, but you didn't have one on the CGI-I.

Sure. Serge, do you want to take the first question? And Kathie, maybe you the second?

Yes, I'll be happy. Based on the study population that we studied in the LAVENDER and in the program as a whole and based on discussions that we had with the FDA so far, we do not anticipate any limitations in terms of the age of the patients considering that we have a fairly wide age range in patients, and the data is very consistent in terms of the efficacy and tolerability of drug. The reason that in the clinical trial we limited up to age 20 is really for a methodological reason. Because as we know, at that age of 21, many patients actually are losing significant support that is being provided through the educational and health system. And from that perspective, in patients that are adults, older than 21, it's a little bit more difficult and it would introduce some variability. But we do have, as Kathie shared with you, a good proportion of patients that are in that range of 17 to 20. So we are -- we don't expect any limitations in terms of the labeling from the age perspective.

Kathie, do you want to take the second one? Also, maybe you want to just offer a quick commentary on the [ data from the study we've done ].

Yes. And just to add on what Serge mentioned, as people are probably aware, we're also conducting an additional study in patients with Rett syndrome age 2 to 5. This is a small study that. [Audio Gap] agreement with the FDA. We are collecting safety pharmacokinetic data to show the exposure in these patients would be consistent with what was observed in the Phase III trial. And based on that, the data from that study will be part of the filing and support a label down to [Audio Gap] That study is going very well. We have all patients identified and don't see any issues with having that data for the NDA. With regards to the CGI-I, the CGI-I is a 7-point scale where clinicians are asked to rate the global impression of the patient's Rett syndrome disease at a certain visit compared to their baseline status. So unlike the RSBQ, it doesn't capture individual data about aspects of the Rett syndrome. It's just a global measure of the Rett syndrome functioning.

Our next question comes from the line of Ritu Baral with Cowen.

I wanted to just round back on the tolerability profile, the diarrhea management strategy and how that's going to, I guess, translate into real-world use and persistence. Maybe I'd love to hear a little bit more from Dr. Pichard about her impressions of the -- and detail about the strategy and how, I guess, on a scale of 1 to 10, how much families would be willing to tolerate, I guess, not just the diarrhea but the potential vomiting in order to achieve those clinical effects seen on, I guess, Slide 25, the subscales, as well as Slide 24, the overall RSBQ. Any detail you could give us on whether you think it would be net less work for the family to deal with that? And do you have any sort of dehydration concerns given the GI profile of the drug?

Sure. Dr. Pichard?

Thank you for the question. While I can't speak to the study participants and how they, in particular, responded in terms of speaking from the patient -- the larger patient community, to have a shift in that GI profile to be more of a diarrhea, if appropriately managed, is an impact that likely each individual family would evaluate. But we're talking about a disorder that has issues in virtually every body system, as I talked about during my presentation. And a community that says that they talk about the GI system on a regular, that's a coffee table conversation for them. And so this is a group of -- this community is significantly impacted by far worse symptoms. And so while I can't say -- speak on behalf of other individuals, the idea of having diarrhea instead of constipation does not seem to be a significant or worsening of quality of life for the families. And as Kathie has mentioned, there was a management plan that was put in place, which, again, these are families that are quite adept at taking medications and managing. You asked specifically about dehydration, which I heard Kathie say that there was not significant severe side effect of the diarrhea or dehydration or hospitalization, I believe Kathie said. And so therefore, it doesn't sound like it would be a significant issue. As I did mention, many of these individuals do have feeding tubes for multiple reasons but certainly to be able to get medications and limit the hydration during any illness. And so the management may actually be a little bit simpler in those that have the feeding tubes.

Got it. And just looking at the whisker plot of the subscores, is there a particular profile of Rett patients that you think this drug would be particularly efficacious for? And if so, do you know like a rough percentage of the overall population that would represent?

Kathie, do you want to take that question?

Sure. So I think when we look at the RSBQ subscores, the important thing is we see a response in favor of trofinetide across the board on all of the subscores. As far as patients with Rett syndrome, there is -- as Dominique mentioned, this is a complex disease. And many of behavior to motor function, even things like GI, are affected. It's a little bit complex to study because patients are affected in one area versus another. And so it's, I think, reassuring that we see that consistent response across all the areas. So no, we don't see this as being applicable to subtypes of Rett syndrome.

Our next question comes from the line of Jay Olson with Oppenheimer.

Congrats on the results. Based on trofinetide's mechanism and the clinical efficacy that you've shown in the LAVENDER study, are there any other indications where trofinetide might have potential benefits beyond Rett syndrome?

Serge, you want to take that question?

Yes. Yes, there is a number of developmental disorders where there may be some applicability of this mechanism. As I will remind you also that in the earlier stages of development, there are also traumatic brain injury studied as well based on the mechanistic involvement. So yes, the answer is yes. But at this point, we are really focused on Rett syndrome, as we have been within the last few years, and I think it's a bit premature for us to talk about that. We are really focused on now filing and getting this drug available to the patients with Rett.

Our next question comes from the line of Tazeen Ahmad with Bank of America.

To follow up on a couple of the bullet points on your slides. As far as prevalence goes, how do we translate -- how many patients do you think are actually diagnosed that you could find today for Rett? And how would that impact the need that you would potentially have to increase the size of your sales force? And then secondly, just to get a little bit more color about discontinuation. You talked about some patients did discontinue due to COVID, but what specifically were the factors about COVID that led to discontinuation?

Sure. Brendan, do you want to take the first question? And Kathie, the second?

Sure. Thanks for the question, Tazeen. So taking us back to when we first acquired the program, we see trofinetide fitting very nicely into our current community footprint, which primarily, as you know, focuses on neurologists. Obviously, with the launch of any product like this, we will make adjustments to make sure we have the right resources in place. There are pediatric neurologists that we will also be focusing on, but we still consider that a natural extension of our existing footprint. So additional but not multiplicative, if that helps.

Right. And how many patients do you think are diagnosed right now?

I'll just add one quick additional thought there. Kathie, you may want to -- so I think in terms of identifying patients, because that's always a consideration when you launch in a rare disease, we're in a very fortunate situation where there are some very well-organized patient advocacy networks in place today that have communications across the majority of patients. So I think we're in a position where unlike many rare diseases where it's just hard to find the patients, we're in a position where news of the LAVENDER results and then ultimately, if we're successful getting an approval, we'll get distributed pretty widely, pretty quickly. Kathie, I don't know if you have anything else you want to add to that.

Yes. I'll just add on the current state of diagnosis in Rett syndrome. There's been a huge change within neurodevelopmental and child neurology within, I'd say, the last 5 to 10 years, where genetic testing is becoming very rapid and very commonplace. What also helps with diagnosis of Rett syndrome is seizures that are part of the phenotype. So probably if you worked at other companies working in other seizure disorders such as [ juve ], you're aware that there are panels through companies like Invitae and GeneDx that are providing sponsored genetic testing. In addition, most academic institutions now will go to genetic testing right away as soon as patients have symptoms. So what that really means for patients, and we see this in the trial, they're getting diagnoses of Rett and genetic testing very quickly usually through their pediatrician or geneticist. They don't even have to make it to the centers of Rett -- excellence before they get that diagnosis. For older patients that may not be in that situation, I think that really the key which we'll be pursuing is to increase awareness in genetic testing in that group, similar to what has happened in the younger patients over the last 5 to 10 years.

So would you care to take a guess as to what percent of patients are diagnosed?

Not at this time. With your COVID question, I just want to clarify, during the conduct of the study, we did temporarily pause the study when the COVID -- the initial stages became quite bad. And part of the reason is that, remember, these are pediatric neurology institutions, so they also took a lot of COVID safety measures. So the few discontinuations we had due to COVID were when we shut down the study for a period of several months, not due to COVID illness in the patients itself. And we did analyze that as part of our sensitivity analysis, whether COVID or COVID discontinuation had a result, and it did not.

Okay. And can you say what percent of patients did drop out because of that shutdown?

Very small. I think it was maybe 3%, somewhere around there. I don't have the number in front of me, but it was a very small number.

Our next question comes from the line of Chris Howerton with Jefferies.

I just wanted to clarify, what is the prevalence of diarrhea in the Rett patient population? And how was potential unblinding managed in the conduct of the study?

Sure. Kathie, do you want to take that?

Yes. Thanks. Happy to. So as I think we've mentioned, Rett patients normally deal with not diarrhea but severe constipation. Dominique, maybe you can add at the end. But it's very prevalent. It's most of the patients. And this has a real impact on their lives. As Dr. Pichard mentioned, it's severe constipation in which they need to seek medical treatment and potentially hospitalization. So not diarrhea but constipation, normally. As far as the diarrhea being potentially unblinding, as I mentioned, we really carefully examined this as soon as we got our efficacy results. We use several different methods to look to see if it had potentially did have an effect on the outcome and feel very comfortable that it did not. When we look at the response of patients with and without diarrhea, both in the placebo and the trofinetide group, we don't see a strong influence of the diarrhea or the vomiting for that measure. And we consistently see an improvement in the trofinetide group compared to the placebo group, even in the patients without diarrhea. Another way we looked at this, just to give another example of the many ways we look at this, is we look for clustering of response with and without diarrhea and just see a really consistent effect irregardless of diarrhea status. So overall, based on all the analysis we did, we feel comfortable that the effects both on the RSBQ and the CGI-I are not being driven by an unblinding.

Our next question comes from the line of Paul Matteis with Stifel.

Congrats on the data. This is Alex on for Paul. I was wondering if you could talk a little bit about the dosing in LAVENDER and how that 3compared to the prior studies for trofinetide.

Sure. Kathie, do you want to take that?

Sure. So the dosing in the LAVENDER study was based on the positive results from the highest dose group in the Phase II study. That is the 200 milligram per kilogram dose group. What we did based on that data and looking at exposure responses is just optimize the base -- the dosing based on the size of the patients for the Phase III LAVENDER study.

So was it 200 mg per kg? Or was it different?

For IP reasons, we don't go into the exact dose. But it was similar to that, just optimized for the different size of the patients in the study based on the results from that Phase II data set that we have.

Right. So the dose is sort of different for each patient then?

Okay. So we -- the doses are weight-based banded dosing. So not different for every individual patients but different for different bands of weight.

Our next question comes from line of Jeff Hung with Morgan Stanley.

Congratulations on the results. I know it's based on small numbers, but it appears that there's a slightly higher rate of moderate seizures with trofinetide. Can you talk about this? And was there any expectation that trofinetide might reduce seizures in patients?

Sure. Kathie?

Yes. Thank you. So taking a step back here, remember, as Dr. Pichard mentioned, seizures are unfortunately a common occurrence for Rett syndrome patients and prevalent in over 80% of the patients. Based on really natural history data, it's also obvious that seizures, you have onset of seizures or we're seeing seizures at any age within the Rett syndrome spectrum. We did notice, as you did, that there was a slight imbalance in seizures in the trofinetide versus placebo groups of the study. As such, we analyzed any potential connection, but we did not see a clear pattern of trofinetide causing onset in new seizures and making seizures worse. For example, in some of the cases, investigators described this seizure to extenuating circumstances such as patients running out of seizure medication in the trial or growing larger and so needing to adjust the dose of their seizure medication, which is weight-based dosing. So bottom line, I think as we carefully looked at this, [ examine these seizure cases ] and do not feel that trofinetide has an impact on seizures. This is within the natural history course of Rett syndrome.

Our next question comes from the line of Jason Butler with JMP Securities.

Congrats on the results. Can you speak to the time course of improvements in the RSBQ and whether it was generally consistent across the various subscore domains? And then that initial placebo response, was it driven by any specific component or components of the RSBQ? And then when the placebo response waned again, was that those same components returning back to baseline? Or was there other components moving around as well?

Yes, sure.

Yes. Thanks. Very detailed questions. So I'll start with placebo response. So as you see, there's kind of a standard text plus placebo response with improvement in week 2, and then it trends back towards baseline. And that was -- overall, I think across the board, we didn't see. [Audio Gap] for that over time. But similarly, for the time course, no big trends where one domain or another was [Audio Gap] Very consistent.

Our next question comes from the line of Ami Fadia with Needham.

Congrats on the data. I have 2 follow-ups on some of the topics discussed before. Firstly, on the CGI scoring, we saw a difference of 3.8 versus 3.5 between the placebo and the drug arm. Can you characterize how clinically meaningful that is? And it seems that on RSBQ, we saw a meaningful change. Do you see the CGI score change is equally meaningful? And I have one more question after that.

Sure. Kathie, go ahead.

Sure. I'll take that. Thank you, and I'll take the question about the clinical meaningfulness. So first, I want to remind you that we're breaking new ground here. So there's really not an established view on what is exactly clinically meaningful in Rett syndrome patients, especially on the CGI-I. However, it's important to note that we are using as co-primary endpoint the RSBQ, which is the caregiver assessment, and the CGI-I, which is the physician assessment. So there's built-in validation that if both are statistically significant, it implies inherently a clinically meaningful and consistent benefit. You also -- we have in the slide deck the effect sizes for both the RSBQ and the CGI-I. And you can see that these would definitely suggest a clinically meaningful improvement.

Got it. Okay. And then just with regards to discontinuations and the change in the protocol for other drugs given to patients to manage their constipation, at what point in the 12 weeks did those changes -- were those changes made? And then also, could you comment on any discontinuation rate in the open-label section of the study?

Yes. Happy to. So the -- with regards to the diarrhea management protocol that we implemented, we really implemented this, this year in the trial, earlier this year. So for patients enrolled later in the trial, they had it for a longer duration of the trial compared to patients enrolled earlier. As I mentioned, where we're starting to see the benefit of this was later on in the trial and then in the open-label extension trials as well. And we continue. And I think especially now that we have the exciting efficacy results, we'll continue to optimize that and implement it. It's much easier to implement in, I'd say, open label or even the real world when these patients aren't in the narrow compliance of the Phase III protocol, where you really have to do things very exactly or they think that they're getting placebo and are very afraid about making the severe constipation that they have even worse. So we see a path forward here. Discontinuation rate. In the LILAC study, which I just want to remind everyone, is a longer study, it's a 9-month study. To date, we've seen 17% of patients discontinued due to diarrhea. And then in the LILAC-2 study, we have not had any discontinuation.

In the interest of time, we have time for 2 more questions. Our next question comes from the line of Gregory Renza with RBC Capital Markets.

Steve and team, let me add my congratulations on the data as well. Steve, just a quick one for me. Perhaps if you don't mind just reminding us of the arrangement you have with Neuren Pharmaceuticals and those economic terms that are associated with trofinetide. And perhaps within that, if you could just confirm how the potential PRV that you cite in the press release and in the call would be potentially shared across both you and Neuren with that market value breakdown?

Sure, sure. Thanks much. So the collaboration we have with Neuren provides for potential milestone payments that aggregate approximately $105 million. Of course, these are subject to achievement of development milestones in various indications, including Rett. And so about half of that number relates to Rett. It also includes up to $350 million subject to achievement of thresholds of annual net sales. So these are sales milestones of trofinetide in North America. And then as would be typical in a deal like this, Neuren is eligible to receive here escalating double-digit royalties on net sales of trofinetide in North America. And I would characterize [ it as multimillion ] stated in the -- starting at the kind of bottom rung of double digits and up to mid-teens. And again, based upon sales levels, they progress. In terms of the PVR, Neuren is eligible to receive 1/3 of the value of any Rare Pediatric Disease Priority Review Voucher. And again, those are awarded by the FDA upon approval of the New Drug Application for trofinetide.

Our final question comes from the line of Danielle Brill with Raymond James.

So in one of the prior Phase II studies, the authors showed this nice separation on the proportion of patients with CGI scores of 2 or less with treatment versus placebo. So I'm curious if you saw a similar difference in LAVENDER and what that breakdown was. And then also, did you see a correlation in magnitude of improvement observed on CGI and RSBQ?

Yes, sure. Kathie?

Yes. So first on the correlation question, we did test the correlation between CGI-I and RSBQ and did see a statistically significant correlation between the 2. With regards to responders, on the CGI-I, we also conducted an analysis post-hoc. It wasn't part of the prespecified analysis, but we looked for and tested statistical significance for responders, and that was also on a post-hoc basis statistically significant.

I would now like to turn the call back over to Mr. Davis for closing remarks.

Great. Thank you, operator. We look forward to keeping you updated on our progress as we endeavor to bring the first FDA-approved treatment for Rett syndrome patients.

Ladies and gentlemen, that concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.