Please note that this call is being recorded. I will now turn the conference over to our host, Vimal Mehta. Thank you. You may begin.
Thank you, operator. Good afternoon, everyone, and thank you for joining us today. I'd like to start by welcoming our distinguished participants. First, Dr. Leslie Citron, Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College. We are grateful to have your deep expertise to help frame today's discussion. I would also like to welcome Sumanth Kulkarni, Analyst at Canaccord Genuity. Finally, my colleague Dusan Kostic, our Senior Vice President of Clinical and Medical Affairs here at BioXcel Therapeutics, who has been instrumental in advancing this program. With today's top-line exploratory efficacy results, together with the positive primary safety data we shared previously, we believe we are taking an important step toward expanding into the home setting, bringing forward a new treatment option for the management of acute agitation.
Our mission has always been to transform patient care, and today's progress brings us closer to easing the burden patients and families face when managing episodes of acute agitation at home. With that, I will turn it over to Dr. Citron to share more about the data and, importantly, about the real-world challenges faced by patients and their families. Dr. Citron.
Thank you very much. Welcome, everybody, and thank you for the opportunity to talk about something that has been part of my career for several decades. Just to put this in context, I used to work for the New York State Office of Mental Health. I ran an inpatient unit dedicated to research and evaluation and included a research program for those who are persistently aggressive. At the same time, I also did on-call at a variety of emergency departments. I left that position in 2010 and became an outpatient psychiatrist, essentially continuing research and evaluation as a consultant, and also served as a voluntary consultant to our assertive community treatment team in the county where I resided. The goal of that assertive community treatment team is to keep people out of the hospital.
What gets them in the hospital is getting agitated, getting aggressive, and brought into the ED and ultimately admitted. This is something that I've looked at in research and in clinical care and very interested in this. I'm going to talk about agitation associated with bipolar disorders or schizophrenia in the at-home setting and describe to you the SERENITY At-Home Pivotal Phase III safety trial top-line results, also placing it into context regarding what we think about clinically as what is important. Here are the forward-looking statements. What is agitation? It's a huge burden with no clear solution here and debilitating not only for patients but also for health care providers and family members. People who are agitated with these disorders have recurring episodes.
Although the symptoms vary from person to person and range from mild to moderate to severe, we do know that they generally escalate if not addressed as soon as possible. If it's not addressed, then it can escalate, lead to an emergency department visit and ultimately hospitalization. Once someone is in an ED and/or hospitalized, the price of care or the cost of care is tremendous compared to what could have been beforehand if we only prevented that progression. Best practices tell us to use behavioral calming techniques. We've learned that in inpatient units and best practices in outpatient clinics to use verbal de-escalation techniques, but very often that is not going to be sufficient, and we need to offer some medication assistance.
Now, in an ED and inpatient unit, we've resorted to intramuscular injections when we had to, but we never really had until very recently oral alternatives that allow us to avoid injections. We never really had anything at home that would be the strength of an intramuscular injection but given orally. We want something that the patient voluntarily agrees to, and that is often not voluntarily agreeing to an injection. It's voluntarily agreeing to take something by mouth. It also has to be calming and not unduly sedating. Our goal is not to put someone to sleep but to calm someone down so they can go on with their day and recover from their agitation episode.
If this does not happen, people end up in the ED, end up in the hospital, end up in physical restraints, end up being oversedated with other means of addressing agitation, such as giving more antipsychotic or using benzodiazepines. There has got to be a better way in order to address this at home, in the clinic, not necessarily under supervision of a medical provider. Right now, we're going to talk about the use of IGALMI, dexmedetomidine, sublingual film, currently only available under health care provider supervision, unfortunately, because this is an ideal way of addressing agitation early. Our goal is to address it early. When someone becomes distressed, and that's the beginning of agitation, it occurs on a continuum, but invariably for many people, it leads to an escalation and ultimately loss of control.
We measure agitation in research by actually quantifying the degree of poor impulse control, tension, hostility, uncooperativeness, and excitement. That forms the key to a rating scale used for pivotal trials in the inpatient unit. In the outpatient unit, we know it when we see it. Someone is visibly agitated, pacing about, making maybe some verbal threats, but we don't want that to escalate to actually physical aggressiveness. At-home intervention may actually allow a patient to really avoid de-escalation, and this requires early intervention with something efficacious. Pre-agitation, someone knows that something's up, and they will ask for, "What can I do now?" Maybe they have self-soothing things that they do, maybe listen to music, maybe go into a room that's more quiet, maybe someone talking to them about other things besides what they're kind of obsessing about. Unfortunately, that can often escalate to actual frank agitation.
The idea here is to intervene here while it's still in the mild range before it becomes moderate or severe. It's been estimated that about 60 to 80 million episodes of agitation occur amongst 23 million patients that we're talking about in the at-home setting. Ultimately, in the hospital, we'll see close to 20 million episodes. It's hard to quantify precisely because it's not something that's always coded as such, but in my experience, it's the most common reason why people get admitted to the hospital or at least brought to the ED. The SERENITY program evaluated IGALMI initially through SERENITY I, SERENITY II, through the pivotal trials leading to approval under health care provider supervision by the FDA in April 2022. Based on studies that I'll show you the highlights of, very interesting studies, I have to say, in terms of the effect size.
Now, what I mean by effect size is the degree of improvement of agitation in a quantifiable term, not just a probability of being better than placebo, but actually the difference from placebo. Up to now, there have been no FDA-approved therapies for agitation associated with bipolar disorder or schizophrenia in the at-home set. That may change if IGALMI is successful in achieving approval for at-home. The SERENITY At-Home clinical trial gives us information about how this is possible. It was initiated in September 2024, and the top-line data readout was very recently, as you already know. What was used here was a dose that was not the top dose. 120 micrograms is not the top dose, but it is an efficacious dose and is a reasonable dose to take at home. The idea here in SERENITY At-Home is to make sure that it is tolerated and actually safe.
People had to understand how to use it and understand what to expect. There's a planned supplemental NDA submission for the first quarter of 2026. IGALMI, dexmedetomidine, sublingual film, is approved currently for the acute treatment of agitation associated with schizophrenia or bipolar I or bipolar II disorder in adults under health care provider supervision. The bipolar I or II disorder indication is broad, whether you're depressed, whether you're manic, whether you're in the maintenance phase of the illness. That's unique amongst all agents approved for agitation associated with that disorder. 120 micrograms is the lower dose, and we're going to take a look on how successfully it was used at home. First, I'd like to go over the two trials that led to its approval by the FDA. They're very impressive in terms of the degree of response here.
On the left-hand side of this slide, you have the usual response over time graph where the PANS excited component total score is used as the outcome measure. It is reduced over time over a period of two hours, which the study was conducted primarily. The primary outcome measure was, of course, the decrease in the PANS excited component at the end of 120 minutes. A difference was noted as early as 20 minutes in the schizophrenia sublingual dexmedetomidine versus placebo study at basically the doses of 120 and 180 micrograms per dose. That's interesting of itself, but look at the difference in size between the gray line and the blue and orange lines. That represents the effect size, and the difference from placebo is actually large. It's not just statistically significant. It's also clinically relevant. When we look at PEC response, that tells the whole story.
That's the responder rate. It's the number of patients who have at least a 40% reduction from baseline at two hours on their PEC total score. This is important because every other study for almost all of them has used this as the outcome measure in terms of measuring responder rate. The rate on placebo, the response is 40%. I'm not surprised. Patients expect some degree of effect. They're blinded. They don't know what they're getting. They're getting reassurance and support for sure, and they expect to get better, but they're on placebo. You would think that someone randomized to a real drug would have a higher response rate, and they do double. If we look in absolute terms, it's a huge difference.
Before I do that, just a brief mention here about the bipolar disorder study. I just want to mention the same degree of response, maybe even a little bit faster in the bipolar population. This was published in JAMA, the JAMA, not JAMA Psychiatry, the actual parent journal. They don't generally publish psychiatric trials unless they're innovative, they're different, and they talk about an intervention that is new. The question asked here, of course, is sublingual dexmedetomidine effective in treating acute agitation associated with bipolar disorder? The answer is yes at both doses that were tested. Here is how I like to look at data. I like to look at number needed to treat. How many patients needed to be randomized to the drug instead of placebo before you expect one additional responder? We define responder here as the 40% decrease from the PANSS excited component from baseline.
The number needed to treat of 3 is actually rounded up from a little less than 3, where for every 3 patients randomized to drug versus placebo, you expect one additional responder. This is actually a very impressive effect size. When you look at the effect sizes for inhaled loxapine, it's a 3. Ziprasidone IM, it's a 3. Olanzapine IM is a 3. We can say the oral sublingual film of dexmedetomidine has an effect size that is equal to intramuscular administration. Aripiprazole IM is no longer commercially available as a fast-acting anti-agitation agent in the U.S., but it is available in Europe. On the right-hand side of this slide, I have a notation here not showing our data for haloperidol or lorazepam that is typically used in the treatment of agitation.
These were the active controls in some of the studies, particularly the olanzapine IM and aripiprazole IM series of studies. I was able to pull together the responder rates for each of those agents, and they turned out to have number needed to treat values of 4, actually weaker than the effect size for dexmedetomidine sublingual film, as well as weaker for inhaled loxapine, ziprasidone, or olanzapine. I want to bring your attention to the vertical lines that you see on this slide. You know those lines that go up and down around the number, that's the number needed to treat estimate. You'll see that there's no vertical line for dexmedetomidine. That's because the 95% confidence interval lower bound is 3, upper bound is 3. The estimate is very precise. If you like Cohen's D as the effect size measure, that's used for continuous measures.
Some of you may be familiar with this, and this is traditionally used in research to calculate, for example, how many patients would you need in a clinical trial and helps you with sample size estimates. Nevertheless, the Cohen's D in standard deviation units is 1, 1 standard deviation unit. That is a large effect size comparable to what we would see with very few treatments in psychiatry. Let's go over the top-line results for SERENITY At-Home and dig down a little deeper with some of the details. Data was collected in about 2,500 treated episodes and about 200 patients who self-administered the film. It was well tolerated with no drug-related serious adverse events. That was the primary goal of the study, to make sure it is safe and usable. There were no syncope, no falls reported in the dexmedetomidine arm.
Adverse event profile was consistent with what we have seen in the IGALMI label and multiple clinical trials in an institutional setting, and I'll show you that. Tolerability with repeat dosing remains similar throughout the trial. This is new information because the actual limitation of use for this agent is, you know, one dose, OK, and under health care provider supervision. Repeated dosing was not actually studied in the pivotal studies done inpatient, but it was necessary to look at in at-home use because typically people will repeat dosing. One of the questions is, is it tolerable and does it continue to be efficacious? Patients experienced similar benefits throughout the study with repeated administrations. Let's go over the trial design and dig a little deeper into the data. Basically, agitation was assessed in people identified with bipolar disorder or schizophrenia residing at home.
In a certain proportion of patients, people had a co-resident family member or informant with them. In others, they did not. It was double-blind, placebo-controlled, and the primary goal is to evaluate the safety of the 120-microgram dose of dexmedetomidine in that at-home setting. After screening, patients were randomized one-to-one to receive either dexmedetomidine or placebo. There was a maximum of one dose of study medication within 12 hours, but it could be repeated. The alternative interventions were permitted. Patients could do whatever they like, essentially, meditation, even alcohol or cannabis or other medications to reflect real-world coping strategies. There were no restrictions based on that. It's a pragmatic at-home trial. Even though it's randomized, double-blind, and placebo-controlled, it is pragmatic in terms of the real-world patients that were enrolled in the study.
Primary objective was safety, and as exploratory objectives, we have a measure of efficacy by a modified clinical global impression two hours after dosing to evaluate a patient's impression. I'm going to show you their experience with dexmedetomidine in that outpatient setting. The included patients were men and women with a wide age range of 18 to 75, with the disorders in question here that we see essentially approval for, bipolar I or II disorders, schizophrenia, schizoaffective disorder, or schizophreniform disorder. It's sometimes difficult to distinguish schizophrenia from schizoaffective disorders. It's based on a history of mood episodes during the lifetime of the disorder. It's just kind of tricky, but they're included. Schizophreniform disorder, if someone has symptoms for longer than six months, they graduate to having schizophrenia. They needed to be on a stable psychotropic regimen for at least 30 days.
These were essentially stable outpatients, but with a history of agitation. There was a certain requirement that they have a history of at least three agitation episodes in the past three months. This is not unusual in day-to-day clinical practice. Discharging patients from the hospital, in my experience, I needed to keep in mind a strategy. What happens if someone gets agitated at home? Excluded were patients with serious medical illness that would prevent the safe use or not under supervision, of course, so congestive heart failure, recent myocardial infection, hepatic disease that is clinically relevant. Also excluded were patients with comorbidities that predate the schizophrenia or bipolar disorder diagnosis because it would interfere with the evaluation of efficacy within the population of interest here.
Also excluded were those with moderate to severe substance use disorder in the past six months because that would also interfere with the assessment of safety and tolerability. Also, efficacy. Agitation due primarily to acute intoxication or substance use was also an exclusionary criterion because this study was not intended to look at that kind of agitation. Top-line results in more detail. Here are the baseline demographics and disease characteristics, well-balanced across the treatment arms. Mean age here, close to 50, about 50/50 men/women, about 50/50 white versus other race or ethnicities. The primary diagnosis, about 50/50, schizophrenia, bipolar disorder. About close to a quarter of the patients had an informant. This was by design. The time since diagnosis, at least a decade. These are typical outpatients with schizophrenia or bipolar disorder. In total, I mentioned close to two and a half thousand agitation episodes in about 200 patients.
About 80% of treated patients completed the full 12-week study. There was an average of about 12 agitation episodes recorded per treated patient, reflective of the repeated nature of agitation. We are going to show data collected for the episodes, over in total, of what was collected here. A total of 246 patients were randomized. Importantly, all patients were able to successfully self-administer the film. When used in clinical practice inpatient, patients also self-administer the film under supervision. No one places this under anyone's tongue. It is not safe to put one's fingers in someone's mouth when they're agitated. Dentists don't like to do that too instantly. This is actually a very important point. Can the patient put it under their tongue successfully to gain actually the benefit of this drug? The answer is yes, they can. Well tolerated.
The primary objective of the pivotal study trial was met, and no patients discontinued due to a treatment emergent adverse event in the dexmedetomidine arm. The adverse event profile, as I mentioned earlier, was consistent with the approved IGALMI label and other clinical trials that were conducted in the institutional setting. There were no drug-related SAEs, no falls, no syncopes, no new or unexpected treatment emergent adverse events either, and no severe treatment emergent adverse events associated with the dexmedetomidine treatment. Most treatment emergent adverse events were mild. Tolerability remained consistent across multiple repeated dosing throughout the trial. I say it's comparable to the institutional setting data. Let's take a look at somnolence, single dose. The rate of somnolence with IGALMI was 22%. That with placebo was 6%. That was in the single dose SERENITY I or II pivotal trials done in institutions. What about at home?
At the first dose, the rate of somnolence was 22%. With placebo, a little higher, 17% than what we saw inpatient, not to be unexpected here in this kind of trial. In terms of all doses, when we look at that, the rate of somnolence as an AE was down to 14% versus 8% for placebo. The remainder adverse events in the SERENITY At-Home trial were low in percentages. Single digits and the difference from placebo are reasonably small. Overall, well tolerated. As I mentioned before, generally rated as mild. When we look at repeated dosing after doses 1 to 3, after doses 4 to 12, and after doses 13 and beyond, we see no signal that there are problems that are a surprise later on with somnolence, oral paresthesias, dizziness, dry mouth, nausea, or headache. It is so well tolerated. When used once, used again and again, no surprises.
In terms of the incidence, they did not increase over time. Exploratory assessments of treatment benefit. Let's take a look here. This was exploratory. This was not the main intent of the study. The study was not actually powered, but they're very interesting in terms of descriptive information. Similar reductions in symptom severity with repeat dosing over the 12-week period. The efficacy of the 120-microgram dose for single dose administration was proven and is as approved in the inpatient studies. The safety and exploratory objective was to assess continued benefit with repeat dosing, and that was found. There was a demonstrated mean reduction in the CGI-S score as measured by the patient from baseline compared to placebo at two hours across close to 2,500 treated episodes and was statistically significant. Complete resolution of agitation, that is, a zero, was significantly higher with dexmedetomidine compared to placebo across agitation episode severity.
There was a similar reduction in agitation symptoms in both the duration of the trial and number of treated episodes. No matter how you look at it, it continued to work. Let's take a look graphically at the percent of fully resolved episodes by baseline severity. A difference was noted between drug and placebo across severe, moderate, mild, and overall. In the chat, I noticed there was a question regarding, what about moderate? Why do those two bars look closer together? I think statistically, it is a dead heat. The study was not really intended to actually go to such fine granularity. I wouldn't say this is altogether something that I would worry about clinically. I am pleased that, of course, severe has the biggest drop. I am not surprised there because they had a lot of ways to go, and the expectation there is that they would get better.
Nice to know severe, moderate, or mild. Overall, the difference was still better for dexmedetomidine sublingual film in terms of fully resolved episodes versus placebo. Remember, placebo is not no treatment here. Placebo is given double-blind to someone who doesn't know they're getting placebo, who actually repeat the doses of placebo over time with the expectation that they're getting something out of it. They're getting the placebo effect. Now, the drug effect would be over and above the placebo effect. Let me summarize. We have a drug that is well tolerated with repeat dosing across the trial duration. The safety profile was consistent with what we know with the prior inpatient SERENITY trials. No discontinuations due to treatment emergent adverse events in the dexmedetomidine arm. No serious drug-related adverse events at all. No falls or syncopes. All patients, importantly, successfully self-administered the film. Benefit was maintained over time.
No attenuation of effect on agitation symptoms across multiple episodes. It continued to work with no loss of efficacy there. Results are supportive of this new indication, and hopefully, the FDA will look favorably upon this. I want to thank you for your attention here. I'm going to be more than happy to address any of your questions.
Thank you, Dr. Citron, for your very insightful presentation. We will now move to our Q&A session, which will be moderated by Sumanth Kulkarni with Dr. Leslie Citron. Sumanth.
Thanks, Vimal, and thank you, Dr. Citron, for your time and perspective. We'll jump right into Q&A. You went through all the data that the company has presented so far in the SERENITY At-Home trial, which showed consistent rates of adverse events in this trial. What is the performance in earlier trials?
You're breaking up a little bit.
Yeah, your microphone is not sounding great right now.
Let me try to expand really quickly. Is this better?
Is there some way to type it in?
I don't think there is, but let me check.
It's better now. Go ahead, sir.
OK, great. I'll start again. You went through some of the data that the company presented in the SERENITY At-Home Phase III trial. What do you think really stood out in this data?
I'm sorry. The sound has deteriorated again. You sounded good at the beginning, and then it's kind of choppy. Does everyone else notice that?
Yes, it was. It was chopping again.
Is this better? Sorry about that. This is the same mic I've always used. I'm not sure what's going on. The question is, what do you think really stood out in the data to you? If you had to pick, was there anything that you thought that could have been better in the data?
I'm sorry. I couldn't understand. Maybe what people can do is type it in the chat. That would work. There are several questions in the chat that possibly would be of interest to others. Let's go by that. Meanwhile, if you can have a headset or another microphone, that would be helpful. I answered the question, why do you think mild or severe episodes are treated better than moderate severity? I think it's a dead heat. Statistically, it's an exploratory measure and not powered to look at that. I'm happy to see that across the board, we have descriptively, at least we can say it was statistically separating. Do you think the totality of the 215 patients included in the efficacy analysis will be included in the FDA's assessment of the supplemental NDA?
Or is it possible some patients could be screened based on length of follow-up given 168 completed the full 12-week trial on something or something else? The FDA will look at completers. They will do last observation carried forward. They will do all sorts of things. You got to remember, this is a safety study. The efficacy analysis is there supportive. It reassures us that we're not wasting time here or wasting effort here, but it's a safety thing. I think they'll look primarily on that. Of course, I don't have a crystal ball, and I don't quite know exactly what they are going to decide. I would go by what is the primary intent of the study, and also maybe the company can provide additional detail regarding that. Next question, Dr. Citron. What is your opinion about inhaled loxapine as an episodic treatment alternative? Yes, not bad.
However, it requires something a bit more difficult than putting something under one's tongue. It also must be administered under health care supervision, basically because you have to assess the lung function before making sure they're cleared medically regarding that because of some concerns there. It also is very expensive. That's an issue too with inhaled loxapine. It's a good drug. When I looked at the effect sizes there, it was on par. The 95% confidence interval was a little wider. I say it's a reasonable option regarding a non-invasive way of treating agitation. Again, under health care supervision, and there's I don't think any way that would be proved outside that setting. Is there a way to compare the efficacy demonstrated in the institutional setting with the at-home data reported today? Indirectly, we can say it's all in the same direction that there is improvement.
There may be efforts underway looking at this outcome measure. I'll leave that to the company to describe further information regarding that. Again, this study was a safety and tolerability study. The efficacy is there to make sure that we're not spinning our wheels here. What is the % use in the at-home setting? Does he expect or would predict to see in mildly agitated patients, moderately agitated patients, severely agitated patients? If someone has this at home and knows that it works to treat their agitation, I would think that they would use it. In the past, people have used their antipsychotic, which is actually not always optimal because they're already on the antipsychotic. What is more oral antipsychotic going to do for them? The pharmacokinetics are not favorable in terms of leveraging the sedative part of that antipsychotic.
They may have a benzodiazepine on hand, but that's a problem. Benzos are scheduled. They can be easily diverted. It's known that taking a high dose of a benzodiazepine gets someone high. It's not something I'd like to prescribe. I do when I know the patient is going to be not using that excessively. Basically, what I do there is I give a prescription. It needs to last a very long time. If it doesn't, then I worry about them either diverting it or misusing it. I like the idea of dexmedetomidine sublingual film there because it's not going to be used in that manner. There's always the risk that it'll be used in case of emergency break glass, but that's OK if someone needs that. If the self-soothing or calming doesn't work, that would be a logical next step.
What sort of evaluation do you need to make as a physician before you would write an at-home prescription for IGALMI? I want to make sure they understand what it is and how to take it. What I would do is, for example, take a placebo IGALMI product, have them put it underneath their tongue as instructed, and make sure they can actually do it, follow those instructions. Beyond that, I want to make sure that they understand that this is for emergency use, at-home use emergencies. The idea here is to nip things in the bud if you feel you're going in the wrong direction. Patients often know when they're revving up, and they ask for something. I know this from my inpatient work and outpatient work.
Inpatient, it is not unusual for someone to come up to me and say, "I need a PRN." It is not unusual to ask, "I want the injection of ziprasidone, olanzapine." This was quite a surprise to me, but they had expected olanzapine or ziprasidone IM to work faster, and that's what they wanted. I never had anyone ask me for a shot of haloperidol, which was the standard of care in my institution before the availability of olanzapine and ziprasidone IM. No one asked for that because it was unpleasant. They do ask for things that are easier to tolerate, that they know will work relatively quickly. OK. How long is this therapeutic effect? I think the best measure of that would be to look at finer detail about repeated episodes and all of that. That is to come.
If we can look at the pivotal studies, we have some degree of information there over a course of time. I don't have this at my fingertips, but it is readily available. Let's see. We already addressed the proportion who would be compliant. I would assess the compliance ahead of time to make sure they understand that. Usually, people are more adherent to medicines that they take for something that is acute because they know something is wrong. They feel bad, and so they'll take something for that, something sort of like pain. Someone who will not tolerate the pain will take something for it. This is different than adherence to something that's on a maintenance use. Someone being maintained for their stability may feel good one day and may not be adherent that day.
By the way, this is not only the problem with bipolar disorder or schizophrenia, but also for diabetes, hypertension, and asthma. You feel good. You may not feel the need to take your regular medicine.
Dr. Cobb, let me know. Sumanth Kulkarni is connected again. Thank you.
OK, great.
Thanks. I hope this is better, Dr. Citron. Let me know if you can hear me better now.
Much better. Much better.
Great. Thank you. Sorry about that. I was asking, you went through some of the Phase III SERENITY At-Home trial data that the company presented. What do you think really stood out in that data set to you? If you had to pick, was there anything you thought could have been better?
The thing I was looking at, I'm going to make full disclosure. I was the Chair of the Data Safety Management Board or Drug Monitoring Committee for this study, and our charge was to assess the safety and tolerability primarily. I think we were encouraged at the lack of a safety or tolerability signal, and there was no worry there. At the end, when the blind was broken and for all to see, I think that struck me here. What also struck me is the persistence of effect with repeated use. This was an unknown going into the study. That really struck me. What can we do differently? If only we had other measures to look at. The company intends to look at all the data that's collected and fully understand what goes on in terms of the efficacy side of the story as best they can.
The study was not powered or intended to look at that specifically. We know the drug works based on its initial approval for inpatient use. We know that people endorsed its efficacy. We know people had resolution of their agitation superior to that seen with placebo, but those were exploratory.
Thanks. In the recent safety data set, and you alluded to this just recently, we saw the rate of somnolence go down with repeated dosing. Why do you think efficacy also did not go down? What sort of reasons would you ascribe to that?
Yeah, efficacy does not equate with sedation. When you have an adverse event or somnolence or sedation, it represents something untoward, something that someone complains about, and it's not something they want. That's how it would come to be that it would be an adverse event. Someone taking a medicine for calming purposes, ideally, they should not feel sedated. They should feel calm. Over time, they may be more used to thinking about what the medicine is doing for them, and they'll be better able to identify the calming effect than the sedating effect. The other possibility, and this is purely conjecture on my part, is that with repeated use, there wouldn't be as much sedation. I don't know that for a fact, but this is how it was reported. I want to disabuse anyone of the idea that sedation equals efficacy here. That's not the case.
In the old days, that's all we can do. Essentially, we would put people to sleep. We don't want to do that today. If I could just go off on a tangent for a moment here, in the ED, what we want is people to come down, cooperate with tests and procedures, cooperate with admission procedures if they're being admitted. We don't want them sleeping because if they're sleeping, they cannot be medically cleared, and they'll need assistance with their activities of daily living, with toileting, and so on. Our goal is calming, not sedation.
Right. With the caveat that you do not have access to the full set of interactions between the company and the FDA, given the at-home data we have seen so far, how would you handicap the chances of a supplemental NDA for BXCL501 being approved for at-home use?
I'm always asked this question no matter what I'm consulting about and who I'm consulting with. I usually hedge and say, well, 50/50. I would go higher than that with this based on the data and how it looks. How much higher? Anyone's guess. In a normal world, I would say yes, but we're maybe not in a normal world right now. I would think so.
Thank you for that. I'm going to tap into your expertise here on your past examples of any psychiatric products that were primarily used in institutional settings initially that went on to become hits when used at home and what led to that successful transition.
Very often, it's a seat of the pants. If you get upset at home, just take more of your regular medicine. Make sure you tell me about it. It may be an issue that we have to adjust their dose of their foundational antipsychotic. They may have had breakthrough episodes of agitation despite their stability, in which case you need another strategy. It's not going to work giving more of the antipsychotic. In the past, we tried our best to train patients to take benzodiazepines sparingly and use that. There's always the problem of diversion or taking more than what you want. I've heard countless times of people coming to the ED and saying, "I ran out of my Ativan," or "I dropped it down the toilet," or something like that. This is a problem because I don't want to prescribe Ativan for them to take home.
This is an issue here. If I had something that I am fairly comfortable that they wouldn't divert or abuse, then I'd be happy with that.
In your real-world experience, do you have any estimates for the number of agitation episodes your typical patient may experience in a month?
Yeah, so my clinical experience may be different from someone else's because remember, I ran an inpatient unit dedicated to patients who were persistently aggressive. When we discharged them, we fully expected them to run into problems. Also, when I consulted for the assertive community treatment team, that too was a problematic patient population. In that case, when they became agitated, they would end up in the ED and potentially hospitalized. Our goal was to keep people out of the hospital. It was fairly frequent that I would consider something for at home or something at least that they can call and say, "You know, time to take this medicine that we prescribed for you to take now." Having that available is useful. Also, if someone's living in a communal care setting, there's a caregiver, some staff available, then they can be also very helpful to give something.
Staff, importantly, want to give something that works. They will be very unhappy if they're giving something that just doesn't do the job because they feel perhaps in danger. Something that works, predicts what's comfortable with, will go a long way. In my case, lots of patients. If you have a suburban private practice and treat only patients with depression, that's a different story.
Right. Is there any type of patient who presents themselves with an agitation episode that you would not prescribe this product to, and why would that be?
Yeah, so someone who is incapable of sitting down, calming down, and taking something by mouth, despite my best efforts with verbal de-escalation, despite everything I have in terms of past relationship with the patient, the therapeutic alliance with the institution, and so on, they're still not going to sit down for you and take something. I have no choice there than to give something parenterally. I don't like to do it, but I have no choice. When I do that, I need five staff, one for each limb and one to give the injection. That's something I really try to avoid.
I'm going to flip the script a little bit. If you were to place yourself in a sales rep's shoes detailing the at-home use product to a psychiatrist, what features or data of this product would you call out to convince a doctor like yourself to prescribe the product?
I would describe the foundation as the efficacy profile done with the pivotal placebo-controlled trials. That gives me the ammunition necessary to say this is as good as intramuscular olanzapine, intramuscular ziprasidone, and the effect size at least is nominally greater than intramuscular haloperidol or intramuscular lorazepam. Yet it's not an injection. It's given by mouth, it's under the tongue, and patients can go home with it. How does that sound to you? It's not going to be like a benzo where they don't work as well, I think, and you have the risk of diversion and perhaps misuse. I think it's a compelling argument to have something like this on hand.
Thank you. In your view, what do you think the typical psychiatrist would need to see to start prescribing this product relatively quickly? Would that happen or not?
Yeah, so basically, you need an educational effort, right? You need to teach about what agitation is, how it can escalate, and how we can manage it outside the institution to prevent someone from actually coming to the institution. I think for those who work in community mental health who have a cadre of patients with schizophrenia or bipolar disorder know exactly what I'd be talking about. That would be the target practitioner that I would contemplate. Nurse Practitioners as well deal a lot with community mental health centers, also on ACT teams and so on, maybe even to a greater extent. I want to make sure that they're included in these educational efforts.
If you fast forward to an eventual label that might be published for this product, assuming at-home use is approved, would you see any potential safety issues that might make it on the label, ability to drive, those kinds of things that may limit real-world use even if the product is approved for outpatient use?
Whatever is in the label now about warnings and precautions would apply to at-home use. There are some caveats to the general use of dexmedetomidine sublingual film that would need to be followed.
All right. Now, in the real world, and you had a slide on this, at what point in the, I guess, spectrum of the agitation episode do you expect to see patients using this product?
I would expect that patients have the ability to detect when they're becoming agitated and when they think they're going to reach the point of no return. Patients generally have that degree of insight. Even amongst my most agitated patients on the inpatient unit, they kind of knew. I mean, they would ask me, "I need my PRN." They knew the consequences of their agitation going out of control. It's not pleasant. They know. By having something on hand, maybe they could actually be better managed over time. I think there's a huge opportunity here to help patients along and keep them out of the hospital.
You mentioned the price and cost initially in some of your remarks. How price-sensitive do you think reimbursers could be to this product? Do you think that prescribing physicians will think of cost or price as a variable in real-world usage?
Yeah, the only people who are stymied by cost as a practical obstacle that is actually quite substantial are inpatient providers who need to prescribe something for inpatient use where the hospital has to pay for each drug because it's in their per diem. They're often restricted by the formulary. However, preventing the escalation of agitation can save a lot of money. It could save hospital days. It could save time in the ED. There is still that use of dexmedetomidine sublingual film in the ED and the outpatient setting despite the cost because ultimately, you save money. In terms of outpatient use, I find that providers are generally insensitive to price as long as they can access the drug. If there's a prior authorization process, they'll do it. If there's a fail-first process, that gets more tricky because who wants to fail first before giving something that actually works?
In any case, it depends on the plan. Those receiving Medicaid benefits actually have better access than lots of people on commercial insurance. I'm not terribly worried about outpatient access provided that the providers are understanding the value of this intervention and willing to do the prior auth, which they have done for branded antidepressants, branded antipsychotics quite regularly.
Got it. I apologize if you already addressed this question because I think it's part of the audience questions as well. Do you think patients would be compliant with using this product at home in a real-world setting?
Yeah, so it all boils down to does it work for them? If it works for them, they'll be adherent to it. If it doesn't work for them, they won't. In reality, someone who is in the maintenance phase of a psychotic disorder or a mood disorder feels OK, and they may not be adherent with their foundational treatment. This is true, as I mentioned, for all chronic illnesses, including asthma, hypertension, diabetes, and so on. When someone is in crisis, it's different.
Right. Now, we have two patient populations here, one schizophrenia, one with bipolar disorder. Do you have any reason to believe the product may work differentially better in any of those patient populations?
Than what?
Than, let's say, it works better in agitation and schizophrenia versus agitation and bipolar disorders type I or type II.
Oh, yeah.
If there's any data for that.
Yeah, no, I'd see no difference there between the two diagnoses. It's transdiagnostic, this anti-agitation effect. The company only studied it in those broad disease states. They didn't look at it in others. I would think it would work in the others because of the nature of what this does. It's been studied in schizophrenia and bipolar disorder, hence the approval.
Got it. On background atypical antipsychotic use, do you expect this product to work better with any background molecule? Is there any reason to expect that or not?
No, I don't expect it to have any differential effect. It's very hard to tell with combinations because patients who are agitated are receiving all sorts of things, and the sample size is so small to be able to know if there's any advantage of one combination or another. I can't think of any that would make sense pharmacodynamically or pharmacokinetically. It's much the same thing as when someone asked me, which antidepressant does this second-generation antipsychotic work best with for adjunctive use in MDD? I have no answer for that either.
That's what I had, Dr. Citron. I think you probably went through several of the questions already that we have from the audience. If there's any that you'd like to pick, please go ahead because I was out for some time.
OK. Let me scroll down here and make sure I covered. Yeah, I think I basically covered most of these questions. What is the, oh yes, what is the NNT for the CGI? I can't wait to get my hands on that. I need categorical data and then calculate it. Maybe I'll do that if the data is provided to me.
Thank you, Dr. Citron. We'll turn it back to Vimal now for some closing comments.
Thank you, Dr. Citron, for sharing your perspective. Thank you as well to Sumanth for your valuable contributions. Most importantly, I want to thank everyone who joined us today for your time and engagement. We are excited about the progress we have made with the SERENITY At-Home program and remain committed to advancing this potential new treatment option for patients and families who face the daily challenges of agitation. As we move toward our planned supplemental NDA submission in the first quarter of 2026, we look forward to keeping you updated on our progress. Have a great day.